N-substituted-heterocycloalkyloxybenzamide compounds and methods of use

1. A compound having the structural formula

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

each R 3 is independently selected from halo, cyano, —(C 1 -C 4 fluoroalkyl), —O—(C 1 -C 4 fluoroalkyl), acyl, carboxylate, carboxamide and nitro;

w is 0, 1, 2 or 3;

each R 4 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 fluoroalkyl), -halogen, —NO 2 and —CN, and two R 4 on the same carbon optionally combine to form oxo;

x is 0, 1, 2, 3 or 4;

each R 5 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 fluoroalkyl), —(C 0 -C 6 alkyl)-L-R 7 , —(C 0 -C 6 alkyl)-NR 8 R 9 , —(C 0 -C 6 alkyl)-OR 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

y is 0, 1, 2, 3 or 4;

G is a single bond, —CH 2 — or —C(O)—;

v is 0, 1, 2, 3 or 4;

each R 15 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 fluoroalkyl), -halogen, —NO 2 and —CN, and two R 15 on the same carbon optionally combine to form oxo; and

R 17 is optionally-substituted aryl;

in which

each L is independently selected

from —NR 9 C(O)O—, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —NR 9 C(O)—, —NR 9 C(S)O—, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —NR 9 C(S)—, —OC(O)NR 9 —, —SC(O)NR 9 —, —C(S)NR 9 —, —OC(S)NR 9 —, —SC(S)NR 9 —, —C(S)NR 9 —, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 9 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 — and —NR 9 SO 2 NR 9 —,

each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 fluoroalkyl), —(C 0 -C 6 alkyl)-L-(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-NR 9 (C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-O—(C 0 -C 6 alkyl) and —(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl),

each R 9 is independently selected from —H, —(C 1 -C 4 alkyl) and —C(O)—(C 1 -C 4 alkyl), and

each R 16 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 fluoroalkyl), and two R 16 on the same carbon optionally combine to form oxo;

provided that the compound is not

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-benzylpiperidin-4-yloxy)-3-methoxybenzamide; or

N-(1-benzylpiperidin-4-yl)-3-(1-benzylpiperidin-4-yloxy)benzamide.

2. A compound according to claim 1 , wherein y is 0.

3. A compound according to claim 1 , wherein y is 1.

4. A compound according to claim 1 , wherein y is 1, 2, 3 or 4 and at least one R 5 is halo, cyano, trifluoromethyl or trifluoromethoxy.

5. A compound according to claim 1 , wherein y is 1 and R 5 is selected from the group consisting of halo, cyano, —(C 1 -C 4 fluoroalkyl), —O—(C 1 -C 4 fluoroalkyl), carboxylate, carboxamide and nitro.

6. A compound according to claim 1 , wherein the compound has the structural formula

7. A compound according to claim 1 , wherein the compound has the structural formula

8. A compound according to claim 1 , wherein G is —CH 2 —.

9. A compound according to claim 1 , wherein G is —C(O)—.

10. A compound according to claim 1 , wherein R 17 is phenyl substituted with an electron withdrawing group.

11. A compound according to claim 1 , wherein R 17 is unsubstituted phenyl.

12. A compound according to claim 1 , wherein w is 0.

13. A compound according to claim 1 , wherein w is 1.

14. A compound according to claim 1 , wherein x is 0 and v is 0.

15. A compound according to claim 1 , wherein

w is 0 or 1;

x is 0;

v is 0;

y is 0, 1, 2 or 3; and

G is —CH 2 — or —CO—.

16. A compound according to claim 15 , having the structural formula

17. A compound according to claim 1 , having the structural formula

in which

R 3 is H or halo;

R 11 is H, halo, cyano, or a carboxylate; and

R 12 and R 13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

18. A compound according to claim 1 , the having structural formula

in which

R 11 is H, halo, cyano, or a carboxylate; and

R 12 and R 13 are independently H, trifluoromethyl, trifluoromethoxy, halo or cyano.

19. A compound according to claim 1 , wherein the compound is selected from the group consisting of:

N-(1-benzylpiperidin-4-yl)-4-(1-benzylpiperidin-4-yloxy)-3-chlorobenzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(4-tert-butylbenzyl)piperidin-4-yloxy)-3-chlorobenzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-fluorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(4-tert-butylbenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(2-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

4-(1-(4-tert-butylbenzyl)piperidin-4-yloxy)-3-fluoro-N-(1-phenylpiperidin-4-yl)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(4-cyanobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(4-methylbenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-2-chloro-4-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-fluoro-4-(1-(4-fluorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3,5-dichloro-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(4-chlorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-chlorobenzyl)piperidin-4-yloxy)benzamide;

3-chloro-4-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzamide;

3-chloro-N-(1-(4-fluorobenzyl)piperidin-4-yl)-4-(1-(4-methylbenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-(4-chlorobenzyl)piperidin-4-yl)-4-(1-(4-cyanobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-(4-chlorobenzyl)piperidin-4-yl)-4-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-(4-chlorobenzyl)piperidin-4-yl)-4-(1-(4-chlorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-(4-chlorobenzyl)piperidin-4-yl)-3-fluoro-4-(1-(4-methylbenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3,5-dichloro-4-(1-(4-chlorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3,5-dichloro-4-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3,5-dichloro-4-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzamide;

N-(1-(4-chlorobenzyl)piperidin-4-yl)-4-(1-(3,4-dichlorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-(3,4-dichlorobenzyl)piperidin-4-yloxy)-3-fluorobenzamide;

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(3,4-dichlorobenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-3-(1-(3-cyanobenzyl)piperidin-4-yloxy)benzamide;

or a pharmaceutically acceptable salt or N-oxide thereof.

20. A pharmaceutical composition comprising a compound according to claim 1 or a compound selected from the group consisting of

N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzamide;

N-(1-benzylpiperidin-4-yl)-4-(1-benzylpiperidin-4-yloxy)-3-methoxybenzamide; and

N-(1-benzylpiperidin-4-yl)-3-(1-benzylpiperidin-4-yloxy)benzamide,

or a pharmaceutically acceptable salt or N-oxide thereof.

21. A method for activating the AMPK pathway in a cell, the method comprising contacting the cell with an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.

22. A method for reducing triglyceride levels in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described in claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.

23. A method for treating type II diabetes in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described in claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.

24. A method for treating atherosclerosis in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described in claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.