Combination therapy for treating cancer

1. A method of treating follicular lymphoma comprising administering to a subject in need thereof a therapeutically effective dose of a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof and a therapeutically effective dose of rituximab, wherein

each of R a and R b , independently, is H or C 1 -C 6 alkyl; or R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms; wherein the C 1 -C 6 alkyl or the 4 to 7-membered heterocycloalkyl ring are optionally substituted with one or more -Q 3 -T 3 , in which Q 3 is a bond or unsubstituted or substituted C 1 -C 3 alkyl linker, and T 3 is H, halo, 4 to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, OR d , COOR d , —S(O) 2 R d , or —NR d R e , in which each of R d and R e is independently H or C 1 -C 6 alkyl, or -Q 3 T 3 is oxo;

R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , in which Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5 - or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; and

R 8 is H, methyl, or ethyl;

wherein the follicular lymphoma is resistant or refractory to at least one prior therapy; and

wherein the compound of Formula (IIa) and said rituximab are administered simultaneously or sequentially.

2. The method of claim 1 , wherein the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, is administered prior to administration of said rituximab.

3. The method of claim 1 , wherein said subject has demonstrated resistance to the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof when administered as a single agent.

4. The method of claim 1 , wherein the follicular lymphoma is resistant to at least one prior monotherapy.

5. The method of claim 1 , wherein the follicular lymphoma is resistant to at least one prior combination therapy.

6. The method of claim 1 , wherein said subject has demonstrated resistance to rituximab when administered as a single agent.

7. The method of claim 1 , wherein the compound of Formula (IIa) is Compound 44:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein R 7 is a C 1 -C 6 alkyl, a 4 to 12-membered heterocycloalkyl, or a C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl is isopropyl, the 4 to 12-membered heterocycloalkyl is selected from piperidinyl, tetrahydropyran, and tetrahydro-2H-thiopyranyl, and the C 3 -C 8 cycloalkyl is selected from cyclopentyl and cyclohexyl.

9. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective dose of a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof, a therapeutically effective dose of rituximab, and a therapeutically effective dose of lenalidomide, wherein

each of R a and R b , independently, is H or C 1 -C 6 alkyl; or R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms; wherein the C 1 -C 6 alkyl or the 4 to 7-membered heterocycloalkyl ring are optionally substituted with one or more -Q 3 -T 3 , in which Q 3 is a bond or unsubstituted or substituted C 1 -C 3 alkyl linker, and T 3 is H, halo, 4 to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, OR d , COOR d , —S(O) 2 R d , or -NR d R e , in which each of R d and R e is independently H or C 1 -C 6 alkyl, or -Q 3 T 3 is oxo;

R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , in which Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5 - or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; and

R 8 is H, methyl, or ethyl;

wherein the cancer is resistant or refractory to at least one prior therapy; and

wherein the compound of Formula (IIa) and said rituximab and said lenalidomide are administered simultaneously or sequentially.

10. The method of claim 9 , wherein the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, is administered prior to administration of said rituximab, said lenalidomide, or a combination of said rituximab and said lenalidomide.

11. The method of claim 9 , wherein the cancer is resistant to at least one prior monotherapy.

12. The method of claim 9 , wherein said subject has demonstrated resistance to the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof when administered as a single agent.

13. The method of claim 9 , wherein the cancer is resistant to at least one prior combination therapy.

14. The method of claim 9 , wherein said subject has demonstrated resistance to lenalidomide when administered as a single agent.

15. The method of claim 9 , wherein said subject has demonstrated resistance to rituximab when administered as a single agent.

16. The method of claim 9 , wherein said subject has demonstrated resistance to rituximab and to lenalidomide when administered as single agents or in combination.

17. The method of claim 9 , wherein the cancer is lymphoma, leukemia, or melanoma.

18. The method of claim 17 , wherein the cancer is follicular lymphoma.

19. The method of claim 9 , wherein the compound of Formula (IIa) is Compound 44:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 9 , wherein R 7 is a C 1 -C 6 alkyl, a 4 to 12-membered heterocycloalkyl, or a C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl is isopropyl, the 4 to 12-membered heterocycloalkyl is selected from piperidinyl, tetrahydropyran, and tetrahydro-2H-thiopyranyl, and the C 3 -C 8 cycloalkyl is selected from cyclopentyl and cyclohexyl.