5-pyridinone substituted indazoles
View Patent ↗Various 5-substituted 1-substituted indazoles are described, as are pharmaceutical compositions containing these compounds and methods of treatment of diseases using these compounds. Other embodiments are also described.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof
wherein
R 5 is H or lower alkyl which is optionally substituted by up to 3 halo atoms;
m and p are each 0 or 1, provided that m+p is at least 1;
R 3 and R 4 are each independently selected from H, —OH and lower alkyl;
R is —OH, alkoxy, hydroxyalkoxy, alkoxyalkoxy, or —NR 1 R 2 , wherein (i) R 1 and R 2 are each independently selected from H and optionally substituted alkyl, or (ii) R 1 and R 2 , together with the N atom to which they are attached, form a 4 to 7-membered optionally substituted non-aromatic ring system which optionally contains 1 or 2 heteroatoms in addition to the N atom shown, or (iii) NR 1 R 2 , taken together with CR 3 R 4 and, if present, the CH 2 between NR 1 R 2 and CR 3 R 4 , forms a 5 to 10-membered optionally substituted non-aromatic ring system which optionally contains 1 or 2 heteroatoms in addition to the N atom shown;
X is selected from —O—, —NH—, —N-alkyl-, and —CH 2 —;
R 6 is selected from H and lower alkyl;
or X and CHR 6 are taken together to form —CH═CH—;
Y is selected from C 3-10 non-aromatic hydrocarbon and
wherein B is an aromatic hydrocarbon or aromatic heterocycle, and R 7 , R 8 and R 9 are each independently selected from H, —OH, —O-alkyl, -alkyl, halo, —S(O)-alkyl, —SO 2 -alkyl, —CF 3 , —CN and phenyl, wherein the compound is not in the form of a solvate or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R is selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, 2-methylpiperidin-1-yl, 3-fluoropyrrolidin-1-yl, dimethylamino, hydroxyl, diisopropylamino, 3,3-difluoropiperidin-1-yl, (2R,6S)-2,6-dimethylpiperidin-1-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl, piperazin-1-yl, 3,5-dimethylmorpholin-4-yl, 4-acetylpiperazin-1-yl, 4,4-difluoropiperidin-1-yl, piperazin-2-one-4-yl, (2R,5R)-2,5-dimethylpyrrolidin-1-yl, isobutylamino, 2,2,6,6-tetramethylpiperidin-1-yl, 2,2-dimethylmorpholin-4-yl, (S)-3-methoxypyrrolidin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 4-fluoropiperidin-1-yl, (S)-3-fluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-hydroxypiperidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (R)-2-methoxymethylpyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxymethylpyrrolidin-1-yl, (S)-2-hydroxymethylpyrrolidin-1-yl, and cyclopentylamino.
3. A compound according to claim 1 wherein R is NR 1 R 2 which, taken together with CR 3 R 4 and, if present, the CH 2 between NR 1 R 2 and CR 3 R 4 , is a moiety selected from morpholin-2-yl, (R)-pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, 4-(R)-hydroxypyrrolidin-2-yl, 4,5-dihydroimidazol-2-yl, (S)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-d]midazol-2-yl, 1-methyl-4,5-dihydro-1H-imidazol-2-yl, and 4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl.
4. A compound according to claim 1 , wherein m+p is 1.
5. A compound according to claim 1 , wherein m+p is 2.
6. A compound according to claim 1 , wherein R 3 and R 4 are both H.
7. A compound according to claim 1 , wherein R 3 and R 4 are both methyl.
8. A compound according to claim 1 , wherein one of R 3 and R 4 is H and the other of R 3 and R 4 is hydroxyl.
9. A compound according to claim 1 , wherein R 6 is H.
10. A compound according to claim 1 , wherein R 6 is lower alkyl.
11. A compound according to claim 10 wherein R 6 is methyl.
12. A compound according to claim 1 , wherein X is O.
13. A compound according to claim 1 , wherein X is NH.
14. A compound according to claim 1 , wherein X is N-alkyl.
15. A compound according to claim 1 , wherein X is CH 2 .
16. A compound according to claim 1 , wherein X and R 6 are taken together to form —CH═CH—.
17. A compound according to claim 1 , wherein Y is a C 3-10 non-aromatic hydrocarbon.
18. A compound according to claim 17 wherein Y is selected from cyclohexane, —CH 2 C(CH 3 ) 3 , cycloheptane, cyclopropyl, adamant-1-yl, and cyclopentyl.
19. A compound according to claim 1 , wherein Y is
20. A compound according to claim 19 wherein B is selected from phenyl, pyridinyl and naphthyl.
21. A compound according to claim 20 wherein B is selected from pyridin-2-yl, pyridin-3-yl and naphth-2-yl.
22. A compound according to claim 19 , wherein R 7 , R 8 and R 9 are selected from H, —OH, —O-alkyl, -alkyl, -halo, —CF 3 , —CN and phenyl.
23. A compound according to claim 19 wherein B, R 7 , R 8 and R 9 taken together are selected from phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 4-methoxyphenyl, naphthyl, 4-fluorophenyl, pyridin-2-yl, 5-chloropyridin-2-yl, 4-cyanophenyl, pyridin-3-yl, biphenyl-4-yl, and 3,5-difluorophenyl.
24. A compound according to claim 1 , wherein R 5 is H.
25. A compound according to claim 1 , wherein R 5 is lower alkyl which is optionally substituted by up to three halo atoms.
26. A compound according claim 25 wherein R 5 is methyl.
27. A compound according to claim 25 wherein R 5 is —CF 3 .
28. A compound according to claim 1 wherein m is 0, p is 1, R is pyrrolidin-1-yl, R 6 is H, and B is phenyl.
29. A compound according to claim 1 wherein the compound is selected from:
30. A compound according to claim 1 , wherein the compound is in a pharmaceutically acceptable salt form.
31. A compound according to claim 30 wherein the salt is an HCl salt.
32. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent therefore.
33. A method of treating obesity, comprising administering to a patient in need of obesity reduction an obesity-reducing effective amount of a compound according to claim 1 , wherein treating does not include prevention.
34. A method of treating anxiety, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 , wherein treating does not include prevention.
35. A method of treating depression, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 , wherein treating does not include prevention.
36. A method of treating non-alcoholic fatty liver disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 , wherein treating does not include prevention.