Indazole compounds and their uses

1. A compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is a bond;

R 1a is selected from methyl, C(O)cyclopropyl, and C(O)-phenyl;

wherein the C(O)-phenyl can be substituted with -piperazinyl-CH 3 ;

R 1b is H;

R A is selected from H, methyl, and QR 5 , provided that one instance of R A is QR 5 ;

wherein QR 5 is selected from —C(O)—C 1-6 alkyloxy, —C(O)N(H)—C 1-6 alkyl, —C(O)N(H)-phenyl, —NHC(O)—C 3-6 cycloalkyl, —NHC(O)-phenyl, and —N(H)C(O)N(H)-phenyl; wherein the phenyl ring is optionally substituted with one to two substituents wherein the substituents are selected from one each of CF 3 , —CH 2 -piperazinyl-C 1-6 alkyl, and -imidazolyl-C 1-6 alkyl; and

n is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

QR 5 is selected from:

3. A compound of formula (II), or a pharmaceutically acceptable salt thereof,

wherein:

X is a bond;

R 1a is selected from H, C 1-6 alkyl, C(O)—C 3-6 cycloalkyl, C(O)-phenyl and C(O)-phenyl-piperazinyl-C 1-6 alkyl;

R 1b is H;

R 2 is selected from H and C 1-6 alkyl;

R 3 is H;

R 4 is QR 5 ,

wherein Q is selected from —C(O)N(H)—, —NHC(O)— and —N(H)C(O)N(H)—;

R 5 is:

wherein R 6 is H;

R 7 is selected from H and C 1-6 trihaloalkyl;

R 8 is selected from H and —C 1-6 alkyl-heterocyclyl-C 1-6 alkyl; and

R 9 is selected from H and -heteroaryl-C 1-6 alkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:

R 1a is H, CH 3 , C(O)-cyclopropyl, C(O)Ph or C(O)Ph-piperazinyl-CH 3 ;

R 2 is H or CH 3 ;

R 7 is selected from H and CF 3 ;

R 8 is selected from H, —CH 2 -piperazinyl-CH 3 and —CH 2 -piperazinyl-CH 2 CH 3 ; and

R 9 is selected from H and -imidazolyl-CH 3 .

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:

R 1a is selected from H and C(O)-cyclopropyl;

R 7 is CF 3 ;

R 8 is selected from H and 1-ethyl-4-methylpiperazinyl;

R 9 is selected from H and 4-methyl-1H-imidazolyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

R 1a is C(O)-cyclopropyl.

7. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein:

R 1a is selected from H, C 1-6 alkyl, C(O)—C 3-6 cycloalkyl, and C(O)-phenyl; and

R 4 is C(O)N(H)—R 5 ;

wherein R 5 is:

wherein R 8 is 1-ethyl-4-methylpiperazinyl and R 9 is H; or

R 4 is C(O)N(H)—R 5 ;

wherein R 5 is:

wherein R 8 is H and R 9 is 4-methyl-1H-imidazolyl; or

R 4 is N(H)C(O)—R 5 ;

wherein R 5 is:

wherein R 8 is 1-ethyl-4-methylpiperazinyl and R 9 is H.

8. A compound selected from

or a pharmaceutically acceptable salt thereof.

9. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the cancer is selected from the group consisting of adenocarcinoma, multiple myeloma, chronic myelogenous leukemia, pancreatic cancer, non-small cell lung cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, malignant melanoma, non-melanoma skin cancers, gastrointestinal stromal tumors, hematologic tumors, hematologic malignancies, childhood leukemia, childhood lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic origin, lymphomas of cutaneous origin, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.

11. The method of claim 9 , wherein the cancer is resistant to treatment with imatinib.

12. The method of claim 9 further comprising administering a pharmaceutically effective amount of an additional anti-cancer agent.

13. The method of claim 12 wherein the additional anti-cancer agent is imatinib or nilotinib.

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is NR;

wherein R is selected from H and C 1-6 alkyl;

R 1a is C(O)cyclopropyl;

R 1b is H;

R A is selected from H, methyl, methoxy, and QR 5 , provided that one instance of R A is QR 5 ;

wherein QR 5 is C(O)N(H)-phenyl, wherein the phenyl ring is substituted with one or two substituents—selected from one each of CF 3 and —CH 2 -piperazinyl-C 1-6 alkyl; and

n is 1 or 2.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein:

R is H; and

QR 5 is selected from:

17. A compound of formula (II), or a pharmaceutically acceptable salt thereof,

wherein:

X is NR;

wherein R is selected from H and C 1-6 alkyl;

R 1a is C(O)—C 3-6 cycloalkyl;

R 1b is H;

R 2 is selected from H and C 1-6 alkyl;

R 3 is H;

R 4 is QR 5 , wherein Q is —C(O)N(H)—;

R 5 is:

wherein R 6 is H;

R 7 is selected from H and C 1-6 trihaloalkyl;

R 8 is selected from H and —C 1-6 alkyl-heterocyclyl-C 1-6 alkyl; and

R 9 is H.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein:

R is H;

R 1a is C(O)-cyclopropyl;

R 2 is H or CH 3 ;

R 7 is selected from H and CF 3 ; and

R 8 is selected from H, —CH 2 -piperazinyl-CH 3 and —CH 2 -piperazinyl-CH 2 CH 3 .

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CF 3 .

20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 8 is —CH 2 -piperazinyl-CH 3 or —CH 2 -piperazinyl-CH 2 CH 3 .

21. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CF 3 .

22. The compound of claim 20 , wherein the compound of Formula I is selected from

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 15 or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the cancer is selected from the group consisting of adenocarcinoma, multiple myeloma, chronic myelogenous leukemia, pancreatic cancer, non-small cell lung cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, malignant melanoma, non-melanoma skin cancers, gastrointestinal stromal tumors, hematologic tumors, hematologic malignancies, childhood leukemia, childhood lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic origin, lymphomas of cutaneous origin, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.

26. The method of claim 24 , wherein the cancer is resistant to treatment with imatinib.

27. The method of claim 24 further comprising administering a pharmaceutically effective amount of an additional anti-cancer agent.

28. The method of claim 27 wherein the additional anti-cancer agent is imatinib or nilotinib.