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 II:
or a pharmaceutically acceptable salt thereof,
wherein Hal is —Cl, —F, —I, or —Br;
x is an integer ranging from 0 to 5;
each R 1 is independently —Cl, —F, —I, —Br, —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, —CN, —CF 3 , —C(O)NH(CH 3 ), or —C≡CCH 2 OH;
y is an integer ranging from 0 to 5;
each R 2 is independently —Cl, —F, —Br, —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, —CN, —CF 3 , —C(O)NH(CH 3 ), or —C≡CCH 2 OH;
R 3 is —H, —C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-OH, —(C 1 -C 6 alkylene)-phenyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —C 2 -C 6 alkenyl, —(C 1 -C 6 alkylene)-C(O)R 4 , —(C 1 -C 6 alkylene)-R 5 ,
R 4 is —OH, —O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH((C 1 -C 6 alkylene)-OH), —NH((C 1 -C 6 alkylene)N(C 1 -C 6 alkyl) 2 ), N(C 1 -C 6 alkyl)((C 1 -C 6 alkylene)-CN), —N(C 1 -C 6 alkyl)((C 1 -C 6 alkylene)N(C 1 -C 6 alkyl) 2 ), —NH(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl),
a is an integer ranging from 0 to 10;
b is an integer ranging from 0 to 8;
c is an integer ranging from 0 to 6; and
R 5 is
2. A compound of Formula III:
or a pharmaceutically acceptable salt thereof,
wherein Hal is —Cl, —F, —I, or —Br;
x is an integer ranging from 0 to 5;
each R 1 is independently —Cl, —F, —I, —Br, —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, —CN, —CF 3 , —C(O)NH(CH 3 ), or —C≡CCH 2 OH;
R 3 is —H, —C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-OH, —(C 1 -C 6 alkylene)-phenyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —C 2 -C 6 alkenyl, —(C 1 -C 6 alkylene)-C(O)R 4 ,—(C 1 -C 6 alkylene)-R 5 ,
R 4 is —OH, —O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH((C 1 -C 6 alkylene)-OH), —NH((C 1 -C 6 alkylene)N(C 1 -C 6 alkyl) 2 ), N(C 1 -C 6 alkyl)((C 1 -C 6 alkylene)-CN), —N(C 1 -C 6 alkyl)((C 1 -C 6 alkylene)N(C 1 -C 6 alkyl) 2 ), —NH(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl),
a is an integer ranging from 0 to 10;
b is an integer ranging from 0 to 8;
c is an integer ranging from 0 to 6;
R 5 is
and
each R 6 and R 7 is independently —H or —I, wherein at least one of R 6 and R 7 is —I,
and wherein when R 3 is —C 1 -C 3 alkyl, R 7 is —H.
3. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
4. A compound having the structure:
or a salt thereof.
5. The compound or salt of claim 4 , wherein the compound or salt is bound to a protein.
6. A compound of Formula IV:
or a salt thereof,
wherein R 8 is —C 1 -C 3 alkyl.
7. The compound of claim 6 , having the structure:
or a salt thereof.
8. The compound of claim 2 , having the structure:
or a pharmaceutically acceptable salt thereof.
9. A composition comprising a compound or pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.
10. A composition comprising a compound or pharmaceutically acceptable salt of the compound of claim 2 and a pharmaceutically acceptable carrier or vehicle.
11. 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 .
12. 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 .
13. 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 .
14. 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 .