Compounds for treating ophthalmic diseases and disorders
Provided are compounds, pharmaceutical compositions thereof, and methods of treating ophthalmic diseases and disorders, such as age-related macular degeneration and Stargardt's Disease, using said compounds and compositions.
1. A compound of Formula (V) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt, or N-oxide thereof:
wherein,
Z is —C(R 9 )(R 10 )—C(R 1 )(R 2 )—;
G is selected from —N(R 42 )C(═O)—R 40 , or —N(R 42 )—C(R 42 )(R 42 )—R 40 ;
R 40 is selected from —C(R 16 )(R 17 )(R 18 );
each R 42 is independently selected from hydrogen, or alkyl;
R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 ; or R 1 and R 2 together form an oxo;
R 3 and R 4 are each hydrogen;
R 9 and R 10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or —OR 19 ; or R 9 and R 10 form an oxo; or optionally, R 9 and R 1 together form a direct bond to provide a double bond; or optionally, R 9 and R 1 together form a direct bond, and R 10 and R 2 together form a direct bond to provide a triple bond;
R 11 and R 12 are each independently selected from hydrogen, CH 3 , —C(═O)R 23 , or CO 2 R 23 ;
R 23 is alkyl;
R 6 and R 19 are each independently hydrogen or alkyl;
R 16 and R 17 , together with the carbon to which they are attached form a carbocyclyl;
R 18 is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl;
each R 33 is independently selected from halogen, hydroxyl, alkoxy, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4.
2. The compound of claim 1 wherein,
R 9 and R 10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR 19 ; or R 9 and R 10 form an oxo.
3. The compound of claim 1 wherein,
R 11 and R 12 are each independently selected from hydrogen, CH 3 , or —C(═O)R 23 .
4. The compound of claim 3 wherein,
R 9 and R 10 are each independently selected from hydrogen, halogen, —OH; or R 9 and R 10 together form an oxo.
5. The compound of claim 3 wherein,
G is selected from —N(R 42 )C(═O)—R 40 ; and R 11 and R 12 are each hydrogen.
6. The compound of claim 3 wherein,
G is selected from —N(R 42 )—C(R 42 )(R 42 )—R 40 ; and R 11 and R 12 are each hydrogen.
7. The compound of claim 4 wherein,
G is selected from —N(R 42 )C(═O)—R 40 ; and R 11 and R 12 are each hydrogen.
8. The compound of claim 4 wherein,
G is selected from —N(R 42 )—C(R 42 )(R 42 )—R 40 ; and R 11 and R 12 are each hydrogen.
9. The compound of claim 3 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
10. The compound of claim 9 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopentyl, cyclohexyl, or cycloheptyl; and
n is 0, 1, or 2.
11. The compound of claim 4 wherein, R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
12. The compound of claim 5 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
13. The compound claim 6 wherein,
R 16 and R 17 together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
14. The compound of claim 7 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
15. The compound of claim 8 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
16. The compound of claim 4 wherein,
G is selected from —N(R 42 )C(═O)—R 40 ; and R 11 is hydrogen and R 12 is C(═O)R 23 .
17. The compound of claim 4 wherein,
G is selected from —N(R 42 )—C(R 42 )(R 42 )—R 40 ; and R 11 is hydrogen and R 12 is C(═O)R 23 .
18. The compound of claim 16 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
19. The compound of claim 17 wherein,
R 16 and R 17 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and
n is 0, 1, or 2.
20. The compound of claim 1 selected from the group consisting of:
21. A compound selected from:
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (V) of claim 1 or tautomer, stereoisomer, geometric isomer, or pharmaceutically acceptable salt, or N-oxide thereof.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as provided in claim 21 or tautomer, stereoisomer, geometric isomer, or pharmaceutically acceptable salt, or N-oxide thereof.