S1P Receptor Modulating Compounds and Use Thereof

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, SR2, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino, arylamino, heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl, halogen-substituted C1-5 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 C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy;
• R13 is selected from the group consisting of H, C1-6alkyl, C1-5alkylthio, C1-5alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl, and halogen-substituted C1-5alkoxy;
• X is selected from the group consisting of WC(O)OR6a, WP(O)R6bR6c, WS(O)2OH, WCONHSO3H and 1H-tetrazol-5-yl;
• W is a direct bond, oxygen or C1-4 alkyl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkylamino, arylamino, heteroarylamino groups, C1-4 alkoxy and CO2H;
• R6a is hydrogen or C1-4 alkyl;
• R6b and R6c are independently hydrogen, hydroxyl, C1-4 alkyl or halogen substituted C1-4 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, SO2, C═ONR and (CR10R11)m;
• m is 0, 1, 2 or 3;
• R7 and R8 are independently selected from the group consisting of hydrogen, halogen, amino, C1-5 alkylamino, hydroxyl, cyano, C1-6 alkyl, C1-6 hydroxyalkyl (e.g., hydroxy-terminated alkyl), C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy;
• R9 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy;
• R10 and R11 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy;
• Z1 is independently selected from the group consisting of O, NR3, S, S(O), S(O)2NR3, (CR4R5)n, C═O, C═S, C═N—R3, and a direct bond;
• Z2 is independently selected from the group consisting of O, NR3, S, S(O), S(O)2, S(O)2NR3, (CR4R5)n, C═O, C═S, C═N—R3, and a direct bond;
• R3 is selected from the group consisting of hydrogen, hydroxyl, SO2, C═O, C═S, C═NH, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy, aryl and heteroaryl, or when Z2 is a direct bond, R3 is a C3-C6 ring optionally containing a heteroatom;
• R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy, aryl and heteroaryl, or together form C═O;
• n is 0, 1, 2 or 3;
• and
• R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl, heteroaryl, and heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 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, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, and C3-6 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.

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 C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6 alkyl and halogen-substituted C1-5 alkoxy;
• A is phenyl optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, SR2, S(O)2R2, S(O)2NR2, NHS(O)2R2, COR2, CO2R2, cyano, amino, C1-5 alkylamino, arylamino, heteroarylamino, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen-substituted C1-6 alkyl, and halogen-substituted C1-5 alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, arylamino, C1-6 alkyl, C1-5 alkoxy, C1-5 alkylthio, halogen-substituted C1-6 alkyl, halogen-substituted C1-5 alkoxy, aryl and heteroaryl;
• X is —C(O)OR6a, where R6a is hydrogen or C1-4 alkyl;
• Y is a residue of formula (a)
• wherein
• Q is (CR10R11)m;
• m is 0, 1, 2, 3 or 4;
• R7 and R8 are independently hydrogen, hydroxyl, or lower alkyl;
• R9 is selected from the group consisting of hydrogen, halogen, hydroxyl, and cyano;
• Z1 and Z2 are independently O or (CR4R5)n;
• R4 and R5 are independently hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, or C1-5 alkoxy;
• n is 0, 1, 2 or 3;
• R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, C1-5 alkylamino, aryl heteroaryl, and heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-5 alkoxy, and C1-5 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, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, and C3-6 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.

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