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, Behcet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma; and for treating other conditions.

Description

Claims

1. A compound having the formula

2. The compound of claim 1, wherein A is a C1-6 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, S R2, 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.

4. The compound of claim 1, wherein A is substituted with two adjacent substituents that, taken with Z1 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)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, wherein 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 and halogen-substituted C1-5 alkoxy; and aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring.

6. The compound of claim 5, wherein 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 and halogen-substituted C1-5 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 C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy.

9. The compound of claim 1, wherein Z1 and Z2 are 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, or a direct bond.

10. The compound of claim 9, wherein R3 is selected from the group consisting of hydrogen, hydroxyl, S(O)2, 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 or heteroaryl.

11. The compound of claim 9, wherein 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 or heteroaryl or together form C═O.

12. The compound of claim 1, wherein 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 or heteroaryl.

13. The compound of claim 12, wherein R1 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, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, C3-6 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

17. The compound of claim 16, wherein A is a C1-6 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, S R2, 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.

19. The compound of claim 16, wherein A is substituted with two adjacent substituents that, taken with Z1 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 wherein A is optionally substituted with one, two or three substituents selected from the group consisting of halogen, hydroxyl, S, 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, wherein 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 and halogen-substituted C1-5 alkoxy; and aryl/heteroaryl; or optionally, two adjacent substituents on A may, taken with Z1 and the ring to which they are attached, form an alicyclic or heterocyclic ring.

21. The compound of claim 17, wherein 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 and halogen-substituted C1-5 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 C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, halogen, hydroxyl, cyano, halogen-substituted C1-6alkyl and halogen-substituted C1-5 alkoxy.

23. The compound of claim 16, wherein 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 or heteroaryl.

24. The compound of claim 22, wherein R1 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, C1-6 alkyl, C1-5 alkylthio, C1-5 alkoxy, C3-6 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. A composition of matter selected from the group consisting of 1-(4-(5-Phenylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-((4-(5-Butylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-(4-(5-Butoxybenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-Benzylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(7-Benzylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-(4-(5-cyclohexylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(4-(5-cyclohexylbenzofuran-2-yl)benzyl)piperidine-4-carboxylic acid; 1-((4-(5-Butylbenzofuran-2-yl)phenyl)methyl)piperidine-4-carboxylic acid; 1-((4-(5-Benzylbenzofuran-2-yl)phenyl)methyl) piperidine-4-carboxylic acid; 1-((4-(5-isobutylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-phenethylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-(4-(5-(pyridin-3-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid, 1-(4-(5-isobutylbenzofuran-2-yl)benzyl)piperidine-4-carboxylic acid; 1-((4-(5-Benzylbenzofuran-2-yl)2-fluorophenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid; 1-(4-(5-Butoxybenzofuran-2-yl)phenyl)methyl)piperidine-4-carboxylic acid; 1-((6-(5-cyclohexylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid; 1-(4-(5-(6-methylpyridin-2-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(4-(5-phenoxybenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-((4-(5-Isopentylbenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(6-Butoxybenzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 1-((2-(5-butoxybenzofuran-2-yl)thiazol-5-yl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-Butoxybenzofuran-2-yl)4-fluorophenyl)methyl)azetidine-3-carboxylic acid, 1-((4-(5-Butoxybenzofuran-2-yl)-3-methoxyphenyl)azetidine-3-carboxylic acid; 1-((5-(5-butoxybenzofuran-2-yl)thiophen-2-yl)methyl)azetidine-3-carboxylic acid; 1-((6-(5-Butoxylbenzofuran-2-yl)pyridin-3-yl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-cyclohexylbenzofuran-2-yl)3-fluorophenyl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-(thiophen-2-yl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid; 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoguinolin-2(1H)-yl)propanoic acid; 1-(4-(5-cyclopentylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(3-fluoro-4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid trifluoroacetic acid salt; 1-((6-(5-benzylbenzofuran-2-yl)piridin-3-yl)methyl)azetidine-3-carboxylic acid; 1-((4-(5-benzylbenzofuran-2-yl)-3-methoxypheny1)methyl)azetidine-3-carboxylic acid; 1-(4-(5-(piperidin-1-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 6-(5-benzylbenzofuran-2-yl)-2-(2-carboxyethyl)-3,4-dihydroisoguinolinium 2,2,2-trifluoroacetate-(4-(5-benzylbenzofuran-2-yl)-3-chlorobenzyl)azetidine-3-carboxylic acid; 3-(6-(5-cyclopentylbenzofuran-2-yl)-3,4-dihydroisoguinolin-2(1H)-yl)propanoic acid: 1-(4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; 1-(4-(5-(cycloventylmethoxy)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 1-(4-(5-benzylbenzofuran-2-yl)-3-cyanobenzyl)azetidine-3-carboxylic acid; 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzyl)pyrrolidine-3-carboxylic acid; 1-(4-(5-cyclopentylbenzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; 1-(4-(5-benzylbenzofuran-2-yl)-3-methylbenzyl)azetidine-3-carboxylic acid; 3-(6-(5-butoxybenzofuran-2-yl)-3,4-dihydroisoguinolin-2(1H)-yl)propanoic acid: 3-(5-(5-benzylbenzofuran-2-yl)-2,3-dihydro-1H-inden-1-ylamino)propanoic acid; 3-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzylamino)-3-methylbutanoic acid; 1-(4-(5-cyclopentylbenzofuran-2-yl)-3-methoxybenzyl)azetidine-3-carboxylic acid; 1-(4-(5-benzylbenzofuran-2-yl)-3,5-difluorobenzyl)azetidine-3-carboxylic acid; 1-(4-(5-(cyclopropylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid; 1-(4-(5-butoxybenzofuran-2-yl)-3-chlorobenzyl)azetidine-3-carboxylic acid; 1-(3-chloro-4-(5-cyclopentylbenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; 3-((4-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)(2-hydroxyethyl)amino)propanoic acid; 1-(3-fluoro-4-(5-morpholinobenzofuran-2-yl)benzyl)azetidine-3-carboxylic acid, 4-(4-(5-benzylbenzofuran-2-yl)-3-fluorobenzyl)morpholine-2-carboxylic acid; 4-(4-(5-(cyclolpentylmethoxy)benzofuran-2-yl)-3-fluorobenzyl)morpholine-2-carboxylic acid, 3-(6-(5-(cyclolpentylmethoxy)benzofuran-2-yl)-3,4-dihydroisoguinolin-2(1H)-yl)propanoic acid; 3-(4-(5-cyclopentylbenzofuran-2-yl)-3-fluorobenzylamino)propanoic acid; 3-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenoxy)propane-1,2-diol; 1-(3-fluoro-4-(5-(1-(methylsulfonyl)piperidin-4-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; and 1-(3-fluoro-4-(5-(tetrahydro-2H-pran-4-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylic acid; or pharmaceutically acceptable salts thereof.

39-97. (canceled)