Nuclear transport modulators and uses thereof

1. 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 represented by structural 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, and

wherein, the disorder is selected from lupus, multiple sclerosis, amyotrophic lateral sclerosis and rheumatoid arthritis.

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

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

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

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

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

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

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

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

11. The method 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 method 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 method eempund 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 method 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 method 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 method 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 method 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 method of claim 1 , wherein the compound is 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 method of claim 8 , wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl.