Di and trifluoro-triazolo-pyridines anti-inflammatory compounds
The present invention relates to novel triazolo-pyridines of the formula I wherein R 1 is fluoro; s is an integer from two to three; R 2 is (C 3 -C 6 )cycloalkyl optionally substituted by one or two moieties independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkyl-(C═O)—O—; or R 2 is (C 1 -C 6 )alkyl optionally substituted by one or two moieties independently selected from the group consisting of halo, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkyl-(C═O)—O—; with the proviso that said compound of formula I cannot be 6-[4-(2,4-Difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine; or 6-[4-(3,4-Difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine; to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
1. A compound of the formula
wherein R 1 is fluoro;
s is an integer from two to three;
R 2 is (C 3 -C 6 )cycloalkyl optionally substituted by one or two moieties independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkyl-(C═O)—O—;
or R 2 is (C 1 -C 6 )alkyl optionally substituted by one or two moieties independently selected from the group consisting of halo, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkyl-(C═O)—O—;
with the proviso that said compound of formula I cannot be
6-[4-(2,4-difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine; or
6-[4-(3,4-difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R 2 is optionally substituted (C 3 -C 6 )cycloalkyl.
3. A compound according to claim 2 wherein R 2 is optionally substituted cyclopropyl, or cyclobutyl.
4. A compound according to claim 3 , wherein the compound has the formula
5. A compound according to claim 3 , wherein the compound has the formula
6. A compound according to claim 3 , wherein the compound has the formula
7. A compound according to claim 3 , wherein R 2 is (C 3 -C 6 )cycloalkyl.
8. A compound according to claim 2 , wherein R 2 is (C 3 -C 6 )cycloalkyl substituted with one or two (C 1 -C 3 )alkyl.
9. A compound according to claim 2 , wherein R 2 is (C 3 -C 6 )cycloalkyl substituted with one or two methyl groups.
10. A compound according to claim 2 , wherein R 2 is (C 3 -C 6 )cycloalkyl substituted with one (C 1 -C 3 )alkyl.
11. A compound according to claim 2 , wherein R 2 is (C 3 -C 6 )cycloalkyl substituted with one methyl, ethyl or propyl group.
12. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
3-Cyclobutyl-6-[4-(2,5-difluoro-phenyl)-oxa-zol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine;
6-[4-(2,4-Difluoro-phenyl)-oxazo-1-5-yl]-3-(1-methyl-cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine;
6-[4-(2,5-Difluoro-phenyl)-oxazol-5-yl]-3-(1-methyl-cyclopropyl)-[1,2,4]t-riazolo[4,3-a]pyridine;
3-Cyclopropyl-6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine; and
3-Cyclopropyl-6-[4-(2,4-difluoro-p-henyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine.
13. A compound according to claim 2 , wherein said compound is selected from the group consisting of:
3-Cyclopropyl-6-[4-(2,4,5-trifluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine; and
3-(1-Methyl-cyclopropyl)-6-[4-(2,4,5-trifluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine.
14. A compound according to claim 1 , wherein R 2 is (C 1 -C 6 )alkyl optionally substituted with one or two groups independently selected from halo, hydroxy, and (C 1 -C 6 )alkoxy.
15. A compound according to claim 1 , wherein R 2 is optionally substituted ethyl, isopropyl, isobutyl, t-butyl or sec-butyl.
16. A compound according to claim 14 , wherein the compound has the formula 59.
17. A compound according to claim 14 , wherein the compound has the formula 60.
18. A compound according to claim 14 , wherein the compound has the formula 61.
19. A compound according to claim 14 , wherein R 2 is (C 1 -C 6 )alkyl, optionally substituted with halo or hydroxy.
20. A compound according to claim 14 , wherein R 2 is ethyl, isopropyl, isobutyl, t-butyl or sec-butyl; optionally substituted with a halo or hydroxy.
21. A compound according to claim 14 , wherein R 2 is (C 1 -C 4 )alkyl.
22. A compound according to claim 14 , wherein said compound is 3-tert-butyl-6-[4-(2,4-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine.
23. A compound according to claim 14 , wherein said compound is 6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine.
24. A compound according to claim 14 , wherein said compound is 3-tert-butyl-6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine.
25. A compound according to claim 14 , wherein said compound is 3-tert-butyl-6-[4-(2,4,5-trifluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4-,3-a]pyridine.
26. A compound according to claim 14 , wherein said compound is 3-isopropyl-6-[4-(2,4,5-trifluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,-3-a]pyridine.
27. A compound according to claim 14 , wherein said compound is selected from the group consisting of:
3-Isopropyl-6-[4-(2,3,4-trifluoro-phenyl)-o-xazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine;
3-Isopropyl-6-[4-(2,3,5-triflu-oro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine;
3-Isopropyl-6-[4-(2,4,6-trifluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo[4,-3-a]pyridine; and
3-Isopropyl-6-[4-(3,4,5-trifluoro-phenyl)-oxazol-5-yl]-[-1,2,4]triazolo[4,3-a]pyridine.
28. A method of treating arthritis in a mammal comprising administering to said mammal an amount of a compound according to claim 1 effective in treating such a condition.
29. A pharmaceutical composition comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.