Liver X. Receptor (LXR) Modulators for the Treatment of Dermal Diseases, Disorders and Conditions

Abstract

Described herein are liver X receptor (LXR) modulators and methods of utilizing LXR modulators in the treatment of dermal diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

1 . A compound of Formula (A): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O— or —S—; 
 A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring; 
 L 1  and L 2  are each independently a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; 
 R 1  is hydrogen, halogen, —CF 3 , —OR 8 , —N(R) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , or —C(═O)OCH 2 SCH 3 ; 
 R 2  is —OR 9 , —N(R 9 ) 2 , —C(═O)R 9 , —C(═O)OR 9 , —C(═O)N(R 9 ) 2 , —NR 10 C(═O)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 3  is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; 
 R 4  is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ; 
 each R 8 , each R 9 , and each R 10  are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl; 
 R 11  is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl; 
 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 4  is aryl. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 1  is —C(═O)OR 8  and R 8  is C 1 -C 6 alkyl. 
     
     
         4 . The compound of  claim 3 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 2  is a bond. 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 2  is optionally substituted aryl. 
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 2  is optionally substituted phenyl. 
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 3  is hydrogen. 
     
     
         8 . The compound of  claim 3 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 2  is C 1 -C 6 alkyl. 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 2  is —OR 9 , —N(R 9 ) 2 , optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 3  is hydrogen. 
     
     
         11 . The compound of  claim 2 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 1  is —CF 3 . 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 2  is C 1 -C 6 alkyl. 
     
     
         13 . The compound of  claim 12 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 2  is —C(═O)OR 9  and R 9  is C 1 -C 6 alkyl. 
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 3  is hydrogen. 
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 4  is phenyl; wherein phenyl is substituted with one R 11 . 
     
     
         16 . The compound of  claim 15 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 11  is —SO 2 R 10  and R 10  is C 1 -C 6 alkyl. 
     
     
         17 .- 40 . (canceled) 
     
     
         41 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
     
     
         42 . (canceled) 
     
     
         43 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 1 ; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof. 
     
     
         44 . A method of treating a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne in a mammal, comprising administering to the mammal a compound according to  claim 1 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
     
     
         45 . A method of modulating LXR activity comprising contacting LXR, or portion thereof, with a compound according to  claim 1 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
     
     
         46 . (canceled)