Compounds and methods for the treatment of ocular disorders

Abstract

Described herein are compositions and methods for the treatment of ocular surface disorders including meibomian gland dysfunction, blepharitis, dry eye disease and other inflammatory and/or infectious disease of the anterior surface of the eye. Said compositions and methods comprise keratolytic conjugates which demonstrate keratolytic activity, and anti-inflammatory or other desirable activities. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from ocular surface disorders.

1 - 44 . (canceled) 
     
     
         45 . A compound, having the structure of Formula (Id): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is optionally substituted heteroaryl; 
 R 2 , R 3 , and R 4  are each independently hydrogen, deuterium, cyano, halo, alkoxy, alkyl, haloalkyl, or cycloalkyl, wherein the alkoxy, alkyl, or cycloalkyl is optionally substituted; 
 R 5  is -L-R 5a ;
 L is alkylene; 
 R 5a  is optionally substituted aryl; 
 
 
         R 6  is hydrogen, deuterium, or alkyl; 
         each R 7  is independently deuterium, halo, or alkyl; 
         n is 0-6; 
         Y is O; and 
         R is alkyl or heteroalkyl substituted with at least one oxo, and further optionally substituted, 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         46 . The compound of  claim 45 , wherein R 1  is unsubstituted heteroaryl. 
     
     
         47 . The compound of  claim 46 , wherein R 1  is benzofuran. 
     
     
         48 . The compound of  claim 45 , wherein L is methylene. 
     
     
         49 . The compound of  claim 45 , wherein R 5a  is substituted aryl. 
     
     
         50 . The compound of  claim 45 , wherein R 5  is a sulfonyl substituted aryl-alkylene. 
     
     
         51 . The compound of  claim 45 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
          and 
         R 5  is 
       
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 45 , wherein R 2 , R 3 , and R 4  are each independently hydrogen, deuterium, or halo. 
     
     
         53 . The compound of  claim 45 , wherein R 6  is hydrogen. 
     
     
         54 . The compound of  claim 45 , wherein n is 1 or 2, and each R 7  is independently halo or C 1 -C 3  alkyl. 
     
     
         55 . The compound of  claim 45 , wherein n is 0. 
     
     
         56 . The compound of  claim 45 , wherein R is: 
       
         
           
           
               
               
           
         
         X is a bond or —O—; 
         R 8  is hydrogen or optionally substituted C 1 -C 4  alkyl; 
         R 9  is optionally substituted alkyl or optionally substituted heteroalkyl, 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         57 . The compound of  claim 56 , wherein R 8  is methyl. 
     
     
         58 . The compound of  claim 56 , wherein X is a bond or —O— and R 9  is optionally substituted C 1 -C 6  alkyl. 
     
     
         59 . The compound of  claim 58 , wherein X is a bond and R 9  is C 1 -C 4  alkyl, —CH(CH 3 )OH, —CH 2 OH, or 
       
         
           
           
               
               
           
         
       
     
     
         60 . The compound of  claim 59 , wherein X is a bond and R 9  is: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of  claim 56 , wherein X is —O— and R 9  is C 1 -C 4  alkyl, 
       
         
           
           
               
               
           
         
       
     
     
         62 . The compound of  claim 56 , wherein X is a bond or —O— and R 9  is unsubstituted C 1 -C 4  alkyl. 
     
     
         63 . The compound of  claim 62 , wherein the C 1 -C 4  alkyl is methyl, ethyl, propyl, isopropyl, or tert-butyl. 
     
     
         64 . A method of treating a dermal or an ophthalmic disease or disorder in an individual in need of thereof, comprising administering to the individual a composition comprising a compound of  claim 45 , or a pharmaceutically acceptable salt thereof.