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.

1 .- 38 . (canceled) 
     
     
         39 . A method of treating a S1P-1 receptor-mediated condition selected from the group consisting of 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 and prostrate cancer; acute lung diseases, autoimmune disease, inflammatory diseases; 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, asthma, surface epithelial cell injury, transcorneal freezing, cutaneous burns, cardiovascular diseases, ischemia, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, systemic lupus erythematosus, uveitis, myasthenia gravis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula, 
       
         
           
           
               
               
           
         
       
       wherein
 A is phenyl optionally 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; 
 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, halogen-substituted C 1-5  alkoxy, aryl, and heteroaryl; 
 B and C are selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       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;
 R 13  is selected from the group consisting of H, 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; 
 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 and 1H-tetrazol-5-yl; 
 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 CO 2 H; 
 R 6a  is hydrogen or C 1-4  alkyl; 
 R 6b  and R 6c  are independently hydrogen, hydroxyl, C 1-4  alkyl or halogen substituted C 1-4  alkyl; 
 Y is formula (a) where the left and right asterisks indicate the point of attachment 
 
       
         
           
           
               
               
           
         
       
       wherein
 Q is selected from the group consisting of a direct bond, C═O, C═S, SO 2 , C═ONR and (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; 
 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 and 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 and halogen-substituted C 1-5  alkoxy; 
 Z 1  is independently selected from the group consisting of O, NR 3 , S, S(O), S(O) 2 NR 3 , (CR 4 R 5 ) n , C═O, C═S, C═N—R 3 , and a direct bond; 
 Z 2  is 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 , and a direct bond; 
 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 and 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 and heteroaryl, or together form C═O; 
 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, heteroaryl, and heterocycle, wherein the 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, and heteroaryl groups are optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, aryl amino, and heteroarylamino, wherein the aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl, halogen, cyano, C 1-6  alkyl, C 1-5  alkylthio, C 1-5  alkoxy, and C 3-6  cycloalkyl, and wherein the heterocyclic groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, aryl, and heteroaryl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         40 . The compound of  claim 39 , 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. 
     
     
         41 . The compound of  claim 39 , 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. 
     
     
         42 . The method according to  claim 39 , 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. 
     
     
         43 . A method of treating a S1P-1 receptor-mediated condition selected from the group consisting of 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 and prostrate cancer; acute lung diseases, autoimmune disease, inflammatory diseases; 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, asthma, surface epithelial cell injury, transcorneal freezing, cutaneous burns, cardiovascular diseases, ischemia, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, systemic lupus erythematosus, uveitis, myasthenia gravis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula. 
       
         
           
           
               
               
           
         
       
       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; 
 A is phenyl optionally 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;
 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, halogen-substituted C 1-5  alkoxy, aryl and heteroaryl; 
 
 X is —C(O)OR 6a , where R 6a  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, or lower alkyl; 
 R 9  is selected from the group consisting of hydrogen, halogen, hydroxyl, and cyano; 
 Z 1  and Z 2  are independently O or (CR 4 R 5 ) n ; 
 R 4  and R 5  are independently hydrogen, halogen, hydroxyl, cyano, C 1-6  alkyl, or C 1-5  alkoxy; 
 n is 0, 1, 2 or 3; 
 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 heteroaryl, and heterocycle, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 1-5  alkoxy, and C 1-5  alkylamino groups are optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, cyano, amino, alkylamino, arylamino, and heteroarylamino, 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, and C 3-6  cycloalkyl, and wherein the heterocyclic groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano, amino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, aryl, and heteroaryl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         44 . The compound of  claim 43 , 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. 
     
     
         45 . The compound of  claim 43 , 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. 
     
     
         46 . The method according to  claim 43  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. 
     
     
         47 . A method of treating a S1P-1 receptor-mediated condition selected from the group consisting of 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 and prostrate cancer; acute lung diseases, autoimmune disease, inflammatory diseases; 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, asthma, surface epithelial cell injury, transcorneal freezing, cutaneous burns, cardiovascular diseases, ischemia, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, systemic lupus erythematosus, uveitis, myasthenia gravis, non-glomerular nephrosis, hepatitis, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
 3-(4-(5-Benzylbenzofuran-2-yl)-3-fluorobenzylamino)-2-methylpropanoic acid;   4-Amino-2-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-4-oxobutanoic acid;   4-Amino-3-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-4-oxobutanoic acid; and   pharmaceutically acceptable salts or hydrates thereof   
     
     
         48 . The method according to  claim 47  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.