AMPK-activating heterocyclic compounds and methods for using the same
Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure wherein E, J, T, the ring system denoted by “B”, T, R 3 , R 4 , w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.
1. A compound having the structural formula:
or a pharmaceutically acceptable salt or N-oxide thereof, wherein
one of X 1 and X 2 is N, and the others are CH or C substituted by one of the w R 3 ;
Y is N or CH;
R 1 is H;
G is —CH 2 —, —C(O)— or S(O) 2 —;
R 17 is phenyl substituted with 0, 1 or 2 substituents each independently selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH 2 , —OH, methoxy, ethoxy, trifluoromethoxy, —SO 2 Me, -halogen, —NO 2 , N 3 , —SF 5 , and —CN;
w is 0, 1 or 2;
each R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH 2 , —OH, methoxy, ethoxy, trifluoromethoxy, —SO 2 Me, -halogen, —NO 2 and —CN;
Q is a single bond, —CH 2 —, —O—, —C(O)— or —S(O) 2 —;
the ring system denoted by “A” is phenyl;
each R 5 is independently selected from methyl, trifluoromethyl, acetyl, methoxy, trifluoromethoxy, -halogen, —NO 2 , N 3 , —SF 5 , and —CN; and
y is 0, 1 or 2.
2. The compound according to claim 1 , wherein Y is N.
3. The compound according to claim 1 , wherein Y is CH.
4. The compound according to claim 3 , wherein Q is —O—.
5. The compound according to claim 1 , wherein Q is —C(O)— or —S(O) 2 —.
6. The compound according to claim 1 , wherein Q is —CH 2 —.
7. The compound according to claim 1 , wherein Q is a single bond.
8. The compound according to claim 1 , wherein y is other than zero and at least one R 5 is halogen, CN, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, —N 3 , —SF 5 or NO 2 .
9. The compound according to claim 1 , wherein w is 0.
10. The compound according to claim 1 , having the structural formula:
11. The compound according to claim 1 having the structural formula:
12. The compound according to claim 1 , wherein the
13. The compound according to claim 1 , wherein the
14. A compound according to claim 1 , wherein G is —CH 2 —.
15. A compound according to claim 1 , wherein G is —C(O)—.
16. A compound according to claim 1 , wherein the compound is
N-(cis-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide;
N-(cis-1-(4-chlorobenzyl)-3-fluoropiperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide;
N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1-carbonyl)picolinamide;
N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1-carbonyl)picolinamide;
N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)picolinamide;
N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)picolinamide;
N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((trans)-3-fluoro-1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((trans)-1-(4-cyano-3-fluorobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((3R,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((3S,4S)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
N-((cis)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide; or
N-((cis)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide;
or a pharmaceutically acceptable salt or N-oxide thereof.
17. A pharmaceutical composition comprising:
at least one pharmaceutically acceptable carrier, diluent or excipient; and
a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
18. A method for treating type II diabetes in a subject, the method comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
19. A method for treating atherosclerosis in a subject, the method comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
20. A method for improving exercise efficiency in a subject, the method comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
21. A method for treating intermittent claudication, the method comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.