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 , 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 method for reducing triglyceride levels, or treating type II diabetes, atherosclerosis or cardiovascular disease in a subject in need thereof, the method comprising administering to the subject an effective amount of 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 3 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -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), -halogen, and two R 4 on the same carbon optionally combine to form oxo;
x is 0, 1 or 2;
Q and G are each independently a bond, —CH 2 —, —C(H)(R 16 )—, —C(R 16 ) 2 —, —S(O) 2 —;
v is 0, 1 or 2;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, and two R 15 on the same carbon optionally combine to form oxo;
R 17 is phenyl or pyridyl, each optionally substituted with 1, 2 or 3 substituents selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, —NO 2 and —CN,
R 5 is selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, —NO 2 and —CN;
in which
each R 16 is independently selected from —(C 1 -C 3 alkyl), and optionally two of R 16 on the same carbon combine to form oxo.
2. A method according to claim 1 , wherein the compound has the structural formula
3. A method according to claim 1 , wherein the compound has the structural formula
4. A method according to claim 1 , wherein the compound has the structural formula
in which one of X 1 , X 2 , X 3 and X 4 is N, and the others are carbons.
5. A method according to claim 1 , wherein Q is —CH 2 —, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—.
6. A method according to claim 1 , wherein R 5 is chloro, fluoro, cyano, trifluoromethyl or NO 2 .
7. A method according to claim 1 , wherein R 1 is H.
8. A method according to claim 1 , wherein w is 0.
9. A method according to claim 1 , wherein w is at least 1, and at least one R 3 is selected from the group consisting of halo, cyano, —(C 1 -C 3 fluoroalkyl) and NO 2 .
10. A method according to claim 1 , wherein x is 0.
11. A method according to claim 1 , wherein two R 4 groups combine to form an oxo.
12. A method according to claim 1 , wherein the compound has the structural formula
13. A method according to claim 1 , wherein the compound has the structural formula
in which R 25 is selected from halo, cyano, —(C 1 -C 3 fluoroalkyl), and NO 2 .
14. A method according to claim 1 , wherein v is 0, w is 0 and x is 0.
15. A method according to claim 1 , wherein Q is —CH 2 — or a single bond.
16. A method according to claim 1 , wherein R 5 is —Cl, —F, cyano, trifluoromethyl or difluoromethyl.
17. A method according to claim 1 , wherein the R 17 phenyl or pyridyl is optionally substituted with one or two substituents selected from halo, cyano, —(C 1 -C 3 fluoroalkyl) and NO 2 .
18. A method according to claim 1 , wherein G is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; or —CH(CH 3 )—.
19. A method according to claim 1 , wherein each R 3 is halo or —(C 1 -C 3 alkyl).
20. A method according to claim 1 , wherein
R 5 is halo, cyano, —(C 1 -C 3 haloalkyl), or NO 2 ;
Q is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; or —CH(CH 3 )—;
x is 0;
w is 0;
R 1 is H;
v is 0;
G is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; or —CH(CH 3 )—; and
R 17 is phenyl or pyridyl, optionally substituted with one or two substituents selected from halo, cyano, —(C 1 -C 3 fluoroalkyl), and NO 2 .
21. A method according to claim 1 , wherein G is —CH 2 —, a single bond, —S(O) 2 —, —C(O)— or —CH(CH 3 )—; and Q is —CH 2 —, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—.
22. A method according to claim 1 , wherein the compound is
5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)picolinamide
(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)pyrrolidin-3-yl)picolinamide;
(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)picolinamide;
(S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)picolinamide;
N-(1-(4-chlorobenzyl)pyrrolidin-3-yl)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)picolinamide; or
5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)picolinamide.
23. A method according to claim 1 , wherein the method is for reducing triglyceride levels in the subject.
24. A method according to claim 1 , wherein the method is for treating type II diabetes in the subject.
25. A method according to claim 1 , wherein the method is for treating atherosclerosis in the subject.
26. A method according to claim 1 , wherein the method is for treating cardiovascular disease in the subject.
27. A method for decreasing ceramide concentration in a cell, the method comprising contacting the cell with an effective amount of 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 3 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -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), -halogen, and two R 4 on the same carbon optionally combine to form oxo;
x is 0, 1 or 2;
Q and G are each independently a bond, —CH 2 —, —C(H)(R 16 )—, —C(R 16 ) 2 —, —S(O) 2 —;
v is 0, 1 or 2;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, and two R 15 on the same carbon optionally combine to form oxo;
R 17 is phenyl or pyridyl, each optionally substituted with 1, 2 or 3 substituents selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, —NO 2 and —CN,
R 5 is selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), -halogen, —NO 2 and —CN;
in which
each R 16 is independently selected from —(C 1 -C 3 alkyl), and optionally two of R 16 on the same carbon combine to form oxo.