Nuclear transport modulators and uses thereof
Compounds of formula I: and pharmaceutically acceptable salts, solvates, or hydrates thereof, pharmaceutical compositions comprising the compounds of formula I, and methods of using the compounds, salts, solvates, or hydrates and the compositions in the treatment of various disorders associated with CRM1 activity.
1. An orally acceptable dosage form comprising a compound of formula I:
or a pharmaceutically acceptable salt, solvate or hydrate 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, and
a pharmaceutically acceptable carrier.
2. The orally acceptable dosage form of claim 1 , wherein
R 2 is selected from O; and
R 3 is selected from —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any heteroaryl portion of R 3 is unsubstituted or 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
wherein any alkyl, alkylene or heterocyclyl portion of R 3 is unsubstituted or 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.
3. The orally acceptable dosage form of claim 1 , wherein
R 2 is O; and
R 3 is -C 1 -C 6 alkyl, wherein 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.
4. The orally acceptable dosage form 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, solvate or hydrate thereof.
5. The orally acceptable dosage form of claim 4 , wherein the compound is selected from any one of compounds 1, 2, 3, 4, 8, 11, 12 and 13 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
6. The orally acceptable dosage form of claim 4 , wherein the compound is compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
7. The orally acceptable dosage form of claim 1 , wherein the orally acceptable dosage form is a capsule, a tablet, a lozenge, a pastille, an aqueous suspension, a micro-encapsulated form, or an aqueous solution.
8. The orally acceptable dosage form of claim 1 , wherein the orally acceptable dosage form comprises an immediate release dosage form.
9. The orally acceptable dosage form of claim 1 , wherein the orally acceptable dosage form comprises a sustained release dosage form.
10. The orally acceptable dosage form of claim 1 , wherein the orally acceptable dosage form comprises a delayed release dosage form.
11. The orally acceptable dosage form of claim 1 , wherein the compound is capable of penetrating the blood-brain barrier.
12. A method of treating a subject suffering from a CRM1 mediated disorder selected from 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, an allergy, stroke, traumatic brain injury, and a respiratory disorder, comprising orally administering the orally acceptable dosage form of claim 1 to the subject.
13. The method of claim 12 , wherein the disorder is selected from lupus, multiple sclerosis, a muscular dystrophy, and amyotrophic lateral sclerosis.
14. The method of claim 13 , wherein the orally acceptable dosage form comprises
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
15. The method of claim 12 , wherein the disorder is lupus.
16. The method of claim 12 , wherein the disorder is multiple sclerosis.
17. The method of claim 12 , wherein the disorder is a CRM1 mediated cancer.
18. The method of claim 12 , wherein the disorder is a muscular dystrophy.
19. The method of claim 12 , wherein the disorder is amyotrophic lateral sclerosis.
20. The method of claim 19 , wherein the orally acceptable dosage form comprises
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
21. The method of claim 12 , wherein the disorder is a traumatic brain injury and wherein the orally acceptable dosage form comprises
or a pharmaceutically acceptable salt, solvate or hydrate thereof.