COMBINATION THERAPY FOR TREATING CANCER

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

or a pharmaceutically acceptable salt thereof, and prednisone, 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.

2 . The method of claim 1 , wherein the cancer is resistant or refractory to at least one prior therapy.

3 . The method of claim 1 , wherein the compound of Formula (IIa) and prednisone are administered simultaneously or sequentially.

4 . 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.

5 . The method of claim 1 , wherein the cancer is resistant to at least one prior monotherapy or at least one prior combination therapy.

6 . The method of claim 1 , wherein the cancer is lymphoma, leukemia, or melanoma.

7 . The method of claim 6 , wherein the lymphoma is follicular lymphoma.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof, and cyclophosphamide, 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 a , or —NR d R e , in which each of R a and R e is independently H or C 1 -C 6 alkyl, or -Q 3 T 3 is oxo;

to 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.

10 . The method of claim 9 , wherein the cancer is resistant or refractory to at least one prior therapy.

11 . The method of claim 9 , wherein the compound of Formula (IIa) and said cyclophosphamide are administered simultaneously or sequentially.

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 monotherapy or at least one prior combination therapy.

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

15 . The method of claim 14 , wherein the lymphoma is follicular lymphoma.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof, and vincristine, 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.

18 . The method of claim 17 , wherein the cancer is resistant or refractory to at least one prior therapy.

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

20 . The method of claim 17 , wherein the compound of Formula (IIa) is Compound 44:

or a pharmaceutically acceptable salt thereof.