Bicyclic 1,3,4-oxadiazole derivatives as sphingosine-1-phosphate receptors' modulators
The present invention relates to bicyclic 1,3,4-oxadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.
1. A compound of Formula I:
X is N or CR 12 ;
R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5-8 cycloalkyl, or substituted or unsubstituted C 5-8 cycloalkenyl;
R 2 is substituted or unsubstituted C 1-8 alkyl;
R 3 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 or hydroxyl;
R 4 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 or hydroxyl;
R 5 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 , hydroxyl or substituted or unsubstituted heterocycle;
R 6 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 , hydroxyl or substituted or unsubstituted heterocycle;
R 7 is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 8 is —OPO 3 H 2 , carboxylic acid, —PO 3 H 2 , —P(O)MeOH, —P(O)(H)OH or OR 10 ;
R 9 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 , hydroxyl or substituted or unsubstituted heterocycle;
R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 12 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13 or hydroxyl;
R 13 is OH, substituted or unsubstituted C 1-8 alkyl or —OC 1-8 alkyl; and
a is 0, 1, 2 or 3;
or an enantiomer or diastereoisomer thereof, or a tautomer or zwitterion of any one of the foregoing, or a pharmaceutically acceptable salt of any one of the foregoing.
2. A compound according to claim 1 , wherein a is 0 or 1.
3. A compound according to claim 2 , wherein:
R 1 is substituted or unsubstituted aryl;
R 2 is substituted or unsubstituted C 1-8 alkyl;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen;
R 8 is carboxylic acid or —PO 3 H 2 ;
R 9 is hydrogen; and
R 12 is hydrogen.
4. A compound according to claim 3 , wherein:
R 1 unsubstituted aryl; and
R 2 is unsubstituted C 1-8 alkyl.
5. A compound according to claim 2 , wherein:
R 1 is substituted or unsubstituted aryl;
R 2 is substituted or unsubstituted C 1-8 alkyl;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen;
R 8 is carboxylic acid or —PO 3 H 2 ; and
R 9 is hydrogen.
6. A compound according to claim 5 , wherein:
R 1 unsubstituted aryl; and
R 2 is unsubstituted C 1-8 alkyl.
7. A compound according to claim 1 selected from:
and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A compound of Formula II:
X a is N or CR 12a ;
R 1a is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5-8 cycloalkyl, or substituted or unsubstituted C 5-8 cycloalkenyl;
R 2a is substituted or unsubstituted C 1-8 alkyl;
R 3a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a or hydroxyl;
R 4a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a or hydroxyl;
R 5a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a , hydroxyl or substituted or unsubstituted heterocycle;
R 6a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a , hydroxyl or substituted or unsubstituted heterocycle;
R 7a is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 8a is —OPO 3 H 2 , carboxylic acid, —PO 3 H 2 , —P(O)MeOH, —P(O)(H)OH or OR 10a ;
R 9a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a , hydroxyl or substituted or unsubstituted heterocycle;
R 10a is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 12a is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, C(O)R 13a or hydroxyl; and
R 13a is hydroxyl, substituted or unsubstituted C 1-8 alkyl or —OC 1-8 alkyl;
or an enantiomer or diastereoisomer thereof, or a tautomer or zwitterion of any one of the foregoing, or a pharmaceutically acceptable salt of any one of the foregoing.
10. A compound according to claim 9 , wherein:
R 1a is substituted or unsubstituted aryl;
R 2a is substituted or unsubstituted C 1-8 alkyl;
R 3a is hydrogen;
R 4a is hydrogen;
R 5a is hydrogen;
R 6a is hydrogen;
R 7a is hydrogen;
R 8a is carboxylic acid; and
R 9a is hydrogen.
11. A compound according to claim 10 , wherein:
R 1a is unsubstituted aryl; and
R 2a is unsubstituted C 1-8 alkyl.
12. A compound according to claim 9 , wherein:
R 1a is substituted or unsubstituted aryl;
R 2a is substituted or unsubstituted C 1-8 alkyl;
R 3a is hydrogen;
R 4a is hydrogen;
R 5a is hydrogen;
R 6a is hydrogen;
R 7a is hydrogen;
R 8a is carboxylic acid; and
R 9a is hydrogen.
13. A compound according to claim 12 , wherein:
R 1a is unsubstituted aryl; and
R 2a is unsubstituted C 1-8 alkyl.
14. A compound according to claim 9 selected from:
and pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of claim 9 and a pharmaceutically acceptable adjuvant, diluent or carrier.
16. A method of treating an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, thereby treating the disease in the subject.
17. The method of claim 16 , wherein the disease is systemic lupus erythematosus or inflammatory bowel disease.
18. A method of treating an autoimmune disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt thereof, thereby treating the disease in the subject.
19. The method of claim 18 , wherein the disease or condition is systemic lupus erythematosus or inflammatory bowel disease.