Substituted heterocyclic compounds for disease treatment
The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted heterocyclic amine derivative compound and pharmaceutical compositions comprising these compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.
1. A compound of Formula (A) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt, or N-oxide thereof:
wherein,
Ring A is a 1,3-disubstituted pyridine selected from the group consisting of:
each R 14 is independently selected from hydrogen, halogen, OR 9 , alkyl, or fluoroalkyl;
G is —X—Y;
X is selected from —C(R 9 ) 2 —C(R 9 ) 2 —, —C(R 9 )═C(R 9 )—, —C≡C—, and —C(R 9 ) 2 —O—;
Y is selected from:
C 3 -C 15 alkyl optionally substituted with a substituent chosen from halo, hydroxy, alkoxy, or fluoroalkyl;
C 3 -C 10 carbocyclyl optionally substituted with a substituent chosen from halo, hydroxy, alkyl, alkoxy, or fluoroalkyl;
carbocyclyalkyl optionally substituted with a substituent chosen from halo, hydroxy, alkyl, alkoxy, or fluoroalkyl;
aryl optionally substituted with a substituent chosen from halo, hydroxy, alkyl, alkoxy, or fluoroalkyl; or
aralkyl optionally substituted with a substituent chosen from halo, hydroxy, alkyl, alkoxy, or fluoroalkyl;
R 1 and R 2 are each independently selected from hydrogen, or —OR 9 ; or R 1 and R 2 form an oxo; or optionally, R 1 and R 3 together form a direct bond to provide a double bond; or optionally, R 1 and R 3 together form a direct bond, and R 2 and R 4 together form a direct bond to provide a triple bond;
R 3 and R 4 are hydrogen;
R 5 and R 6 are hydrogen;
R 7 and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl, or —C(═O)R 13 ;
R 9 is hydrogen;
R 13 is C 1 -C 3 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ring A is selected from:
3. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ring A is selected from:
4. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is a C 3 -C 15 alkyl optionally substituted with a substituent chosen from halo, hydroxy, alkoxy, or fluoroalkyl, or a C 3 -C 10 carbocyclyl optionally substituted with a substituent chosen from halo, hydroxy, alkyl, alkoxy, or fluoroalkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is an optionally substituted C 3 -C 15 alkyl having the formula: —C(R 16 )(R 17 )(R 18 ); wherein R 16 and R 17 are each independently selected from hydrogen, C 1 -C 5 alkyl, halo or fluoroalkyl; and
R 18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo, or fluoroalkyl.
6. The compound of claim 4 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is an optionally substituted C 3 -C 10 carbocyclyl having the formula: —C(R 16 )(R 17 )(R 18 ); wherein R 16 and R 17 are each independently C 1 -C 5 alkyl and R 16 and R 17 together with the carbon to which they are attached form a carbocyclyl; and R 18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo, or fluoroalkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 16 and R 17 , together with the carbon to which they are attached, form a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R 18 is hydrogen or hydroxy.
8. The compound of claim 7 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 16 and R 17 , together with the carbon to which they are attached, form a cyclopentyl, cyclohexyl, or cycloheptyl, and R 18 is hydrogen or hydroxy.
9. The compound of claim 5 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 16 and R 17 is independently selected from C 1 -C 5 alkyl; and R 18 is hydrogen, hydroxy or alkoxy.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is selected from —C(R 9 ) 2 —C(R 9 ) 2 —, or —C(R 9 ) 2 —O—.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 1 and R 2 are both hydrogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 1 is hydrogen and R 2 is —OH.
13. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 1 and R 2 together form an oxo.
14. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 7 and R 8 are both hydrogen.
15. The compound of claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 7 is hydrogen and R 8 is —C(═O)R 13 .
16. The compound of claim 15 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein R 13 is methyl.
17. A compound, or tautomer, stereoisomer, geometric isomer, or pharmaceutically acceptable salt, or N-oxide thereof, selected from the group consisting of:
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (A) as described in claim 1 , or tautomer, stereoisomer, geometric isomer, or pharmaceutically acceptable salt, or N-oxide thereof.