S1P Receptor Modulating Compounds and Use Thereof

Abstract

The present invention relates to compounds of the general formula (I) that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds may be used as immunomodulators, e.g., for treating or preventing diseases such as autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behçet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma; and for treating other conditions.

What is claimed is: 
     
         1 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein
 A is an optionally substituted aryl or heteroaryl group; 
 B and C are an at least partially aromatic bicyclic ring system; 
 X is selected from the group consisting of WC(O)OR 6a , WP(O)R 6b R 6c , WS(O) 2 OH, WCONHSO 3 H or 1H-tetrazol-5-yl; where W is a direct bond, oxygen or C 1-4  alkyl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C 1-4  alkoxy and COO 2 H; R 6a  is hydrogen or C 1-4 alkyl; and R 6b  and R 6c  are independently hydrogen, hydroxyl, C 1-4 alkyl or halogen substituted C 1-4 alkyl; 
 Y is residue of formula (a) where the left and right asterisks indicate the point of attachment 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 Q is selected from the group consisting of direct bond, C═O, C═S, SO 2 , C═ONR or (CR 10 R 11 ) m ; 
 m is 0, 1, 2 or 3; 
 R 7  and R 8  are independently selected from the group consisting of hydrogen, halogen, amino, C 1-5  alkylamino, hydroxyl, cyano, C 1-6  alkyl, C 1-6  hydroxyalkyl (e.g., hydroxy-terminated alkyl), C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; or R 7  and R 8  may be joined together with the atoms to which they are attached to form a 4 to 7-membered ring, optionally having a hetero atom; and 
 R 9  is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl or halogen-substituted C 1-5  alkoxy; 
 R 10  and R 11  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl or halogen-substituted C 1-5  alkoxy and 
 
           Z 1  and Z 2  are independently selected from the group consisting of O, NR 3 , S, S(O), S(O) 2 , S(O) 2 NR 3 , (CR 4 R 5 ) n , C═O, C═S, C═N—R 3 , or a direct bond, where
 R 3  is selected from the group consisting of hydrogen, hydroxyl, SO 2 , C═O, C═S, C═NH, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; aryl or heteroaryl, or when Z 2  is a direct bond, R 3  is a C 3 -C 6  ring optionally containing a heteroatom; 
 R 4  and R 5  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; aryl or heteroaryl or together form C═O; and 
 n is 0, 1, 2 or 3; and 
 
           R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-5  alkoxy, C 1-5  alkylamino, aryl or heteroaryl. 
         
       
     
     
         2 . The compound of  claim 1 , wherein A is a C 1-6  cyclic ring (alicyclic or aromatic) optionally having one or more heteroatoms. 
     
     
         3 . The compound of  claim 1 , wherein A is substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, SR 2 , S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1-5  alkylamino/arylamino/heteroarylamino, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl, and halogen-substituted C 1-5  alkoxy. 
     
     
         4 . The compound of  claim 1 , wherein A is substituted with two adjacent substituents that, taken with Z 1  and the ring A to which they are attached, form a fused ring optionally containing one or more hetero atoms. 
     
     
         5 . The compound of  claim 2 , wherein A is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, S, S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1-5  alkylamino/arylamino/heteroarylamino, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl, and halogen-substituted C 1-5  alkoxy, wherein R 2  is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino/arylamino, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; and aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z 1  and the ring to which they are attached, form an alicyclic or heterocyclic ring. 
     
     
         6 . The compound of  claim 5 , wherein R 2  is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino/arylamino, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; or aryl/heteroaryl. 
     
     
         7 . The compound of  claim 1 , wherein B and C are selected from the group consisting of bicycloaryl, bicycloheteroaryl, dihydrobicyclic and tetrahydrobicyclic aryl and heteroaryl. 
     
     
         8 . The compound of  claim 7 , wherein the bicyclic ring system is optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen, hydroxyl, cyano, halogen-substituted C 1-6 alkyl and halogen-substituted C 1-5  alkoxy. 
     
     
         9 . The compound of  claim 1 , wherein Z 1  and Z 2  are independently selected from the group consisting of O, NR 3 , S, S(O), S(O) 2 , S(O) 2 NR 3 , (CR 4 R 5 ) n , C═O, C═S, C═N—R 3 , or a direct bond. 
     
     
         10 . The compound of  claim 9 , wherein R 3  is selected from the group consisting of hydrogen, hydroxyl, S(O) 2 , C═O, C═S, C═NH, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; aryl or heteroaryl. 
     
     
         11 . The compound of  claim 9 , wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; aryl or heteroaryl or together form C═O. 
     
     
         12 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-5  alkoxy, C 1-5  alkylamino, aryl or heteroaryl. 
     
     
         13 . The compound of  claim 12 , wherein R 1  is optionally substituted with groups selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, heteroarylamino groups 
     
     
         14 . The compound of  claim 13 , wherein the aryl and heteroaryl groups are optionally substituted with one to five substituents selected from the group consisting of hydroxyl, halogen, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, C 3-6  cycloalkyl. 
     
     
         15 . The compound of  claim 1 , 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. 
     
     
         16 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein
 A is an aryl or heteroaryl group; 
 X is —C(O)OR 6a , where R ha  is hydrogen or C 1-4  alkyl; 
 Y is a residue of formula (a) 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 Q is (CR 10 R 11 ) m ; 
 m is 0, 1, 2, 3 or 4; 
 R 7  and R 8  are independently hydrogen, hydroxyl, lower alkyl; or R 7  and R 8 , taken with the atoms to which they are attached, form a ring; and 
 R 9  is selected from the group consisting of hydrogen, halogen, hydroxyl, or cyano; 
 
           Z 1  and Z 2  are independently O or (CR 4 R 5 ) n , where
 R 4  and R 5  are independently hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, C 1-5  alkoxy; and 
 n is 0, 1, 2 or 3; and 
 
           R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-5  alkoxy, C 1-5  alkylamino, aryl or heteroaryl; 
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The compound of  claim 16 , wherein A is a C 1-6  cyclic ring (alicyclic or aromatic) optionally having one or more heteroatoms. 
     
     
         18 . The compound of  claim 16 , wherein A is substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, SR 2 , S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1-5  alkylamino/arylamino/heteroarylamino, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl, and halogen-substituted C 1-5  alkoxy. 
     
     
         19 . The compound of  claim 16 , wherein A is substituted with two adjacent substituents that, taken with Z 1  and the ring A to which they are attached, form a fused ring optionally containing one or more hetero atoms. 
     
     
         20 . The compound of  claim 16 , wherein A is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, S, S(O) 2 R 2 , S(O) 2 NR 2 , NHS(O) 2 R 2 , COR 2 , CO 2 R 2 , cyano, amino, C 1-5  alkylamino/arylamino/heteroarylamino, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen-substituted C 1-6  alkyl, and halogen-substituted C 1-5  alkoxy, wherein R 2  is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino/arylamino, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; and aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z 1  and the ring to which they are attached, form an alicyclic or heterocyclic ring. 
     
     
         21 . The compound of  claim 17 , wherein R 2  is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino/arylamino, C 1-6  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen-substituted C 1-6  alkyl and halogen-substituted C 1-5  alkoxy; or aryl/heteroaryl. 
     
     
         22 . The compound of  claim 16 , wherein the benzofuranyl ring is optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, halogen, hydroxyl, cyano, halogen-substituted C 1-6 alkyl and halogen-substituted C 1-5  alkoxy. 
     
     
         23 . The compound of  claim 16 , wherein R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-5  alkoxy, C 1-5  alkylamino, aryl or heteroaryl. 
     
     
         24 . The compound of  claim 22 , wherein R 1  is optionally substituted with groups selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, arylamino, and heteroarylamino groups. 
     
     
         25 . The compound of  claim 22 , wherein the aryl and heteroaryl groups are optionally substituted with one to five substituents selected from the group consisting of hydroxyl, halogen, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, C 3-6  cycloalkyl. 
     
     
         26 . The compound of  claim 16 , 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. 
     
     
         27 . A pharmaceutical composition comprising the compound of  claim 1  or  16  in an amount effective to treat an S1P-1 receptor mediated condition. 
     
     
         28 . The pharmaceutical composition of  claim 28 , wherein the S1P-1 receptor mediated condition is selected from the group consisting of transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas. 
     
     
         29 . A method of modulating a S1P-1 receptor, comprising contacting the S1P-1 receptor with a compound of  claim 1 . 
     
     
         30 . A method of treating a S1P-1 receptor-mediated condition, comprising administering to a patient in need thereof a pharmaceutical composition comprising the compound of  claim 1  or  16  in an amount effective to treat the condition. 
     
     
         31 . The method of  claim 30 , wherein the S1P-1 receptor mediated condition is selected from the group consisting of transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas. 
     
     
         32 . A method of immunomodulation, comprising administering to a patient in need thereof a pharmaceutical composition comprising the compound of  claim 1  or  16  in an amount resulting in immunomodulation. 
     
     
         33 . The method of  claim 32 , wherein the S1P-1 receptor mediated condition is selected from the group consisting of transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas. 
     
     
         34 . A pharmaceutical composition comprising the compound of  claim 1  or  16  in an amount effective to treat an S1P-1 receptor mediated condition. 
     
     
         35 . The pharmaceutical composition of  claim 35 , wherein the S1P-1 receptor mediated condition is selected from the group consisting of transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas. 
     
     
         36 . A method of treating a S1P-1 receptor-mediated condition, comprising administering to a patient in need thereof a pharmaceutical composition comprising the compound of  claim 1  or  16  in an amount effective to treat the condition. 
     
     
         37 . The method of  claim 36 , wherein the S1P-1 receptor mediated condition is selected from the group consisting of transplant rejection (solid organ transplant and islet cells); transplant rejection (tissue); cancer; autoimmune/inflammatory diseases; rheumatoid arthritis; lupus; insulin dependent diabetes (Type I); non-insulin dependent diabetes (Type II); multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; acute and chronic lymphocytic leukemias and lymphomas. 
     
     
         38 . 1-(4-(5-Phenylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         39 . 1-((4-(5-Butylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         40 . 1-(4-(5-Butoxybenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         41 . 1-((4-(5-Benzylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         42 . 1-((4-(7-Benzylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         43 . 1-(4-(5-cyclohexylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         44 . 1-(4-(5-cyclohexylbenzofuran-2-yl)benzyl)piperidine-4-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         45 . 1-((4-(5-Butylbenzofuran-2-yl)phenyl)methyl)piperidine-4-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         46 . 1-((4-(5-Benzylbenzofuran-2-yl)phenyl)methyl)piperidine-4-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         47 . 1-((4-(5-isobutylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         48 . 1-((4-(5-phenethylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         49 . 1-(4-(5-(pyridin-3-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         50 . 1-(4-(5-isobutylbenzofuran-2-yl)benzyl)piperidine-4-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         51 . 1-((4-(5-Benzylbenzofuran-2-yl)2-fluorophenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         52 . 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         53 . 1-(4-(5-Butoxybenzofuran-2-yl)phenyl)methyl)piperidine-4-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         54 . 1-((6-(5-cyclohexylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         55 . 1-(4-(5-(6-methylpyridin-2-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         56 . 1-(4-(5-phenoxybenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         57 . 1-((4-(5-Isopentylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         58 . 1-((4-(6-Butoxybenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         59 . 1-((2-(5-butoxybenzofuran-2-yl)thiazol-5-yl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         60 . 1-((4-(5-Butoxybenzofuran-2-yl)4-fluorophenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         61 . 1-((4-(5-Butoxybenzofuran-2-yl)-3-methoxyphenyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         62 . 1-((5-(5-butoxybenzofuran-2-yl)thiophen-2-yl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         63 . 1-((6-(5-Butoxylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         64 . 1-((4-(5-cyclohexylbenzofuran-2-yl)3-fluorophenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         65 . 1-((4-(5-(thiophen-2-yl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         66 . 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         67 . 1-(4-(5-cyclopentylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         68 . 1-(3-fluoro-4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid trifluoroacetic acid salt; or pharmaceutically acceptable salts thereof. 
     
     
         69 . 1-((6-(5-benzylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         70 . 1-((4-(5-benzylbenzofuran-2-yl)-3-methoxyphenyl)methyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         71 . 1-(4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         72 . 6-(5-benzylbenzofuran-2-yl)-2-(2-carboxyethyl)-3,4-dihydroisoquinolinium 2,2,2-trifluoroacetate. 
     
     
         73 . 1-(4-(5-benzylbenzofuran-2-yl)-3-chlorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         74 . 3-(6-(5-cyclopentylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         75 . 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         76 . 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         77 . 1-(4-(5-benzylbenzofuran-2-yl)-3-cyanobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         78 . 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzyl)pyrrolidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         79 . 1-(4-(5-cyclopentylbenzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         80 . 1-(4-(5-benzylbenzofuran-2-yl)-3-methylbenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         81 . 3-(6-(5-butoxybenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         82 . 3-(5-(5-benzylbenzofuran-2-yl)-2,3-dihydro-1H-inden-1-ylamino)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         83 . 3-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-3-methylbutanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         84 . 1-(4-(5-cyclopentylbenzofuran-2-yl)-3-methoxybenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         85 . 1-(4-(5-benzylbenzofuran-2-yl)-3,5-difluorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         86 . 1-(4-(5-(cyclopropylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         87 . 1-(4-(5-butoxybenzofuran-2-yl)-3-chlorobenzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         88 . 1-(3-chloro-4-(5-cyclopentylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         89 . 3-((4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)(2-hydroxyethyl)amino)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         90 . 1-(3-fluoro-4-(5-morpholinobenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         91 . 4-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzyl)morpholine-2-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         92 . 4-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)morpholine-2-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         93 . 3-(6-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         94 . 3-(4-(5-cyclopentylbenzofuran-2-yl)-3-fluorobenzylamino)propanoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         95 . 3-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenoxy)propane-1,2-diol; or pharmaceutically acceptable salts thereof. 
     
     
         96 . 1-(3-fluoro-4-(5-(1-(methylsulfonyl)piperidin-4-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 
     
     
         97 . 1-(3-fluoro-4-(5-(tetrahydro-2H-pyran-4-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof.