Selective sphingosine-1-phosphate receptor antagonists

Abstract

Described herein are compounds useful as antagonists of sphingosine-1-phosphate receptors. Further described herein is the use of these compounds and related pharmaceutical compositions to treat disorders associated with sphingosine-1-phosphate-3 (S1P3) receptor modulation.

1 . A compound having a structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from H, C 1 -C 4  alkyl; 
         C is a heteroaryl, having a structure 
       
       
         
           
           
               
               
           
         
         and p is 1 and Z 1 -Z 6  are each independently selected from C and N; 
         R 3  and R 8  are each independently selected from H, C 1 -C 6  straight or branched chain alkyl, alkenyl, or alkynyl, alkoxy (such as O(C 1 -C 6 )), —OH, halogen, —NR 4   2 , —CN, —CO 2 R 4 , —C(O)NR 4 R 5 , —CH 2 OH, —CF 3 , —OCHF 2 , —OCF 3 , —NO 2 , alkylamino, and alkylcarboxyl; 
         m is 0-5; 
         n is 0-5; 
         R 4  and R 5  are each independently selected from H, C 1 -C 6 , branched or unbranched alkyl, alkenyl, or alkynyl, C 3 -C 6  saturated or unsaturated cyclic hydrocarbon, aryl, heteroaryl, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, alkylamino aminocarbonyl, or amino; 
         A is CR 6   3 , CXR 6   2 , CX 2 R 6 , CX 3 , COQ 1 , SOQ 1 , SO 2 Q 1 , CSQ 1 , amide, sulfonyl, sulfone, sulfonamide, sulfoxide, ester, thiocarbonyl, phenyl, substituted phenyl, heterocyclic, heteroaromatic, cycloalkyl, and cycloalkenyl; 
         X is a halogen; 
         R 6  is H, C 1 -C 6  straight or branched chain alkyl, alkenyl, or alkynyl, haloalkyl, perfluorinated alkyl, partially fluorinated alkyl, perhalogenated alkyl, partially halogenated alkyl. 
         Q 1  is an aryl or heteroaryl variably substituted with (R 3 ) n , a phenyl, heteroaromatic or cycloalkyl, cycloalkenyl, or partially saturated or saturated heterocyclic ring a bicyclic compound, NR 4 R 5 ; 
         R 7  is H, C 1 -C 6  branched or unbranched alkyl, alkenyl, or alkynyl, haloalkyl, aryl, herteoaryl, perfluorinated alkyl and partially fluorinated alkyl, perhalogenated alkyl, partially perhalogenated alkyl, phenyl, cyano, ketyl, CF 3 , substituted aryl or heteroaryl and spirocyclic compounds; and 
         B is heteroaromatic. 
       
     
     
         2 . The compound according to  claim 1  wherein
 R 1  and R 2  are H; 
 C is heteroaryl having the structure 
 
       
         
           
           
               
               
           
         
         wherein p is 1, and Z 1 -Z 6  are each independently selected from C and N; 
         R 3  and R 8  are H, halogen; 
         m is 0-2; 
         n is 0-2; 
         A is CR 6   3 , CXR 6   2 , CX 2 R 6 , CX 3 ; 
         X is a halogen; 
         R 6  is H, C 1 -C 6  straight or branched chain alkyl, haloalkyl, perfluorinated alkyl, partially fluorinated alkyl, perhalogenated alkyl, partially halogenated alkyl; 
         R 7  is H, C 1 -C 6  branched or unbranched alkyl, haloalkyl, perfluorinated alkyl and partially fluorinated alkyl, perhalogenated alkyl, partially perhalogenated alkyl; and 
         B is heteroaromatic. 
       
     
     
         3 . The compound according to  claim 2  wherein
 C is pyridyl; 
 A is CX 2 R 6  or CR 6   3 ; 
 R 6  is H, perfluorinated alkyl, partially fluorinated alkyl, partially halogenated alkyl; 
 R 7  is H, perfluorinated alkyl and partially fluorinated alkyl, perhalogenated alkyl, partially perhalogenated alkyl. 
 
     
     
         4 . The compound according to  claim 3  wherein
 A is CX 2 R 6 ; 
 R 6  is perfluorinated alkyl, partially fluorinated alkyl, partially halogenated alkyl; 
 R 7  is H. 
 
     
     
         5 . The compound of  claim 2  having a structure 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 2  having a structure 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 ,
 wherein R 1  and R 2  are H;   C is heteroaryl having the structure   
       
         
           
           
               
               
           
         
         wherein p is 1, and Z 1 -Z 6  are each independently selected from C and N; 
         R 3  and R 8  are halogen; 
         m is 0-2; 
         n is 0-2; 
         A is CR 6   3 , CX 2 R 6 ; 
         X is a halogen; 
         R 6  is H, C 1 -C 6  straight or branched chain alkyl, haloalkyl, perfluorinated alkyl, partially fluorinated alkyl, perhalogenated alkyl, partially halogenated alkyl; 
         R 7  is H; and 
         B is heteroaromatic. 
       
     
     
         8 . The compound according to  claim 7 ,
 wherein m is 1 or 2;   n is 1 or 2;   A is CX 2 R 6 ; and   R 6  is perfluorinated alkyl or partially fluorinated alkyl.   
     
     
         9 . The compound according to  claim 7 ,
 wherein R 3  is bromine and R 8  is chlorine.   
     
     
         10 . The compound according to  claim 1  having a structure selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . An ophthalmic composition comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable adjuvant, diluents or carrier. 
     
     
         12 . An ophthalmic composition according to  claim 11  wherein the compound is selected from: