Pyrazolopyridazines and methods for treating retinal-degenerative diseases and hearing loss associated with usher syndrome
Compounds, compositions and methods for the treatment of retinal degenerative diseases, such as retinitis pigmentosa, Leber's congenital Amaurosis, Syndromic retinal degenerations, age-related macular degeneration and Usher Syndrome, and hearing loss associated with Usher Syndrome are described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein R 1 is:
R 2 is:
and a is 0, 1, or 2.
2. A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein R 3 is:
b is 0 or 1; and
c is 1 or 2.
3. A compound of Formula III:
or a pharmaceutically acceptable salt thereof,
wherein R 4 is
4. A compound of Formula XIII:
or pharmaceutically acceptable salt thereof,
wherein R 5 is:
R 6 is:
a is 0, 1, or 2.
5. A compound of Formula XIV:
or a pharmaceutically acceptable salt thereof,
wherein R 7 is:
b is 0 or 1; and
c is 1 or 2.
6. A compound of Formula XV:
or a pharmaceutically acceptable salt thereof,
wherein R 8 is:
7. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
8. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.
9. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 2 and a pharmaceutically acceptable carrier or vehicle.
10. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 3 and a pharmaceutically acceptable carrier or vehicle.
11. A composition comprising an effective amount of a compound of Formula XIII:
or pharmaceutically acceptable salt thereof,
wherein R 5 is:
R 6 is:
a is 0, 1, or 2;
and a pharmaceutically acceptable carrier or vehicle.
12. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 5 and a pharmaceutically acceptable carrier or vehicle.
13. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 6 and a pharmaceutically acceptable carrier or vehicle.
14. A composition comprising an effective amount of compound or pharmaceutically acceptable salt of the compound of claim 7 and a pharmaceutically acceptable carrier or vehicle.
15. A composition comprising an effective amount of a compound having the structure
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or vehicle.
16. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .
17. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 2 .
18. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 3 .
19. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 4 .
20. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 5 .
21. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 6 .
22. A method for treating a retinal degenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 7 .
23. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 .
24. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 2 .
25. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 3 .
26. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 4 .
27. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 5 .
28. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 6 .
29. A method for treating hearing loss associated with Usher syndrome, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 7 .
30. The compound of claim 1 , having the structure
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 2 , having the structure
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 3 , having the structure
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 4 , having the structure
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 5 , having the structure XIVa:
or pharmaceutically acceptable salt thereof.
35. The compound of claim 6 , having the structure
or a pharmaceutically acceptable salt thereof.
36. A compound of Formula XIII:
or pharmaceutically acceptable salt thereof,
wherein R 5 is:
R 6 is:
a is 0, 1, or 2.
37. The compound of claim 36 , having the structure XIIId:
or a pharmaceutically acceptable salt thereof.
38. The pharmaceutically acceptable salt of claim 36 , having the structure XIIIa: