AMPK-activating heterocyclic compounds and methods for using the same

1. A compound having the structural formula

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

0 or 1 of D 1 , D 2 and D 3 is N, with the others independently being CH or C substituted by J or one of the w R 3 ;

E is —R 2 , —C(O)NR 1 R 2 , —NR 1 R 2 or —NR 1 C(O)R 2 , in which R 1 and R 2 together with the nitrogen to which they are bound form Hca, or R 1 is H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) or —C(O)O—(C 1 -C 4 alkyl), and R 2 is —C(O)Hca, —(C 0 -C 3 alkyl)-Ar, —(C 0 -C 3 alkyl)-Het, —(C 0 -C 3 alkyl)-Cak or —(C 0 -C 3 alkyl)-Hca;

each R 3 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(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)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

w is 0, 1, 2 or 3;

each R 4 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(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)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 4 on the same carbon optionally combine to form oxo, and two R 4 on different carbons optionally combine to form a —(C 0 -C 4 alkylene)- bridge;

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

J is absent, —C(O)—, —NR 13 —, —NR 13 C(O)- or —C(O)NR 13 —, in which R 13 is selected from —H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl);

the ring system denoted by “B” is absent, arylene, heteroarylene,

wherein

each of Y 1 and Y 2 is N, C or CH, provided that at least one of Y and Y 2 is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

wherein Y 1 is N or C and Y 2 is N, C or CH, provided that at least one of Y 1 and Y 2 is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;

T is H, —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-R 23 in which R 23 is Het or Ar and in which one or more non-adjacent carbons of the alkyl is optionally replaced by —O— or —S—, —(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)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 or

wherein

Q is —O—(C 0 -C 3 alkyl)-, —S(O) 2 —, -L- or (C 0 -C 3 alkyl)-, in which each carbon of the —(C 0 -C 3 alkyl)- is optionally and independently substituted with one or two R 16 , in which each R 16 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(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)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and optionally two of R 16 on the same carbon combine to form oxo;

the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl;

each R 5 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(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)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, N 3 , —SF 5 , —NO 2 and —CN; and

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

in which

each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —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 6 , R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(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), —(C 0 -C 6 alkyl)-C(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), —C(O)—(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl),

each Ar is an optionally substituted aryl,

each Het is an optionally substituted heteroaryl,

each Cak is an optionally substituted cycloalkyl,

each Hca is an optionally substituted heterocycloalkyl, and

each alkyl is optionally substituted.

2. The compound according to claim 1 , having the structural formula

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

R 1 is H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) or —C(O)O—(C 1 -C 4 alkyl);

G is —CH 2 —, —C(O)—, —S(O) 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —O—, —C(O)—NH—, —C(O)—NH—CH 2 —, —CH 2 CH 2 —, a single bond, —OCH 2 —, CH 2 CH 2 O—, —CH(COOMe)- or —CH(COOEt)-;

R 17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , —N 3 , —SF 5 , -halogen, —NO 2 and —CN;

each R 3 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

w is 0, 1, 2 or 3;

Q is a single bond, —CH 2 —, —CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 —, —O—, —CHF—, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O) 2 —;

the ring system denoted by “A” is monocyclic heteroaryl or phenyl;

each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 1 , -halogen, —N 3 , —SF 5 , —NO 2 and —CN; and

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

in which

each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —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 2 alkyl), —(C 1 -C 2 haloalkyl), —(C 0 -C 2 alkyl)-L-(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-NR 9 (C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 -C 2 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl), and

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

3. The compound according to claim 2 , wherein Y 1 is N.

4. The compound according to claim 2 , wherein Y 1 is CH.

5. The compound according to claim 3 , wherein Q is —O—.

6. The compound according to claim 2 , wherein Q is —C(O)—, —S(O) 2 —, —CH 2 — or a single bond.

7. The compound according to claim 2 , wherein the

group is

monocyclic heteroaryl substituted with 0, 1 or 2 R 30 ; or monocyclic heteroarylmethyl-, in which the heteroaryl is substituted with 0, 1 or 2 R 30 ; in which each R 30 is independently selected from —F, —Cl, —Br, —C(O)—NH 2 , C(O)N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), NHCO(C 1 -C 2 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), NH 2 , —SH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, —NO 2 , —SF 5 , —N 3 , —(NH) 0-1 SO 2 R 33 , —(NH) 0-1 COR 33 and cyano, in which each R 33 is (C 1 -C 2 alkyl) or (C 1 -C 2 haloalkyl).

8. The compound according to claim 2 , wherein 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.

9. The compound according to claim 2 , wherein w is 0.

10. The compound according to claim 2 , having the structural formula

11. The compound according to claim 2 , having the structural formula

12. The compound according to claim 2 , wherein G is —CH 2 — or —C(O)—.

13. The compound according to claim 2 , wherein R 17 is phenyl substituted with 0, 1 or 2 R 30 , and the

moiety is phenyl substituted with 0, 1 or 2 R 30 , wherein each R 30 is independently selected from halogen, (C 1 -C 2 alkoxy), —(C 1 -C 2 haloalkoxy), —SH, —S(C 1 -C 2 alkyl), —S(C 1 -C 2 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), —C(O)OH, C(O)O(C 1 -C 2 alkyl), —(NH) 0-1 SO 2 R 33 , —(NH) 0-1 COR 33 , in which each R 33 is (C 1 -C 2 alkyl) or (C 1 -C 2 haloalkyl).

14. The compound according to claim 2 , wherein the -G-R 17 moiety is

monocyclic heteroaryl substituted with 0, 1 or 2 R 30 ; monocyclic heteroarylmethyl- in which the heteroaryl is substituted with 0, 1 or 2 R 30 ; or monocyclic heteroaryloxy- in which the heteroaryl is substituted with 0, 1 or 2 R 30 ; in which each R 30 is independently selected from halogen, (C 1 -C 2 alkoxy), —(C 1 -C 2 haloalkoxy), —SH, —S(C 1 -C 2 alkyl), —S(C 1 -C 2 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), —C(O)—NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , —C(O)OH, C(O)O(C 1 -C 2 alkyl), —(NH) 0-1 SO 2 R 33 , —(NH) 0-1 COR 33 , in which each R 33 is (C 1 -C 2 alkyl) or (C 1 -C 2 haloalkyl).

15. The compound according to claim 2 , wherein

G is —CH 2 —, —C(O)—, or —S(O) 2 —;

R 17 is phenyl or monocyclic heteroaryl substituted with 0, 1 or 2 R 3 ;

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;

w is 0 or 1;

Y 1 is N or CH;

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

the ring system denoted by “A” is phenyl or monocyclic heteroaryl; and

y is 0, 1, 2 or 3;

in which

each R 5 and R 30 is independently selected from halogen, (C 1 -C 2 alkoxy), —(C 1 -C 2 Haloalkoxy), —SH, —S(C 1 -C 2 alkyl), —S(C 1 -C 2 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), —C(O)OH, C(O)O(C 1 -C 2 alkyl), —(NH) 0-1 SO 2 R 33 , —(NH) 0-1 COR 33 , in which each R 33 is (C 1 -C 2 alkyl) or (C 1 -C 2 haloalkyl).

16. A method comprising

contacting a cell with an amount of a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.

17. The method of claim 16 , wherein the amount is an amount effective to activate the AMPK pathway in the cell.

18. The method of claim 16 , wherein the cell is in a subject and contacting the cell with the amount of the compound or pharmaceutically acceptable salt or N-oxide thereof comprises administering to the subject the amount of the compound or pharmaceutically acceptable salt or N-oxide thereof.

19. The method of claim 18 , wherein the amount is an amount effective to treat B type II diabetes in the subject, treat atherosclerosis or cardiovascular disease in the subject, or treat intermittent claudication in the subject.

20. The method of claim 18 , wherein the amount is an amount effective to improve exercise efficiency in the subject.