Nuclear transport modulators and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from hydrogen and C 1 -C 4 alkyl;

R 2 is selected from O and S; and

R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted; and

R 4 is selected from hydrogen and C 1 -C 4 alkyl.

2. The compound of claim 1 , wherein, R 1 is selected from hydrogen and methyl.

3. The compound of claim 2 , wherein R 1 is hydrogen.

4. The compound of claim 1 , wherein R 2 is O.

5. The compound of claim 1 , wherein R 4 is hydrogen.

6. The compound of claim 1 , wherein R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 3 -C 6 alkyl, —(C 0 -C 1 alkylene)-heterocyclyl, and —(C 0 -C 1 alkylene)-heteroaryl, wherein:

any alkyl or alkylene portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of oxo and —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;

any heterocyclyl portion of R 3 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl and oxo; and

any heteroaryl portion of R 3 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C 1 -C 4 alkyl.

7. The compound of claim 6 , wherein R 3 is —(C 0 -C 1 alkylene)-heterocyclyl.

8. The compound of claim 7 , wherein R 3 is —(C 1 alkylene)-heterocyclyl.

9. The compound of claim 7 wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl.

10. The compound of claim 9 , wherein the heterocyclyl is morpholinyl.

11. The compound of claim 1 , wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl or C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl.

12. The compound of claim 1 , wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted with an amino group having the formula —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl.

13. The compound of claim 1 , wherein:

any heteroaryl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl; and

any alkyl, alkylene or heterocyclyl portion of R 3 is optionally and independently substituted with one or more substituents selected from the group consisting of oxo, —OH, —SH, nitro, halogen, amino, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and C 1 -C 12 alkyl sulfanyl.

14. The compound of claim 1 , wherein R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 3 -C 6 alkyl, —(C 0 -C 1 alkylene)-heterocyclyl, and —(C 0 -C 1 alkylene)-heteroaryl, wherein:

any alkyl or alkylene portion of R 3 is optionally substituted with —N(R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;

any heterocyclyl, and heteroaryl portion of R 3 comprises at least one nitrogen atom in a ring; and

any heterocyclyl, and heteroaryl portion of R 3 is optionally substituted with C 1 -C 4 alkyl.

15. The compound of claim 14 , wherein R 3 is selected from —C(CH 3 ) 3 , —CH(NH 2 )—CH(CH 3 ) 2 , —NH-cyclopropyl, —(CH 2 ) 0-1 -pyrazinyl, piperidinyl, hydroxypiperidinyl, N-methylpiperidinyl, —CH 2 -morpholin-4-yl, and methylpyrazolyl.

16. The compound of claim 15 , wherein R 3 is selected from —C(CH 3 ) 3 , —CH(NH 2 )—CH(CH 3 ) 2 , —NH-cyclopropyl, —(CH 2 ) 0-1 -pyrazin-2-yl, piperidin-3-yl, —CH 2 -morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl.

17. The compound of claim 16 , wherein R 3 is selected from —C(CH 3 ) 3 , —NH-cyclopropyl, —CH 2 -pyrazin-2-yl, -pyrazin-2-yl, —CH 2 -morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl.

18. The compound of claim 1 , represented by any one of the structural formulas set forth below:

Cmpd

No.

Compound Structure

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 , represented by any one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

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

21. A method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R l is selected from hydrogen and C 1 -C 4 alkyl;

R 2 is selected from O and S; and

R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted; and

R 4 is selected from hydrogen and C 1 -C 4 alkyl.

22. The method according to claim 21 , wherein the disorder is selected from a proliferative disorder, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, allergies, and a respiratory disorder.

23. The method according to claim 22 , wherein the disorder is cancer.

24. The method according to claim 23 , wherein the cancer is lymphoma.

25. The method according to claim 23 wherein the compound of formula I or pharmaceutically acceptable salt thereof is administered together with a second compound useful for treating cancer.

26. The method according to claim 21 , wherein the disorder is arthritis.

27. The method according to claim 21 , wherein the disorder is psoriasis.

28. The method according to claim 21 , wherein the disorder is obesity.

29. A method of promoting wound healing in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from hydrogen and C 1 -C 4 alkyl;

R 2 is selected from O and S; and

R 3 is selected from —N(R 4 )—(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any alkyl, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionally and independently substituted; and

R 4 is selected from hydrogen and C 1 -C 4 alkyl.

30. The method of claim 29 , wherein the wound is a surface wound, a surgical wound, an internal wound, a chronic wound, an ulcer, a burn, or a result of radiation exposure.

31. The method of claim 29 , wherein the wound is selected from the group consisting of a burn wound, an incised wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a thermal burn, a chemical burn, a radiation burn, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation.

32. The compound of claim 6 , wherein R 3 is selected from —C(CH 3 ) 3 , —NH-cyclopropyl, —CH 2 -pyrazin-2-yl, -pyrazin-2-yl, —CH 2 -morpholin-4-yl, and 5-methyl-l-H-pyrazol-4-yl.

33. The compound of claim 18 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

34. The method of claim 21 , wherein the disorder is stroke.

35. The method of claim 21 , wherein the disorder is traumatic brain injury.