Alkene azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators

Abstract

The present invention relates to alkene azetidine 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 I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl or optionally substituted C 3-8  cycloalkenyl; 
 B is optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl or optionally substituted C 3-8  cycloalkenyl; 
 R 1  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 2  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 3  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 4  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 5  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 6  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , NR 12 R 13  or hydroxyl; 
 R 7  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 12 R 13  or hydroxyl; 
 R 8  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 12 R 13  or hydroxyl; 
 R 9  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 12 R 13  or hydroxyl; 
 R 10  is H, halogen, —OC 1-8  alkyl, optionally substituted C 1-8  alkyl, CN, C(O)R 11 , optionally substituted C 6-10  aryl, optionally substituted heterocycle, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, NR 12 R 13  or hydroxyl; 
 L 1  is O, S, S(O), NH or CH 2 ; 
 L 2  is O, S or CHR 12 , 
 R 11  is OH or optionally substituted C 1-8  alkyl; 
 a is 1, 2, 3, 4, 5 or 6; 
 R 12  is H or optionally substituted C 1-8  alkyl; and 
 R 13  is H or optionally substituted C 1-8  alkyl. 
 
     
     
         2 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein: 
       
         
           
           
               
               
           
         
       
       and 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 2  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 3  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 4  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 5  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 6  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 7  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 8  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 9  is H, halogen or optionally substituted C 1-8  alkyl; 
         R 10  is H, halogen or optionally substituted C 1-8  alkyl; 
         L 1  is O, NH, CH 2 , S or S(O); 
         L 2  is CH 2 ; and 
         a is 1, 2 or 3. 
       
     
     
         6 . The method according to  claim 5 , wherein said compound is represented by Formula I, in an E geometrical configuration. 
     
     
         7 . The method according to  claim 5 , wherein said compound is represented by Formula I, in a mixture of E and Z geometrical configuration. 
     
     
         8 . The method according to  claim 5 , wherein said compound is represented by Formula I, wherein L 1  is S(O). 
     
     
         9 . The method according to  claim 5 , wherein said compound is represented by Formula I wherein, L 1  is S. 
     
     
         10 . The method according to  claim 5 , wherein said compound is represented by Formula I wherein, L 1  is O. 
     
     
         11 . The method according to  claim 1 , wherein said compound is selected from:
 1-(4-{[(5E)-5-(3,5-difluorophenyl)-6-(3,4-dimethylphenyl)hex-5-en-1-yl]sulfanyl}benzyl) azetidine-3-carboxylic acid;   1-(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]sulfinyl}benzyl) azetidine-3-carboxylic acid;   1-(4-{[(4E)-4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl) azetidine-3-carboxylic acid;   1-(4-{[(4E)-4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl)azetidine-3-carboxylic acid;   1-(4-{[(4E)-4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pent-4-en-1-yl]oxy}benzyl) azetidine-3-carboxylic acid;   1-(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pent-4-en-1-yl]oxy}benzyl)azetidine-3-carboxylic acid; and   1-(4-{[3-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)but-3-en-1-yl]thio}benzyl)azetidine-3-carboxylic acid.   
     
     
         12 . The method of  claim 1  wherein the mammal is a human.