Novel indole modulators of s1p receptors

Abstract

The present invention relates to novel indole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

What is claimed is: 
     
         1 . A method of treating an immunosuppressant disorder associated with the sphingosine-1-phosphate receptor modulation, wherein the immunosuppressant disorder is selected from: rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis, dry eye, inflammatory bowel diseases, atopic allergy, atopic dermatitis, contact dermatitis, multiple sclerosis, Sjogren's syndrome and organ transplant rejection, in a mammal in need thereof, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by Formula II or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         B is the same or is independently C 1-4  alkyl, methoxy, hydrogen, hydroxyl, halogen, nitrile, trifluoromethyl, amino, carboxylic acid or alkoxy; 
         D is C 1-4  alkyl, methoxy, hydrogen, hydroxyl, halogen, nitrile, trifluoromethyl, amino or carboxylic acid; 
         L is 
       
       
         
           
           
               
               
           
         
         Q is one of the following structures: 
       
       
         
           
           
               
               
           
         
         R 3  is C 1-3  alkyl; 
         R 5  is H or Methyl; 
         R 6  is H or Methyl; 
         p is 1, 2, 3 or 4; 
         R 7  is H, C 1-10  alkyl, aminoalkyl, halogen, nitrile or trifluoromethyl; 
         R 8  is H, C 1-10  alkyl, aminoalkyl, halogen, nitrile or trifluoromethyl. 
       
     
     
         2 . The method according to  claim 1 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is one of the following structures: 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 2 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is 
 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method according to  claim 2 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is 
 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to  claim 1 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is one of the following structures: 
 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 5 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is: 
 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 5 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is 
 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 5 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is 
 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method according to  claim 5 , wherein:
 L is   
       
         
           
           
               
               
           
         
       
       and
 Q is 
 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 1 , wherein the compound is selected from:
 3-[(4-{5-[1-(3,4-dimethylbenzyl)-5-methyl-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;   1-{4-[5-(1-benzyl-5-fluoro-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;   1-(4-{5-[1-(3,4-dimethylbenzyl)-5-methoxy-2-methyl-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid;   3-[(4-{5-[1-(3,4-dimethylbenzyl)-5-fluoro-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;   1-benzyl-3-{3-[4-(1H-imidazol-1-ylmethyl)phenyl]-1,2,4-oxadiazol-5-yl}-1H-indole;   3-({4-[5-(1-benzyl-5-fluoro-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propanoic acid;   1-{4-[5-(1-benzyl-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;   3-[5-(1-benzyl-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]-N-methylpyridin-2-amine;   1-(3,4-dimethylbenzyl)-5-fluoro-3-{3-[4-(1H-imidazol-1-ylmethyl)phenyl]-1,2,4-oxadiazol-5-yl}-1H-indole;   1-(4-{5-[1-(3,4-dimethylbenzyl)-5-fluoro-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid;   1-(4-{5-[1-(3,4-di methylbenzyl)-5-fluoro-2-methyl-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid;   3-({4-[5-(1-benzyl-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propanoic acid;   3-{5-[1-(3,4-dimethylbenzyl)-5-fluoro-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;   1-(4-{5-[1-(3,4-dimethylbenzyl)-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid;   3-[(4-{5-[1-(3,4-dimethylbenzyl)-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid;   1-(4-{5-[1-(3,4-dimethylbenzyl)-5-methyl-1H-indol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; and   5-({4-[5-(1-benzyl-1H-indol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}amino)pentanoic acid.