Carboxamide compounds and methods for using the same
View Patent ↗Disclosed are carboxamide 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 3 , R 4 , D, J, Z, T, p, q, 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
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);
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;
v is 0, 1, 2, 3 or 4;
G is —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 ;
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 , -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;
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 groups optionally combine to form an oxo;
x is 0, 1, 2, 3 or 4;
Q is —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 ;
the ring denoted by “A” is heteroaryl or aryl;
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;
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 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),
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), and
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 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 1 , -halogen, —NO 2 and —CN, and two R 16 on the same carbon optionally combine to form an oxo.
2. A compound according to claim 1 , wherein R 1 is H.
3. A compound according to claim 1 , wherein G is —CH 2 —, —CH(CH 3 )—, —C(O)—, —S(O) 2 — or —C(O)—NH—.
4. A compound according to claim 1 , wherein G is —CH 2 — or —C(O)—.
5. A compound according to claim 1 , wherein v is 0.
6. A compound according to claim 1 , wherein R 17 is phenyl 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 , -halogen, —NO 2 and —CN.
7. A compound according to claim 1 , wherein v is 0.
8. A compound according to claim 1 , wherein x is 0.
9. A compound according to claim 1 , wherein w is 0, x is 0 and v is 0.
10. A compound according to claim 1 , wherein Q is a single bond, —CH 2 —, —CH(CH 3 )—, —C(O)— or —S(O) 2 —.
11. A compound according to claim 1 , wherein Q is a single bond, —CH 2 —, —CH(CH 3 )—, —C(O)— or —S(O) 2 — and G is —CH 2 —, —CH(CH 3 )—, —C(O)—, —S(O) 2 — or —C(O)—NH—.
12. A compound according to claim 1 , wherein the ring system denoted by “A” is a monocyclic aryl or heteroaryl.
13. A compound according to claim 1 , having the structural formula
14. A compound according to claim 13 , 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);
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;
v is 0, 1 or 2;
G is —CH 2 —, —CH(CH 3 )—, —C(O)—, —S(O) 2 — or —C(O)—NH—;
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 , -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 or 2;
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 groups combine to form an oxo;
x is 0, 1 or 2;
Q is a single bond, —CH 2 —, —CH(CH 3 )—, —C(O)— or —S(O) 2 —;
the ring denoted by “A” is monocyclic heteroaryl or aryl;
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 or 2;
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 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).
15. A compound according to claim 14 , wherein x is 0.
16. A compound according to claim 15 , wherein v is 0.
17. A compound according to claim 16 , wherein w is 0.
18. A compound according to claim 13 , wherein
R 1 is H;
v is 0,
G is —C(O)— or —CH 2 —;
w is 0;
x is 0;
Q is a single bond or —CH 2 —; and
the ring denoted by “A” is phenyl or monocyclic heteroaryl.
19. A compound according to claim 18 , wherein R 17 is aryl or heteroaryl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
20. A compound according to claim 18 , wherein each R 5 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
21. A compound according to claim 18 , wherein
R 17 is phenyl or monocyclic heteroaryl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 ; and
each R 5 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
22. A compound according to claim 21 wherein R 17 is phenyl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
23. A compound according to claim 22 , wherein the ring denoted by “A” is phenyl.
24. A compound according to claim 21 , wherein the ring denoted by “A” is phenyl.
25. A compound according to claim 18 , wherein
the ring denoted by “A” is phenyl; and
R 17 is phenyl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
26. A compound according to claim 1 , having the structural formula
27. A compound according to claim 26 , wherein
R 1 is H;
v is 0,
G is —C(O)— or —CH 2 —;
w is 0;
x is 0;
Q is a single bond or —CH 2 —; and
the ring denoted by “A” is phenyl or monocyclic heteroaryl.
28. A compound according to claim 1 , wherein R 17 is aryl or heteroaryl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
29. A compound according to claim 1 , wherein each R 5 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
30. A compound according to claim 1 , wherein
R 1 is H;
v is 0,
G is —C(O)— or —CH 2 —;
w is 0;
x is 0;
Q is a single bond or —CH 2 —; and
the ring denoted by “A” is phenyl or monocyclic heteroaryl.
31. A compound according to claim 30 , wherein R 17 is phenyl or monocyclic heteroaryl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
32. A compound according to claim 30 , wherein each R 5 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
33. A compound according to claim 30 , wherein
R 17 is phenyl or monocyclic heteroaryl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 ; and
each R 5 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
34. A compound according to claim 33 wherein R 17 is phenyl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
35. A compound according to claim 34 , wherein the ring denoted by “A” is phenyl.
36. A compound according to claim 33 , wherein the ring denoted by “A” is phenyl.
37. A compound according to claim 30 , wherein
the ring denoted by “A” is phenyl; and
R 17 is phenyl substituted with 1, 2 or 3 substituents 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 2 alkyl)(C 0 -C 4 alkyl) and NO 2 .
38. A compound according to claim 1 , wherein the compound is
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamide; or
N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamide,
or a pharmaceutically acceptable salt or N-oxide thereof.
39. 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.
40. A method for activating the AMPK pathway in 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.