Substituted pyrazole azetidines as sphingosine receptor modulators
The present invention relates to substituted pyrazole azetidines, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.
1. A compound represented by Formula I, its enantiomers, diastereoisomers, tautomers, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 2 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 3 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 4 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 5 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 6 is H, optionally substituted C 6-10 aryl, optionally substituted heterocycle or optionally substituted C 1-6 alkyl;
R 7 is H, OH or optionally substituted C 1-6 alkyl;
R 8 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 9 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 10 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 11 is H, halogen, optionally substituted C 1-6 alkyl, CN, NO 2 , C(O)R 7 , NR 12 R 13 or OR 14 ;
R 12 is H or optionally substituted C 1-6 alkyl;
R 13 is H or optionally substituted C 1-6 alkyl; and
R 14 is H or optionally substituted C 1-6 alkyl.
2. The compound according to claim 1 wherein:
R 1 is H, halogen or optionally substituted C 1-6 alkyl;
R 2 is H, halogen or optionally substituted C 1-6 alkyl;
R 3 is H, halogen or optionally substituted C 1-6 alkyl;
R 4 is H, halogen or optionally substituted C 1-6 alkyl;
R 5 is H, halogen or optionally substituted C 1-6 alkyl;
R 6 is optionally substituted C 1-6 alkyl;
R 8 is H, halogen or optionally substituted C 1-6 alkyl;
R 9 is H, halogen or optionally substituted C 1-6 alkyl;
R 10 is H, halogen or optionally substituted C 1-6 alkyl; and
R 11 is H, halogen or optionally substituted C 1-6 alkyl.
3. The compound according to claim 1 wherein:
R 1 is H or optionally substituted C 1-6 alkyl;
R 2 is H or optionally substituted C 1-6 alkyl;
R 3 is H or optionally substituted C 1-6 alkyl;
R 4 is H or optionally substituted C 1-6 alkyl;
R 5 is H or optionally substituted C 1-6 alkyl;
R 6 is C 1-3 alkyl;
R 8 is H or halogen;
R 9 is H or halogen;
R 10 is H or halogen; and
R 11 is H or halogen.
4. The compound according to claim 1 wherein:
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is H;
R 5 is H;
R 6 is methyl, ethyl or n-propyl;
R 8 is H;
R 9 is H or halogen;
R 10 is H or halogen; and
R 11 is H or halogen.
5. The compound according to claim 1 wherein:
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is H;
R 5 is H;
R 6 is methyl, ethyl or n-propyl;
R 8 is H;
R 9 is H or F;
R 10 is H or F; and
R 11 is H or F.
6. The compound according to claim 1 selected from:
1-{2-ethyl-4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-2,6-difluorobenzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-3-fluorobenzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid; and
1-{4-[5-(5-phenyl-1-propyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid.
7. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
8. The pharmaceutical composition according to claim 7 wherein the compound is selected from:
1-{2-ethyl-4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-2,6-difluorobenzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]-3-fluorobenzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-ethyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid;
1-{4-[5-(1-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid; and
1-{4-[5-(5-phenyl-1-propyl-4,5-dihydro-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]benzyl}azetidine-3-carboxylic acid.