Styrenyl Derivative Compounds for Treating Ophthalmic Diseases and Disorders

Abstract

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are styrenyl derivative compounds, including but not limited to stilbene derivative compounds, and compositions comprising these compounds, that are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.

1 . A compound having a structure of Formula (A): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; or R 7  and R 8  together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 7  and R 8  together form an imino; 
 R 9  is hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 3 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 R 11  is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 each R 23  is independently selected from alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; 
 Z is a bond, Y or W—Y, wherein 
 W is —C(R 14 )(R 15 )—, —O—, —S—, —S(═O)—, —S(═O) 2 — or —N(R 12 )—, 
 Y is —C(R 16 )(R 17 )— or —C(R 16 )(R 17 )—C(R 21 )(R 22 )—; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19 , carbocyclyl or heterocyclyl; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19 , carbocyclyl or heterocyclyl; or R 16  and R 17  together form an oxo; or 
 optionally, R 14  and R 16  together form a direct bond to provide a double bond connecting W and Y; or 
 optionally, R 14  and R 16  together form a direct bond, and R 15  and R 17  together form a direct bond to provide a triple bond connecting W and Y; 
 each R 18  and R 19  is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 13 ; or R 18  and R 19 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 R 21  and R 22  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —R 12 , —NR 13 R 19 , carbocyclyl or heterocyclyl; 
 provided that when R 11  is phenyl, the compound of Formula (A) is not: 
 
     2-amino-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]acetamide; 
     (2S,3R)--amino-3-hydroxy-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)-ethenyl]phenyl]-butanamide; 
     L-glutamic acid, 1-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]ester; 
     glycine, 3-hydroxy-5-[(1E)-2-(4-hydroxyphenyl)ethenyl]phenyl ester; 
     (2S)-2-amino-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide; 
     (2S)-2-amino-3-hydroxy-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide; 
     (2S)-2-amino-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]-4-methyl-pentanamide; 
     (2S)-2-amino-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]-3-methyl-butanamide; or 
     2-amino-N-[2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenylbutanamide. 
   
   
       2 . The compound of  claim 1 , wherein each of R 1  and R 8  is hydrogen, and the compound has a structure of Formula (B): 
     
       
         
         
             
             
         
       
     
     wherein
 R 2  is H or C 1 -C 6  alkyl; 
 each of R 3 , R 4 , R 5 , and R 6  is the same or different and independently hydrogen, halo, C 1 -C 6  alkyl, or —OR 12 ; 
 R 7  is H or C 1 -C 6  alkyl; 
 R 9  is hydrogen, C 1 -C 6  alkyl, —(CH 2 ) n OH wherein n is 2-6, or —C(═O)R 13 ; 
 R 10  is hydrogen or C 1 -C 6  alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 W is C(R 4 )(R 15 )—, —O—, —S—, —S(═O)—, —S(═O) 2 — or —N(H)—; 
 Y is C(R 16 )(R 7 )—; 
 each R 12  is independently hydrogen or C 1 -C 6  alkyl; 
 each R 13  is independently a C 1 -C 6  alkyl; 
 R 14  and R 15  are each the same or different and independently selected from hydrogen, halogen, C 1 -C 6  alkyl fluoroalkyl, —OR 12 , or —NH 2 ; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, C 1 -C 6  alkyl, or —OR 12 ; or R 16  and R 17  together form an oxo; or 
 optionally, R 14  and R 16  together form a direct bond to provide a double bond connecting W and Y; or optionally, R 14  and R 16  together form a direct bond, and R 15  and R 17  together form a direct bond to provide a triple bond connecting W and Y; and 
 R 11  is selected from:
 a) alkyl; 
 b) phenyl substituted with alkyl, —OR 12 , —O(CH 2 ) m OCH 3  wherein m is 1-6, alkenyl, alkynyl, halogen, fluoroalkyl, phenyl, —SCH 3 , or aralkyl; 
 c) naphthenyl optionally substituted with alkyl, halogen, or —OR 12 ; 
 d) carbocyclyl; or 
 e) cyclohexenyl optionally substituted with alkyl, 
 provided that R 11  is not 3,4,5-tri-methoxyphenyl. 
 
 
   
   
       3 . The compound of either  claim 1  or  claim 2  wherein R 2  is hydrogen or n-butyl. 
   
   
       4 . The compound of either  claim 1  or  claim 2  wherein halogen is fluoro or chloro. 
   
   
       5 . The compound of either  claim 1  or  claim 2 , wherein each of R 3 , R 4 , R 5 , and R 6  is the same or different and independently hydrogen, halogen, methyl, or methoxy. 
   
   
       6 . The compound of either  claim 1  or  claim 2 , wherein at least two of R 3 , R 4 , R 5 , and R 6  are hydrogen. 
   
   
       7 . The compound of either  claim 1  or  claim 2 , wherein W is —C(R 14 )(R 15 )—, and wherein R 14  and R 15  are each the same or different and independently hydrogen, fluoro, methyl, ethyl, trifluoromethyl, —OH, —OCH 3 , or —NH 2 , 
   
   
       8 . The compound of  claim 7 , wherein each of R 14  and R 15  is hydrogen. 
   
   
       9 . The compound of either  claim 1  or  claim 2 , wherein Y is —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —C(H)OH—, —C(H)F—, —CF 2 —, or C(O)—. 
   
   
       10 . The compound of either  claim 1  or  claim 2 , wherein R 11  is phenyl substituted with alkyl, —OR 12 , —O(CH 2 ) n OCH 3  wherein n is 2-6, alkenyl, alkynyl, halogen, fluoroalkyl, phenyl, or —SCH 3 . 
   
   
       11 . The compound of either  claim 1  or  claim 2 , wherein R 11  is naphthenyl substituted with —OR 12 , wherein R 12  is hydrogen or C 1 -C 6  alkyl. 
   
   
       12 . The compound of either  claim 1  or  claim 2 , wherein R& 1 is cyclohexenyl optionally substituted with C 1 -C 6  alkyl. 
   
   
       13 . The compound of  claim 12 , wherein R 11  is tri-methyl-cyclohexenyl. 
   
   
       14 . The compound of either  claim 1  or  claim 2 , wherein R 11  is alkyl optionally substituted with —OR 12  wherein R 12  is hydrogen or C 1 -C 6  alkyl. 
   
   
       15 . The compound of  claim 1  wherein R 11  is aryl or carbocyclyl. 
   
   
       16 . The compound of  claim 15  wherein R 11  is aryl and the compound has a structure of Formula (C): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; 
 R 9  is hydrogen, alkyl, carbocyclyl or —C(═O)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 R 13  is alkyl, carbocyclyl or aryl; 
 W is —C(R 14 )(R 5 )—, —O—, —S—, —S(═O)—, —S(═O) 2 — or —N(R 12 )—; 
 Y is —C(R 16 )(R 17 )—; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 16  and R 17  together form an oxo; 
 optionally, R 14  and R 16  together form a direct bond to provide a double bond connecting W and Y; or 
 optionally, R 14  and R 16  together form a direct bond, and R 15  and R 17  together form a direct bond to provide a triple bond connecting W and Y; 
 each R 18  and R 19  is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 ; 
 t is 0, 1, 2, 3, 4 or 5; and 
 each R 20  is the same or different and independently selected from alkyl, —OR 12 , —SR 12 , alkenyl, alkynyl, halo, fluoroalkyl, aryl or aralkyl; or two adjacent R 20  groups, together with the two carbon atoms to which they are attached, form a fused phenyl ring. 
 
   
   
       17 . The compound of  claim 16  wherein each of R 9  and R 10  is hydrogen and the compound has a structure of Formula (D): 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 17  wherein W is —C(R 14 )(R 15 )— and the compound has a structure of Formula (E): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 R 13  is alkyl, carbocyclyl or aryl; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 14  and R 15  form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 16  and R 17  form an oxo; 
 each R 18  and R 19  are each the same or different and independently hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 ; 
 t is 0, 1, 2, 3, 4 or 5; and 
 each R 20  is the same or different and independently alkyl, —OR 12 , —SR 12 , alkenyl, alkynyl, halo, fluoroalkyl, aryl or aralkyl, or two adjacent R 20 , together with the two carbon atoms to which they are attached, form a fused phenyl ring. 
 
   
   
       19 . The compound of  claim 18  wherein:
 t is 0, 1, 2 or 3;   each R 20  is independently alkyl, —OR 12 , —SR 12 , alkynyl, phenyl, halo or fluoroalkyl; and   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, —OR 12 , halo or fluoroalkyl.   
   
   
       20 . The compound of  claim 19 , wherein R 7 , R 8 , R 14 , R 15 , R 16  and R 17  are each independently hydrogen, halogen, alkyl or —OR 12 , wherein each R 12  is independently selected from hydrogen or alkyl. 
   
   
       21 . The compound of  claim 18 , wherein:
 t is 2 or 3; two adjacent R 20 , together with the two carbon atoms to which they are attached, form a fused phenyl ring; and R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, halo or fluoroalkyl.   
   
   
       22 . The compound of  claim 21 , wherein R 7 , R 8 , R 14 , R 15 , R 16  and R 17  are each independently hydrogen, halogen, alkyl or —OR 12 . 
   
   
       23 . The compound of  claim 25  wherein W is —O—, —S—, —S(═O)—, —S(═O) 2 — or —N(R 12 )—. 
   
   
       24 . The compound of  claim 23  wherein:
 t is 0, 1, 2 or 3;   each R 20  is independently alkyl, —OR 12  or halo; and   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl or halo.   
   
   
       25 . The compound of  claim 17  wherein W and Y are connected by a double bond. 
   
   
       26 . The compound of  claim 16  wherein R 9  and R 10  together with the nitrogen to which they are attached form a N-heterocyclyl. 
   
   
       27 . The compound of  claim 26  wherein the N-heterocyclyl is morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl. 
   
   
       28 . The compound of  claim 27  wherein:
 each of R 1  and R 2  is hydrogen;   t is 0, 1, 2 or 3;   each R 20  is independently alkyl or halo; and   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl or halo.   
   
   
       29 . The compound of  claim 28  wherein W is —C(R 14 )(R 15 )—. 
   
   
       30 . The compound of  claim 16  wherein R 9  is alkyl or —C(═O)R 13 , wherein R 13  is alkyl, and R 10  is hydrogen or alkyl. 
   
   
       31 . The compound of  claim 30  wherein:
 each of R 1  and R 2  is hydrogen;   t is 0, 1, 2 or 3;   each R 20  is independently alkyl or halo; and   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl or halo.   
   
   
       32 . The compound of  claim 31  wherein W is —C(R 14 )(R 15 )—. 
   
   
       33 . The compound of  claim 1  wherein R 11  is 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl. 
   
   
       34 . The compound of  claim 33  wherein R 11  is cyclohexyl. 
   
   
       35 . The compound of  claim 1  wherein R 11  is 5-, 6-, or 7-member cycloalkenyl. 
   
   
       36 . The compound of  claim 35  wherein R 11  is cyclohexenyl and the compound has a structure of Formula (F): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 5  are each the same or different and independently hydrogen or alkyl; 
 R 9  is hydrogen, alkyl, carbocyclyl or —C(═O)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 each R 13  is independently selected from alkyl, carbocyclyl or aryl; 
 W is C(R 14 )(R 15 )—, —O—, —S—, —S(═O)—, —S(═O) 2 — or —N(R 12 )—; 
 Y is C(R 16 )(R 17 )—; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 16  and R 17  together form an oxo; 
 optionally, R 14  and R 16  together form a direct bond to provide a double bond connecting W and Y; or 
 R 14  and R 16  together form a direct bond, and R 15  and R 17  together form a direct bond to provide a triple bond connecting W and Y; 
 each R 18  and Ret is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 ; 
 p is 0, 1, 2, 3, 4, 5, 7, 8 or 9; and 
 each R 21  is the same or different and independently selected from alkyl, —OR 12 , alkenyl, alkynyl, halo, fluoroalkyl or aralkyl. 
 
   
   
       37 . The compound of  claim 36  wherein W is —C(R 14 )(R 15 )—, and the compound has a structure of Formula (G): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl, 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; 
 R 9  is hydrogen, alkyl, carbocyclyl or —C(═O)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 ), together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 each R 13  is independently alkyl carbocyclyl or aryl; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19  or carbocyclyl; or R 16  and R 17  together form an oxo; 
 optionally, R 14  and R 16  together form a direct bond to provide a double bond connecting W and Y; or R 14  and R 16  together form a direct bond, and R 15  and R 17  together form a direct bond to provide a triple bond connecting W and Y; 
 each R 18  and R 19  is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13    
 p is 0, 1, 2, 3, 4, 5, 7, 8 or 9; and 
 each R 21  is the same or different and independently alkyl, —OR 12 , alkenyl, alkynyl, halo, fluoroalkyl or aralkyl. 
 
   
   
       38 . The compound of  claim 37  wherein each of R 9  and R 10  is hydrogen. 
   
   
       39 . The compound of  claim 38  wherein:
 each of R 1  and R 2  is hydrogen;   p is 0, 1, 2 or 3;   each R 21  is independently alkyl, halo or fluoroalkyl; and   each of R 3 , R 4 , R 5  and R 6  is independently hydrogen, alkyl, halo, fluoroalkyl or —OR 12 .   
   
   
       40 . The compound of  claim 39 , wherein:
 R 7 , R 8 , R 14 , R 15 , R 16  and R 17  are each independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12  or —NR 18 R 19 , wherein each R 12  is independently hydrogen or alkyl; and each R 18  and R 19  are independently hydrogen or alkyl.   
   
   
       41 . The compound of  claim 37  wherein R 9  is alkyl and R 10  is hydrogen. 
   
   
       42 . The compound of  claim 41  wherein:
 each of R 1  and R 2  is hydrogen;   p is 0, 1, 2 or 3;   each R 21  is independently alkyl, halo or fluoroalkyl; and   each of R 3 , R 4 , R 5  and R 6  is independently hydrogen, alkyl, halo, fluoroalkyl or —OR 12 .   
   
   
       43 . The compound of  claim 42 , wherein R 7 , R 8 , R 4 , R 15 , R 16  and R 17  are each independently hydrogen, halogen, alkyl, fluoroalkyl or —OR 12 , wherein each R 12  is independently hydrogen or alkyl. 
   
   
       44 . The compound of  claim 37  wherein:
 R 7 , R 8 , R 16  and R 17  are each independently hydrogen) halogen, alkyl, fluoroalkyl or —OR 12 , wherein R 12  is hydrogen or alkyl; and   R 14  and R 15  together form oxo.   
   
   
       45 . The compound of  claim 36  wherein W is —NH— or —O—. 
   
   
       46 . The compound of  claim 45  wherein each of R 1 , R 2 , R 9  and R 10  is hydrogen. 
   
   
       47 . The compound of  claim 46 , wherein:
 p is 0, 1, 2 or 3;   each R 21  is independently alkyl or halo; and   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, halo or fluoroalkyl.   
   
   
       48 . The compound of  claim 36  wherein W and Y are connected by a double or triple bond. 
   
   
       49 . The compound of  claim 48  wherein each of R 1 , R 2 , R 9  and R 10  is hydrogen. 
   
   
       50 . The compound of  claim 49 , wherein:
 p is 0, 1, 2 or 3;   each R 21  is independently alkyl or halo;   R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, halo or fluoroalkyl; and   R 15  and R 17  are each independently hydrogen, alkyl or halogen.   
   
   
       51 . The compound of  claim 1 , wherein R 11  is alkyl. 
   
   
       52 . The compound of  claim 51  wherein W is —C(R 14 )(R 15 )—. 
   
   
       53 . The compound of  claim 52  wherein, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently hydrogen or alkyl. 
   
   
       54 . The compound of  claim 1 , wherein Z is —C(R 16 )(R 17 )— and the compound has the structure of Formula (H): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; or R 7  and R 8  together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 7  and R 8  together form an imino; 
 R 9  is hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 R 11  is alkyl alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 each R 13  is independently selected from alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 1 , —NR 18 R 19 , carbocyclyl or heterocyclyl; 
 each R 18  and R 19  is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 13 ; or R 18  and R 19 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl. 
 
   
   
       55 . The compound of  claim 54 , wherein
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are all hydrogen;   R 11  is aryl or carbocyclyl; and   R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl or —OR 12 .   
   
   
       56 . The compound of  claim 1 , wherein Z is a bond and the compound has the structure of Formula (J): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; or R 7  and R 8  together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 7  and R 8  together form an imino; 
 R 9  is hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 R 11  is alkyl alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyd and 
 each R 13  is independently selected from alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl. 
 
   
   
       57 . The compound of  claim 56 , wherein
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are hydrogen; and   R 11  is aryl or carbocyclyl.   
   
   
       58 . The compound of  claim 1 , wherein Z is —C(R 14 )(R 15 )—C(R 16 )(R 17 )—C(R 21 )(R 22 )— and the compound has the structure of Formula (K): 
     
       
         
         
             
             
         
       
     
     as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer or as a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 R 1  and R 2  are each the same or different and independently hydrogen or alkyl; 
 R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, nitro, —NH 2 , —NHR 13 , —N(R 13 ) 2 , —OR 12 , alkyl or fluoroalkyl; 
 R 7  and R 8  are each the same or different and independently hydrogen or alkyl; or R 7  and R 8  together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 7  and R 8  together form an imino; 
 R 9  is hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or —CON(H)R 13 ; 
 R 10  is hydrogen or alkyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
 R 11  is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl; 
 each R 12  is independently selected from hydrogen or alkyl; 
 each R 13  is independently selected from alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; 
 R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl fluoroalkyl, —OR 12 , —NR 18 R 19 , carbocyclyl or heterocyclyl; or R 14  and R 15  together form an oxo, an imino, an oximo, or a hydrazino; 
 R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19 , carbocyclyl or heterocyclyl; or R 16  and R 17  together form an oxo; 
 each R 18  and R 19  is independently selected from hydrogen, alkyl, carbocyclyl, or —C(═O)R 13 , —SO 2 R 13 , —CO 2 R 13 , —CONH 2 , —CON(R 13 ) 2  or CON(H)R 3 ; or R 18  and R 19 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; and 
 R 21  and R 22  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , —NR 18 R 19 , carbocyclyl or heterocyclyl. 
 
   
   
       59 . The compound of  claim 58  wherein
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are hydrogen;   R 11  is aryl or carbocyclyl;   R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl or —OR 12 ; and   R 16 , R 17 , R 21  and R 22  are each independently hydrogen or alkyl.   
   
   
       60 . A compound selected from: 
     (E)-3-(3-(2,6-dimethylstyryl)phenyl)propan-1-amine; 
     (Z)-3-(3-(2,6-dimethylstyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-methylstyryl)phenyl)propan-1-amine; 
     (Z)-3-(3-(2-methylstyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,6-dimethylstyryl)-2-methylphenyl)propan-1-amine; 
     (Z)-3-(3-(2,6-dimethylstyryl)-2-methylphenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-ethyl-6-methylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2,5-dimethylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2,4-dimethylstyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,4,6-trimethylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-ethylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-ethynylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(3,4-dimethylstyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-isopropylstyryl)phenyl)propan-1-amine; 
     (E/Z)-4-(3-(3,5-dimethylstyryl)phenyl)propan-1-amine; 
     (E/Z)-4-(3-(2-methoxystyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,6-dichlorostyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2,3-dimethylstyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,6-dimethylstyryl)-4-fluorophenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-(trifluoromethyl)styryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,6-dimethoxystyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2,6-bis(trifluoromethyl)styryl)phenyl)propan-1-amine; 
     (E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol; 
     (E)-3-amino-1-(3-(2-chloro-6-methylstyryl)phenyl)propan-1-ol; 
     (E)-2-(3-(3-aminopropyl)styryl)phenol; 
     (E)-3-(5-(2,6-dichlorostyryl)-2-methoxyphenyl)propan-1-amine; 
     (R,E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol; 
     (S,E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol; 
     (E/Z)-(3-(3-(2,6-diethoxystyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-ethoxystyryl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-isopropoxystyryl)phenyl)propan-1-amine; 
     (E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-one; 
     (E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-one; 
     (R,E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol; 
     (S,E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol; 
     (S,E)-3-(3-(2,6-dichlorostyryl)phenyl)-2-fluoropropan-1-amine; 
     (E)-3-(3-(2,6-dichlorostyryl)phenyl)-2,2-difluoropropan-1-amine; 
     (Z)-3-(3-(2-(2-methoxyethoxy)styryl)phenyl)-propan-1-amine; 
     (E)-3-(3-(3-methoxystyryl)phenyl)propan-1-amine; 
     (Z)-3-(3-(4-chlorostyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propan-1-amine; 
     (E)-3-(3-(3-chlorostyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-butoxystyryl)phenyl)propan-1-amine; 
     (E)-3-(3-(4-methoxystyryl)phenyl)propan-1-amine; 
     (Z)-3-(3-(2-Propoxystyryl)phenyl)propan-1-amine; 
     (E)-3-(5-(2-Chloro-6-(methylthio)styryl)-2-methoxyphenyl)propan-1-amine; 
     (E)-3-(3-(2-(1-methoxynaphthalen-2-yl)vinyl)phenyl)propan-1-amine; 
     (Z)-3-(3-(2-(naphthalen-1-yl)vinyl)phenyl)propan-1-amine; 
     (Z)-3-(3-(2-(3-methoxynaphthalen-2-yl)vinyl)phenyl)propan-1-amine; 
     (E/Z)-3-(3-(2-(2-methoxynaphthalen-1-yl)vinyl)phenyl)propan-1-amine; 
     (E)-2-amino-N-(3-(2,6-dimethylstyryl)phenyl)acetamide; 
     (E)-2-(3-(2,6-dimethylstyryl)phenylthio)ethanamine; 
     (E)-2-(3-(2,6-dimethylstyryl)phenylsulfinyl)ethanamine; 
     (E)-2-(3-(2,6-dimethylstyryl)phenylsulfonyl)ethanamine; 
     (E)-3-(3-(2,6-dimethylstyryl)phenyl)prop-2-en-1-amine; 
     (E)-4-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)morpholine; 
     (Z)-4-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)morpholine; 
     (E)-1-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)pyrrolidine; 
     (Z)-1-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)pyrrolidine; 
     (E)-1-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)piperidine; 
     (Z)-1-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)piperidine; 
     (E)-3-(3-(2,6-dimethylstyryl)phenyl)-N-methylpropan-1-amine; 
     (Z)-3-(3-(2,6-dimethylstyrylphenyl)-N-methylpropan-1-amine; 
     (E)-3-(3-(2,6-dimethylstyryl)phenyl)-N,N-dimethylpropan-1-amine; 
     (Z)-3-(3-(2,6-dimethylstyryl)phenyl)-N,N-dimethylpropan-1-amine; 
     (E/Z)-N-(3-(3-(2,6-dimethylstyryl)phenyl)propyl)acetamide; 
     (E)-1-(3-(3-aminopropyl)styryl)cyclohexanol; 
     (E)-1-(3-(3-aminopropyl)styryl)cyclopentanol; 
     (E)-1-(3-(3-aminopropylstyryl)cycloheptanol; 
     (E)-3-(3-(2-cyclohexylvinyl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-cyclopentylvinyl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-cycloheptylvinyl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol; 
     (S,E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol; 
     (R,E)-3-Amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol; 
     (E)-2-methyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-amine; 
     (E)-3-(2-methyl-5-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E/Z)-4-amino-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-ol; 
     (E)-3-fluoro-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-4-amino-1,1,1-trifluoro-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-ol; 
     (E)-3-amino-2,2-dimethyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol; 
     (E)-3-amino-2-methyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol; 
     (E)-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propane-1,3-diamine; 
     (E)-4,4,4-trifluoro-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-amine; 
     (E)-3-methoxy-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-4-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-amine; 
     (E)-1-amino-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-2-ol; 
     (E)-2-(3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylamino)ethanol; 
     (E)-3-methoxy-N-methyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one; 
     (E)-3-amino-2,2-dimethyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one; 
     (E)-3-amino-2-methyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one; 
     (E)-3-amino-2-fluoro-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one; 
     (E)-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenoxy)ethanamine; 
     (E)-2-amino-N-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)acetamide; 
     (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-yn-1-amine; 
     (E)-2-fluoro-3-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-en-1-amine; 
     (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-yn-1-amine; 
     (E)-2-fluoro-3-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-en-1-amine; 
     (E)-3-(3-(pent-1-enyl)phenyl)propan-1-amine; 
     (E)-3-(3-(hept-1-enyl)phenyl)propan-1-amine; 
     (E)-3-(3-(non-4-en-5-yl)phenyl)propan-1-amine; 
     (E)-4-(3-(3-aminopropyl)phenyl)-2-methylbut-3-en-2-ol; 
     (E)-4-(3-(3-aminopropyl)styryl)heptan-4-ol; 
     (E)-1-(3-(3-aminopropyl)phenyl)hex-1-en-3-ol; 
     (E)-4-(3-(2-aminoethoxy)styryl)heptan-4-ol; 
     (E)-1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-en-3-ol; 
     (E)-3-(3-(3-aminopropyl)phenyl)prop-2-en-1-ol; 
     (E)-3-(3-(3-methoxyprop-1-enyl)phenyl)propan-1-amine; 
     (E)-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)methanamine; 
     (E)-1-(3-(2,6-dimethylstyryl)phenyl)-N,N-dimethylmethanamine; 
     (E)-4-(3-(2,6-dimethylstyryl)phenyl)butan-1-amine; 
     (E)-2-(3-(2,6-dimethylstyryl)phenyl)ethanamine; 
     (E)-2-(3-(2,6-dimethylstyryl)benzylamino)ethanol; 
     (E)-3-(3-(2,6-dimethylstyrylphenyl)-3-hydroxypropanimidamide; 
     (E)-3-hydroxy-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propanimidamide; 
     (Z)-3-amino-1-(3-(2,6-dimethylstyryl)phenyl)propan-1-one oxime; 
     (Z)-3-amino-1-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one oxime; 
     (Z)-3-(3-(2,6-dimethylstyryl)phenyl)-3-hydrazonopropan-1-amine; 
     (Z)-3-hydrazono-3-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine; 
     (E)-2-(3-(2,6-dimethylstyryl)phenyl)ethanamine; 
     (E)-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)ethanamine; 
     (E)-2-amino-1-(3-(2,6-dimethylstyryl)phenyl)ethanol; 
     (E)-2-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)ethanol; 
     (E)-1-(3-(3-aminopropyl)phenyl)-3-methylhex-1-en-3-ol; and 
     (E)-1-(3-(3-aminopropyl)phenyl)-3-ethylhex-1-en-3-ol. 
   
   
       61 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1  or  claim 60 . 
   
   
       62 . A compound that inhibits 11-cis-retinol production with an IC50 of about 1 uM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room temperature. 
   
   
       63 . A non-retinoid compound that inhibits an isomerase reaction resulting in production of 11-cis retinol, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED50 value of 1 mg/kg or less when administered to a subject. 
   
   
       64 . The non-retinoid compound of  claim 63  wherein the ED50 value is measured after administering a single dose of the compound to said subject for about 2 hours or longer. 
   
   
       65 . The compound of  claim 62  or  63 , wherein the compound is a styrenyl compound. 
   
   
       66 . The compound of  claim 62 , wherein the compound is a non-retinoid compound. 
   
   
       67 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 62  or  63 . 
   
   
       68 . A method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a compound of  claim 1 ,  60 ,  61 , or  62 . 
   
   
       69 - 84 . (canceled)