AMPK-activating heterocycloalkyloxy(hetero)aryl carboxamide, sulfonamide and amine compounds and methods for using the same
View Patent ↗Disclosed are carboxamide, sulfonamide and amine compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure in which R 1 , R 2 , R 4 , E, T, n 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
“B” represents
in which X is O or S;
E is —C(O);
R 1 is H, —(C 1 -C 4 alkyl) or —C(O)O—(C 1 -C 4 alkyl);
each R 3 is substituted on a benzo or pyrido carbon of the ring system denoted by “B” and is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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 14 is substituted on a non-benzo, non-pyrido carbon of the ring system denoted by “B”, and is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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;
k is 0, 1 or 2;
each R 4 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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;
x is 0, 1, 2, 3 or 4;
the ring system denoted by “A” is heteroaryl or aryl;
each R 5 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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 , —(C 0 -C 6 alkyl)-C(O)R 10 , -halogen, —NO 2 and —CN; and
y is 0, 1, 2, 3 or 4;
Q and G are each independently a bond, —CH 2 —, —C(H)(R 16 )—, —C(R 16 ) 2 — or —S(O) 2 —;
v is 0, 1, 2, 3 or 4;
each R 15 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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 15 on the same carbon optionally combine to form oxo; and
R 17 is Het or Ar,
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 2 )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)-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) and —C(O)O—(C 1 -C 4 alkyl),
each G is independently —(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 , or —S(O) 2 —,
each R 16 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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,
each Ar is an aryl optionally substituted with 1, 2, 3 or 4 optional substituents,
each Het is a heteroaryl optionally substituted with 1, 2, 3 or 4 optional substituents,
each Cak is cycloalkyl optionally substituted with 1, 2, 3 or 4 optional substituents,
each Hca is heterocycloalkyl optionally substituted with 1, 2, 3 or 4 optional substituents, and
each alkyl is optionally substituted with 1, 2, 3 or 4 optional substituents,
in which optional substituents on saturated carbon atoms are selected from —R 60 , halo, —O − M + , ═O, —OR 70 , —SR 70 , —S − M + , ═S, —NR 80 R 80 , ═NR 70 , ═N—OR 70 , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —SO 2 R 70 , —SO 2 O − M + , —SO 2 OR 70 , —OSO 2 R 70 , —OSO 2 O − M + , —OSO 2 OR 70 , —P(O)(O − ) 2 (M + ) 2 , —P(O)(OR 70 )O − M + , —P(O)(OR 70 ) 2 , —C(O)R 70 , —C(S)R 70 , —C(NR 70 )R 70 , —C(O)O − M + , —C(O)OR 70 , —C(S)OR 70 , —C(O)NR 80 R 80 , —C(NR 70 )NR 80 R 80 , —OC(O)R 70 , —OC(S)R 70 , —OC(O)O − M + , —OC(O)OR 70 , —OC(S)OR 70 , —NR 70 C(O)R 70 , —NR 70 C(S)R 70 , —NR 70 CO 2 − M + , —NR 70 CO 2 R 70 , —NR 70 C(S)OR 70 , —NR 70 C(O)NR 80 R 80 , —NR 70 C(NR 70 )R 70 and —NR 70 C(NR 70 )NR 80 R 80 ;
optional substituents on unsaturated carbon atoms are selected from —R 60 , halo, —O − M + , —OR 70 , —SR 70 , —S − M + , —NR 80 R 80 , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —SO 2 R 70 , —SO 3 − M + , —SO 3 R 70 , —OSO 2 R 70 , —OSO 3 − M + , —OSO 3 R 70 , —PO 3 −2 (M + ) 2 , —P(O)(OR 70 )O − M + , —P(O)(OR 70 ) 2 , —C(O)R 70 , —C(S)R 70 , —C(NR 70 )R 70 , —CO 2 − M + , —CO 2 R 70 , —C(S)OR 70 , —C(O)NR 80 R 80 , —C(NR 70 )NR 80 R 80 , —OC(O)R 70 , —OC(S)R 70 , —OCO 2 − M + , —OCO 2 R 70 , —OC(S)OR 70 , —NR 70 C(O)R 70 , —NR 70 C(S)R 70 , —NR 70 CO 2 − M + , —NR 70 CO 7 R 70 , —NR 70 C(S)OR 70 , —NR 70 C(O)NR 80 R 80 , —NR 70 C(NR 70 )R 70 and —NR 70 C(NR 70 )NR 80 R 80 , and
optional substitutents on nitrogen atoms are selected from —R 60 , —O − M + , —OR 70 , —SR 70 , —S − M + , —NR 80 R 80 , trihalomethyl, —CF 3 , —CN, —NO, —NO 2 , —S(O) 2 R 70 , —S(O) 2 O − M + , —S(O) 2 OR 70 , —OS(O) 2 R 70 , —OS(O) 2 O − M + , —OS(O) 2 OR 70 , —P(O)(O − ) 2 (M + ) 2 , —P(O)(OR 70 )O − M + , —P(O)(OR 70 )(OR 70 ), —C(O)R 70 , —C(S)R 70 , —C(NR 70 )R 70 , —C(O)OR 70 , —C(S)OR 70 , —C(O)NR 80 R 80 , —C(NR 70 )NR 80 R 80 , —OC(O)R 70 , —OC(S)R 70 , —OC(O)OR 70 , —OC(S)OR 70 , —NR 70 C(O)R 70 , —NR 70 C(S)R 70 , —NR 70 C(O)OR 70 , —NR 70 C(S)OR 70 , —NR 70 C(O)NR 80 R 80 , —NR 70 C(NR 70 )R 70 and —NR 70 C(NR 70 )NR 80 R 80 ,
wherein
each R 60 is H, alkyl or heteroalkyl;
each R 70 is H, alkyl or heteroalkyl;
each R 80 is H, alkyl or heteroalkyl or alternatively, two R 80′ s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C 1 -C 3 alkyl substitution; and
each M + is a counterion with a net single positive charge.
2. A compound according to claim 1 , wherein X is O.
3. A compound according to claim 1 , wherein no R 14 is substituted on the furano or thieno carbon.
4. A compound according to claim 1 , wherein R 14 is substituted on the furano or thieno carbon, and wherein 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, in which 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 9 -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).
5. A compound according to claim 1 , wherein each R 16 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 , alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 16 on the same carbon optionally combine to form an oxo, in which 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).
6. A compound according to claim 1 , wherein Q is —CH 2 —, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—.
7. A compound according to claim 1 , wherein each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), 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, in which 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 9 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl).
8. A compound according to claim 1 , wherein the ring system denoted by “A” is an aryl or a heteroaryl.
9. A compound according to claim 1 , wherein the ring system denoted by “A” is a phenyl.
10. A compound according to claim 1 , wherein G is —CH 2 — or —CH(CH 3 —.
11. A compound according to claim 1 , wherein G is —C(O)— or —S(O) 2 —.
12. A compound according to claim 1 , wherein 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, in which 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 9 -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).
13. A compound according to claim 1 , wherein each R 4 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 4 optionally combine to form oxo, in which each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl), —(C 1 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).
14. A compound according to claim 1 , wherein each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 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, in which 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).
15. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or —CO—O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
16. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or -CO-O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
17. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or -CO-O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
18. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or —CO—O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
19. A compound according to claim 1 , having the structural formula
20. A compound according to claim 1 , having the structural formula
in which R 25 is selected from halo, cyano, —(C 1 -C 4 haloalkyl), —O—(C 1 -C 4 haloalkyl), —(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl), —C(O)—(C 0 -C 4 alkyl), —C(O)O—(C 0 -C 4 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 4 alkyl), NO 2 and —C(O)—Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, in which no alkyl or haloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.
21. A compound according to claim 1 , having the structural formula
in which Q is —C(O)— or —S(O) 2 —.
22. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or —CO—O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
23. A compound according to claim 1 , having the structural formula
in which R 27 is selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(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)-(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R 29 is —H, —(C 1 -C 4 alkyl) or —CO—O—(C 1 -C 4 alkyl) in which no (C 1 -C 4 alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R 27 and R 29 together with the nitrogen to which they are bound form Hca.
24. A compound according to claim 1 , having the structural formula
25. A compound according to claim 1 , wherein the compound is
tert-butyl 4-(3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate;
3-methyl-N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(3-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
3-methyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
5-(1-(4-cyanobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
tert-butyl 4-(N-methyl-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate;
N-methyl-N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-methyl-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-N-methyl-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-methyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(3-cyanobenzyl)piperidin-4-yl)-N-methyl-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-N-methyl-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-isonicotinoylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-isonicotinoylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-methyl-N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-(1-isonicotinoylpiperidin-4-yl)-N-methyl-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
N-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)—N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)—N-(1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)—N-(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)—N-(1-isonicotinoylpyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(R)—N-(1-(pyridin-3-ylsulfonyl)pyrrolidin-3-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(pyrrolidin-3-yl)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide;
(S)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-isonicotinoylpiperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylbenzyl)piperidin-4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-isonicotinoylpiperidin-4-yl)benzofuran-2-carboxamide;
5-(1-(4-carbamoylphenyl)piperidin-4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)benzofuran-2-carboxamide, formate salt;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-chlorophenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(3-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide; or
3-chloro-N-(1-isonicotinoylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide.
26. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound according to claim 1 .
27. 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 .