Nuclear transport modulators and uses thereof
View Patent ↗The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula I, and methods of using the compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.
1. A method of treating a neurodegenerative disease 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, 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, 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 neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease and Huntington's disease.
2. The method of claim 1 , wherein the compound represented by structural formula (I) is administered together with an additional therapeutic agent used to treat Parkinson's disease, Alzheimer's disease or Huntington's disease.
3. The method 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.
4. 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, solvate or hydrate thereof.
5. The method of claim 4 , wherein compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
6. The method of claim 4 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
7. A method of treating a viral infection 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, 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, 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 viral infection is caused by a viral pathogen selected from adenovirus, coxsackie virus, dengue virus, encephalitis virus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, human herpesvirus type 8, human immunodeficiency virus, influenza virus, measles virus, mumps virus, human papillomavirus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, varicella-zoster virus, west nile virus, dungee, and yellow fever virus.
8. The method of claim 7 , wherein the compound represented by structural formula (I) is administered together with an additional therapeutic agent used to treat a viral infection.
9. The method of claim 7 , 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.
10. The method of claim 7 , 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.
11. The method of claim 10 , wherein compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
12. The method of claim 10 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
13. A method of treating an inflammatory disease 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, 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, alkylene, heterocyclyl, and heteroaryl portion of R 3 is optionallly and independently substituted; and
R 4 is selected from hydrogen and C 1 -C 4 alkyl and wherein
the inflammatory disease is selected from: rheumatoid arthritis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, eczema, atopic dermatitis, contact dermatitis, urticarial, scleroderma, pemphigus, pemphigoid and allergic dermatitis.
14. The method of claim 13 , wherein the compound represented by structural formula (I) is administered together with an additional therapeutic agent used to treat an inflammatory disease.
15. The method of claim 13 , 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.
16. The method of claim 13 , 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.
17. The method of claim 16 , wherein compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
18. The method of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.