5- or 6-substituted benzofuran-2-carboxamide compounds and methods for using them

1. A compound having the structural formula

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 a bond, —CH 2 —, —C(O)—, —CH(CH 3 )—, —O— or —S(O) 2 —;

each R 15 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, and two R 15 on the same carbon optionally combine to form oxo; and

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

R 17 is phenyl optionally substituted with 0, 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 , -halogen, —SF 5 , —NO 2 and —CN;

R 3 is a substituent on a benzo carbon of the benzofuran ring system, which substituent 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 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

R 14 is 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;

Q is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; —O— or —CH(CH 3 )—;

the ring system denoted by “A” is 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 10 , -halogen, —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 —, —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 2 )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) and —C(O)O—(C 1 -C 4 alkyl),

or a pharmaceutically-acceptable salt thereof.

2. A compound according to claim 1 , wherein the

moiety is

wherein y3 is 0, 1, 2 or 3, and each R 36 is independently selected from halo, cyano, —(C 1 -C 3 haloalkyl), —O—(C 1 -C 2 haloalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl), —S(O) 2 (C 1 -C 2 alkyl), —SF 5 , and NO 2 .

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

4. A compound according to claim 1 , having the formula

in which R 25 is selected from halo, cyano, —(C 1 -C 3 haloalkyl), —O—(C 1 -C 2 haloalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl), and NO 2 .

5. A compound according to claim 1 , wherein R 1 is H.

6. A compound according to claim 1 , wherein (R 3 ) 0-1 is (R 3 ) 0 .

7. A compound according to claim 1 , wherein v is 0.

8. A compound according to claim 1 , wherein (R 14 ) 0-1 is (R 14 ) 0 .

9. A compound according to claim 1 , wherein F (0-1) is F (0) .

10. A compound according to claim 1 , wherein (R 3 ) 0-1 is (R 3 ) 0 , (R 14 ) 0-1 is (R 14 ) 0 , and v is 0.

11. A compound according to claim 10 , having the structural formula

12. A compound according to claim 4 , having the structural formula

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

14. A compound according to claim 1 , wherein Q is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; or —CH(CH 3 )—.

15. A compound according to claim 1 , selected from

5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(6-(4-cyanophenoxy)pyridin-3-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;

5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)benzofuran-2-carboxamide;

N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)benzofuran-2-carboxamide;

5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(4-methoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)benzofuran-2-carboxamide;

5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;

N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

and

N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

17. A method for

activating the AMPK pathway in a cell

comprising contacting the cell with an effective amount of a compound or salt of claim 1 .