Fused heterocyclic derivatives as S1P modulators

Abstract

This invention relates to new fused heterocyclic derivatives having affinity to S1P receptors, a pharmaceutical composition containing said compounds, as well as the use of said compounds for the preparation of a medicament for treating, alleviating or preventing diseases and conditions in which any S1P receptor is involved or in which modulation of the endogenous S1P signaling system via any S1P receptor is involved.

The invention claimed is: 
     
       1. A compound of the formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an N-oxide of any of the foregoing, 
         wherein
 R1 is selected from the group consisting of:
 a cyano group, 
 a group independently selected from a (2-4C)alkenyl group, a (2-4C)alkynyl group, and a (1-4C)alkyl group, wherein each group is optionally substituted with a substituent independently selected from CN and at least one halogen atom, 
 a group independently selected from a (3-6C)cycloalkyl group, a (4-6C)cycloalkenyl group, and a (8-10C)bicyclic group, wherein each group is optionally substituted with a substituent independently selected from a halogen atom and a (1-4C)alkyl group optionally substituted with at least one halogen atom, a group independently selected from a phenyl group, a biphenyl group, and a naphthyl group, wherein each group is optionally substituted with at least one substituent independently selected from halogen, cyano, (1-4C)alkyl optionally substituted with at least one halogen atom, (1-4C)alkoxy optionally substituted with at least one halogen atom, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with a phenyl group wherein the phenyl group is optionally substituted with a substituent independently selected from (1-4C)alkyl and a halogen atom, and 
 
 a group independently selected from a phenyl group, a biphenyl group, and a naphthyl group, wherein each group is optionally substituted with at least one substituent independently selected from halogen, cyano, (1-4C)alkyl optionally substituted with at least one halogen atom, (1-4C)alkoxy optionally substituted with at least one halogen atom, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with a phenyl group wherein the phenyl group is optionally substituted with a substituent independently selected from (1-4C)alkyl and a halogen atom, and 
 a phenyl group substituted with a group selected from the group consisting of a phenoxy group, a benzyl group, a benzyloxy group, a phenylethyl group, and a monocyclic heterocycle group, wherein each group is optionally substituted with (1-4C)alkyl, 
 
         Z is a —W—(C n -alkylene)-T-group wherein
 W is attached to R1 and selected from the group consisting of a bond, —O—, —CO—, —S—, —SO—, —SO 2 —, —NH—, —CH═CH—, —C(CF 3 )═CH—, —C≡C—, —CH 2 —O—, —O—CO—, —CO—O—, —CO—NH—, NH—CO— and a trans-cyclopropylene; 
 n is an integer from 0 to 10; and 
 T is attached to the phenylene/pyridyl moiety and selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, —NH—, —CO—, —C═C— —CH═CH—, —C≡C—, and a trans-cyclopropylene; 
 
         R2 is selected from the group consisting of H and at least one substituent independently selected from cyano, halogen, (1-4C)alkyl optionally substituted with at least one halogen atom, and (1-4C)alkoxy optionally substituted with at least one or more halogen atom; ring structure A optionally contains a nitrogen atom; 
         X is selected from the group consisting of C and N;
 wherein if X is C, R3 is selected from H and (1-4C)alkyl, and if X is N, R3 is not present; 
 
         Y is selected from the group consisting of NH, O and S O; 
         structure Q is selected from the group consisting of a 5-, 6- and 7-membered cyclic amine; and 
         R4 is selected from
 a (1-4C)alkylene-R5 group wherein at least one carbon atom in the alkylene group may independently be substituted with a substituent selected from at least one halogen atom and a (CH 2 ) 2  to form a cyclopropyl moiety, or 
 a group independently selected from (3-6C)cycloalkylene-R5, —CH 2 -(3-6C)cycloalkylene-R5, (3-6C)cycloalkylene-CH 2 —R5 and —CO—CH 2 —R5, wherein R5 is selected from —OH, —PO 3 H 2 , —OPO 3 H 2 , —COOH, —COO(1-4C)alkyl and tetrazol-5yl tetrazol-5-yl. 
 
       
     
     
       2. The compound of  claim 1 , wherein
 R1 is selected from
 a group independently selected from a (3-6C)cycloalkyl group and a (8-10C)bicyclic group wherein the group is optionally substituted with a halogen atom, (1-4C)alkyl, or a phenyl group wherein the phenyl group is optionally substituted with at least one substituent independently selected from the group consisting of a halogen atom, cyano, (1-4C)alkyl, (1-4C)alkoxy, a trifluoromethyl, and a trifluoromethoxy; 
 
 W is selected from the group consisting of a bond, —O—, —CO—, —S—, —SO—, —SO 2 —, —NH—, —CH═CH—, —C≡C—, and a trans-cyclopropylene; 
 n is an integer from 0 to 4; and 
 R2 is selected from the group consisting of H, at least one substituent independently selected from a halogen atom, (1-4C)alkyl optionally substituted with at least one fluoro and (1-4C)alkoxy optionally substituted with at least one fluoro atom. 
 
     
     
       3. The compound of  claim 1 , wherein the compound has the structure (Ia) 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, R5, Q, T, W, X, Y, Z, and n are as defined in  claim 1 . 
       
     
     
       4. The compound of  claim 1 , wherein the compound has the structure (Ib) 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, R5, Q, T, W, X, Y, Z, and n are as defined in  claim 1 . 
       
     
     
       5. The compound of  claim 1 , wherein Y is O. 
     
     
       6. The compound of  claim 1 , wherein R4 is selected from the group consisting of —(CH 2 ) 2 —COOH, —(CH 2 ) 3 —COOH, —CH 2 —CHCH 3 —COOH, —CH 2 —C(CH 3 ) 2 —COOH, —CHCH 3 —CH 2 —COOH, —CH 2 —CF 2 —COOH, and 1,3-cyclobutylene-COOH. 
     
     
       7. The compound of  claim 1 , wherein R1 is a phenyl group optionally substituted with at least one substituent independently selected from the group consisting of halogen, cyano, (1-4C)alkyl optionally substituted with at least one halogen atom, (1-4C)alkoxy optionally substituted with at least one halogen atom, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with a phenyl group wherein the phenyl group is optionally substituted with a substituent independently selected from (1-4C)alkyl and a halogen atom. 
     
     
       8. The compound of  claim 7 , wherein R1 is a phenyl group optionally substituted with at least one substituent independently selected from a halogen atom, cyano, (1-4C)alkyl, (1-4C)alkoxy, a trifluoromethyl, and a trifluoromethoxy. 
     
     
       9. The compound of  claim 1 , wherein Z is —CH 2 O—. 
     
     
       10. The compound of  claim 1 , wherein X is N. 
     
     
       11. The compound of  claim 1 , wherein the compound is selected from:
 3-{2-[4-(2-Fluoro-benzyloxy)-phenyl]-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl}-propionic acid, 
 3-{2-[4-(4-Chloro-benzyloxy)-phenyl]-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl}-2-methyl-propionic acid, 
 3-{2-[4-Benzyloxy-phenyl]-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl}-butyric acid, 
 4-{2-[4-(2-Fluoro-benzyloxy)-phenyl]-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl}-butyric acid, 
 4-{2-[4-(2-Fluoro-benzyloxy)-2-fluoro-phenyl]-6,7-dihydro-4H-furo[3,2-c]pyridine-5-yl}-butyric acid, 
 3-{2-[4-(Benzyloxy)-phenyl)]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-propionic acid, 4-{2-[4-(2,3-Difluoro-benzyloxy)-phenyl)]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-Benzyloxy-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-(4-Trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-(2-Fluoro-benzyloxy)-2-methyl-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-(3,4-Dichloro-benzyloxy)-2-fluoro-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-(2-Fluoro-benzyloxy)-3-chloro-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 4-{2[4-(4-Chloro-benzyloxy)-3-fluoro-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 3[2-(4-Benzyloxy-phenyl)-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl]-2-methyl-propionic acid,3-[2-(4-Benzyloxy-phenyl)-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl]-2-methyl-propionic acid, 
 3-{2[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-2-methyl-propionic acid, 
 3-{2[4-(4-Chloro-benzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-2-methyl-propionic acid, 
 3-{2[4-(2,3-Difluoro-benzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-butyric acid, 
 3-{2[4-(4-Trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-2-methyl-propionic acid, 
 Cis and trans 3-{2[4-(4-Trifluoromethoxybenzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-cyclobutane carboxylic acid, 
 Cis and trans 3-{2[4-(3,4-Difluorobenzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-cyclobutane carboxylic acid, 
 3[2-(4-(2-Fluoro-benzyloxy)-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl]-propionic acid, 
 4-{2-[4-(3,5-Difluoro-benzyloxy)-phenyl]-6,7-dihydro-4H-thiazolo-[4,5c]-pyridin-5-yl}-butyric acid, 
 2-{2-[4-(3,5-Difluoro-benzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-acetic acid, 
 2-{2-[4-(3,5-Difluoro-benzyloxy)-phenyl]-6,7-dihydro-H-oxazolo[4,5-c]pyridine-5-yl}-propionic acid, 
 3-{2-[4-(3,5-Difluoro-benzyloxy)-phenyl]-6,7-dihydro-4H-oxazolo[4,5-c]-pyridin-5-yl}-cyclopentane carboxylic acid, 
 4-{2-[4-(2,3-Difluoro-benzyloxy)-2-methyl-phenyl]-6,7-dihydro-4H-oxazolo[4,5c]-pyridin-5-yl}-pentanoic acid, 
 4-{2-[4-(2,3-Difluoro-benzyloxy)-2-methyl-phenyl]-6,7-dihydro-4H-oxazolo[4,5-c]-pyridin-5-yl}-2-methyl-butyric acid, 
 4-{2[4-(2,3-Difluoro-benzyloxy)-2-methyl-phenyl]-6,7-dihydro-4H-oxazolo-[4,5c]-pyridin-5-yl}-3-methyl-butyric acid, 
 3-{2-[4-(2-phenyl-cyclopropyl)-3-fluoro-phenyl]-6,7-dihydro-4H-oxazolo-[4,5-c]-pyridin-5-yl}-cyclobutane carboxylic acid, 
 4-(2-{4-(2-(3,5-Difluoro-phenyl)-vinyl]-phenyl}-6,7-dihydro-4H-oxazolo-[4,5c]-pyridin-5-yl)-butyric acid, and 
 4-(2-{4-[2-(3,5-Difluoro-phenyl)-ethyl]-phenyl}-6,7-dihydro-4H-oxazolo[4,5c]pyridin-5-yl)-butyric acid, 
 or a pharmaceutically acceptable salt, solvateor solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
 
     
     
       12. A pharmaceutical composition comprising the compound of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
       13. A compound selected from the group consisting of:
 3-(2-(4-((2-fluorobenzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)propanoic acid; 
 3-(2-(4-((4-chlorobenzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)-2-methylpropanoic acid; 
 2-methyl-3-(2-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)propanoic acid; 
 Trans 3-(2-(4-((3,4-difluorobenzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)cyclobutanecarboxylic acid; 
 3-(2-(4-((4-cyanobenzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)butanoic acid; and 
 3-(2-(4-((2,3-difluorobenzyl)oxy)phenyl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)butanoic acid, 
 or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
 
     
     
       14. A compound comprising: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       15. A compound comprising: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       16. A compound comprising: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       17. A compound comprising: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       18. A compound comprising: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       19. A compound comprising 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
       
     
     
       20. A compound comprising the plus (+) enantiomer of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
     
     
       21. A compound comprising the minus (−) enantiomer of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, a solvate or hydrate thereof, or an N-oxide of any of the foregoing. 
     
     
       22. A pharmaceutical composition comprising a compound of  claim 11 , and at least one pharmaceutically acceptable excipient. 
     
     
       23. A pharmaceutical composition comprising a compound of  claim 13 , and at least one pharmaceutically acceptable excipient. 
     
     
       24. A pharmaceutical composition comprising a compound of  claim 14 , and at least one pharmaceutically acceptable excipient. 
     
     
       25. A pharmaceutical composition comprising a compound of  claim 15 , and at least one pharmaceutically acceptable excipient. 
     
     
       26. A pharmaceutical composition comprising a compound of  claim 16 , and at least one pharmaceutically acceptable excipient. 
     
     
       27. A pharmaceutical composition comprising a compound of  claim 17 , and at least one pharmaceutically acceptable excipient. 
     
     
       28. A pharmaceutical composition comprising a compound of  claim 18 , and at least one pharmaceutically acceptable excipient. 
     
     
       29. A pharmaceutical composition comprising a compound of  claim 19 , and at least one pharmaceutically acceptable excipient. 
     
     
       30. A pharmaceutical composition comprising a compound of  claim 20 , and at least one pharmaceutically acceptable excipient. 
     
     
       31. A pharmaceutical composition comprising a compound of claim  21  20, and at least one pharmaceutically acceptable excipient. 
     
     
       32. A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, which is the cis isomer. 
     
     
       34. The compound of claim 32, or a pharmaceutically acceptable salt thereof, which is the trans isomer. 
     
     
       35. A pharmaceutical composition comprising the compound of claim 32, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
       36. A pharmaceutical composition comprising the compound of claim 33, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
       37. A pharmaceutical composition comprising the compound of claim 34, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
       38. A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R4 is -cyclobutyl-COOH. 
     
     
       39. A pharmaceutical composition comprising the compound of claim 38, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.