S1P Receptor Modulating Compounds and Use Thereof

Abstract

The present invention relates to compounds that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. In certain embodiments, the compounds of the invention relate to aryl oxoimidazolidinyls.

1 . A method of treating an S1P-1 receptor mediated condition, wherein the condition is transplant rejection, ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer, prostate cancer, acute lung diseases, autoimmune disease, an inflammatory disease, rheumatoid arthritis, lupus, insulin dependent diabetes, non-insulin dependent diabetes, multiple sclerosis, psoriasis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, acute and chronic lymphocytic leukemias, lymphomas, adult respiratory distress syndrome, acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury such as transcorneal freezing or cutaneous burns, cardiovascular diseases such as ischemia, vasoconstriction in cerebral arteries, autoimmune and related immune disorders including systemic lupus erythematosus, uveitis, myasthenia gravis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, or Wegner's granuloma, in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof; 
       
       wherein,
 p and q are independently 0, 1, 2, 3 or 4; 
 Z is O, NR 2 , S, S(O), S(O) 2 , S(O) 2 NR 2 , (CR 3 R 4 ) n , C═O, C═S, or C═N—R 2 ; 
 n is 1, 2, 3 or 4; 
 R 1  is aryl or heteroaryl; 
 R 2  is hydrogen, hydroxyl, S(O) 2 , C═O, C═S, C═NH, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halo-substituted C 1-6  alkyl, halo-substituted C 1-5  alkoxy, aryl, or heteroaryl; 
 R 3  and R 4  are independently hydrogen, halo, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halo-substituted C 1-6  alkyl, halo-substituted C 1-5  alkoxy, aryl, or heteroaryl; or R 3  and R 4 , taken together, may form C═O; 
 X is WC(O)OR 5a , WP(O)R 5b R 5c , WS(O) 2 OH, WS(O) 2 NH 2 ,WCONHSO 3 H or 1H-tetrazol-5-yl; 
 W is a direct bond, O, or C 1-4  alkylene optionally substituted with one or more of halo, hydroxyl, cyano, amino, alkylamino, aryl amino, heteroaryl amino group, C 1-4  alkoxy, or CO 2 H; 
 R 5a  is hydrogen or C 1-4  alkyl; 
 R 5b  and R 5c  are independently hydrogen, hydroxyl, C 1-4  alkyl, or halo substituted C 1-4  alkyl; 
 
       Y is 
       
         
           
           
               
               
           
         
         Q is a direct bond, C═O, C═S, SO 2 , C(O)NR 9 , or)(CR 9 R 10 ) m ; 
         m is 0 or 1; 
         R 6  and R 7  are independently hydrogen, halo, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halo-substituted C 1-6  alkyl or halo-substituted C 1-5  alkoxy; or R 6  and R 7  may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring, or R 6  is an alkylene group with the omega end of said alkylene group attached to ring A; 
         R 8  is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halo-substituted C 1-6  alkyl, or halo-substituted C 1-5  alkoxy; 
         R 9  and R 10  are independently hydrogen, halo, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halo-substituted C 1-6  alkyl, halo-substituted C 1-5  alkoxy, or —CO 2 R 5a ; 
         A is aryl or heteroaryl, either of which may optionally be substituted with 1, 2, or 3 substituents selected from the group consisting of halo, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1 -C 5  alkoxy, halo-substituted C 1-6  alkyl, and halo-substituted C 1 -C 5  alkoxy; 
         B has the formula: 
       
       
         
           
           
               
               
           
         
         in which, the asterisks indicate the point of attachment in formula I; 
         r is 1; 
         U is CH 2 , C(H)CH 3 , C(CH 3 ) 2 , C(H)(CF 3 ) or C(CF 3 ) 2 ; and 
         V is C(═O) or C(═S). 
       
     
     
         2 . The method according to  claim 1  wherein Z is (CR 3 R 4 ) n . 
     
     
         3 . The method according to  claim 1 , wherein X is WC(O)OR 5a . 
     
     
         4 . The method according to  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
         Q is (CR 9 R 10 ) m , and 
         R 6  and R 7  are joined together with the atoms to which they are attached to form a 4- to 7-membered ring. 
       
     
     
         5 . The method according to  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
       Q is (CR 9 R 10 ) m , and R 6  and R 7  are joined together with the atoms to which they are attached to form a 4- to 7-membered ring. 
     
     
         6 . The method according to  claim 1 , wherein V is C(═O) and Z is (CR 3 R 4 ) n . 
     
     
         7 . The method according to  claim 1  wherein the condition is ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer or prostate cancer. 
     
     
         8 . A method of treating an S1P-1 receptor mediated condition, wherein the condition is transplant rejection, ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer, prostate cancer, acute lung diseases, autoimmune disease, an inflammatory disease, rheumatoid arthritis, lupus, insulin dependent diabetes, non-insulin dependent diabetes, multiple sclerosis, psoriasis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, acute and chronic lymphocytic leukemias, lymphomas, adult respiratory distress syndrome, acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury such as transcorneal freezing or cutaneous burns, cardiovascular diseases such as ischemia, vasoconstriction in cerebral arteries, autoimmune and related immune disorders including systemic lupus erythematosus, uveitis, myasthenia gravis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, or Wegner's granuloma, in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of formula (II), wherein the compound of formula (II) is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
       
       wherein,
 A 1  is H, C 1-8  alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —OR 2 , —SR 2 , —S(O)R 2 , —S(O) 2 R 2 ; —C(O)R 2 , —CO 2 R 2 , or —C(R 3 ) 2 R 2 ; 
 A 2  is 
 
       
         
           
           
               
               
           
         
         A 3  is 
       
       
         
           
           
               
               
           
         
       
       each of which may optionally be substituted with a halogen, trifluoromethyl, or alkoxy;
 p and q represent independently 0, 1, 2, 3 or 4; 
 Z is (CR 3 R 4 ) n , or C(O); 
 n is 1, 2, 3 or 4; 
 R 1a  is H or C 1-6  alkyl; 
 R 2  is alkyl, aryl, heteroaryl, or aralkyl; 
 R 3  and R 4  represent independently for each occurrence hydrogen, halo, hydroxyl, C 1-6  alkyl, C 1-5  alkoxy, or aryl; 
 X is WC(O)OR 5  or WS(O) 2 NH 2 ; 
 R 5  is hydrogen or C 1-4  alkyl; 
 W is a direct bond, oxygen or C 1-4  alkylene; 
 Y is 
 
       
         
           
           
               
               
           
         
         Q is a direct bond, C═O or (CR 9 R 10 ) m ; 
         m is 1; 
         R 6  and R 7  each represent independently hydrogen, halo, hydroxyl, C 1-6  alkyl, or C 1-5  alkoxy; or R 6  and R 7  may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring; 
         R 8  is hydrogen, halogen, hydroxyl, amino, C 1-6  alkyl, or C 1-5  alkoxy; and 
         R 9  and R 10  each independently represent hydrogen, halo, C 1-6  alkyl, or —CO 2 R 5 . 
       
     
     
         9 . The method according to  claim 8 , wherein A 2  is 
       
         
           
           
               
               
           
         
       
       A 3  is 
       
         
           
           
               
               
           
         
       
       and Y is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 8 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, succinate, tartarate, mesylate, sodium, potassium, magnesium, and calcium salts. 
     
     
         11 . The method according to  claim 8 , wherein the compound of formula (II) is 1-(4-(3-(4-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(4-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(3-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(2-oxo-3-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,
 1-(4-(3-(4-benzylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(biphenyl-4-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(3-(3-benzylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid, or   1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid, or pharmaceutically acceptable salts thereof.   
     
     
         12 . The method according to  claim 8 , wherein the compound of formula (II) is 1-(4-(3-(3-benzoylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;
 1-(4-(2-oxo-3-(3-(1-phenylethyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(hydroxy(phenyl)methyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(difluoro(phenyl)methyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)-azetidine-3-carboxylic acid;   1-(4-(2-oxo-3-(3-phenoxyphenyl)imidazolidin-1-yl)benzyl)azetidine-3-carbo-xylic acid; 1-(4-(3-(3-(cyclobutylmethoxy)phenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(cyclopropylmethoxy)phenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;   1-(4-(3-(4-cyclohexylpyridin-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid,   1-(4-(3-(5-cyclohexylpyridin-3-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(2-cyclohexylpyridin-4-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(2-oxo-3-(3-(phenylsulfonyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(2-oxo-3-(3-(phenylsulfinyl)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(2-oxo-3-(3-(phenylthio)phenyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(2-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(3-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(4-fluorobenzyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(4-cyclohexyloxazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexyl-1,2,4-thiadiazol-5-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-(cyclohexyloxymethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(5-methylbenzo[d]thiazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(4-cyclohexylfuran-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(4-cyclohexylthiazol-2-yl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)pyrrolidine-3-carboxylic acid;   2-amino-3-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)propanoic acid;   3-amino-1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)-3-hydroxyazetidine-3-carboxylic acid;   1-(4-(3-(2H-tetrazol-5-yl)azetidin-1-yl)methyl)phenyl)-3-(3-cyclohexylphenyl)imidazolidin-2-one;   3-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)propanoic acid;   4-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)butanoic acid;   3-((4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzyl)(methyl)amino)propanoic acid;   4-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)-4-oxobutanoic acid;   2-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)succinic acid;   3-(6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid;   2-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzylamino)ethanesulfonamide;   146-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)methyl)-azetidine-3-carboxylic acid;   1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)pyridin-2-yl)methyl)-azetidine-3-carboxylic acid;   14443-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;   14443-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-3-methoxybenzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-2-fluorobenzyl)azetidine-3-carboxylic acid;   145-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)thiazol-2-yl)methyl)azetidine-3-carboxylic acid;   1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-3-carboxylic acid;   1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzo[d]thiazol-2-yl)methyl)azetidine-3-carboxylic acid;   1-((6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;   1-((6-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)oxazolo[5,4-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;   1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)furo [2,3-b]pyridin-2-yl)methyl)azetidine-3-carboxylic acid;   1-((5-(3-(3-cyclohexylphenyl)-2-oxoimidazolidin-1-yl)benzofuran-2-yl)methyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexyl-4-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-5-methyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-4-methyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-5,5-dimethyl-2-oxoimidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid;   1-(4-(3-(3-cyclohexylphenyl)-2-oxo-5-(trifluoromethyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid; or   1-(4-(3-(3-cyclohexylphenyl)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof.   
     
     
         13 . The method according to  claim 8  wherein the condition is ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer or prostate cancer.