Nuclear transport modulators and uses thereof
Compounds of formula I: and pharmaceutically acceptable salts, hydrates, or solvates thereof, pharmaceutical compositions comprising the compounds of formula I, and methods of using such compounds and compositions to treat various disorders associated with CRM1 activity.
1. A compound of formula I:
or a pharmaceutically acceptable salt, hydrate, or solvate 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 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; 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 1 , wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl.
10. The compound of claim 9 , wherein the heterocyclyl is morpholinyl 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.
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. A compound 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, hydrate, or solvate thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.
20. A method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 19 .
21. The method of claim 20 , wherein the disorder is a proliferative disorder, an angiogenesis disorder, an inflammatory disorder, an autoimmune disorder, a viral infection, a wound, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a food intake disorder, allergy, stroke, traumatic brain injury, or a respiratory disorder.
22. The method of claim 20 , wherein the disorder is lupus, multiple sclerosis, a muscular dystrophy, or amyotrophic lateral sclerosis.
23. The method of claim 20 , wherein the disorder is lupus.
24. The method of claim 20 , wherein the disorder is multiple sclerosis.
25. The method of claim 20 , wherein the disorder is a muscular dystrophy.
26. The method of claim 20 , wherein the disorder is amyotrophic lateral sclerosis.