Substituted pyridine, pyridazine, pyrazine and pyrimidine compounds and methods for using the same
View Patent ↗Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure wherein E, J, T, the ring system denoted by “B”, T, R 3 , R 4 , 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);
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 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, —N 3 , —SF 5 , —NO 2 and —CN;
each R 3 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 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, 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 1 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;
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 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 , -halogen, —N 3 , —SF S , —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 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), —C(O)—(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl).
2. The compound according to claim 1 , wherein x is 0.
3. The compound according to claim 1 , wherein the ring system denoted by “B” is arylene or heteroarylene.
4. The compound according to claim 1 , wherein the ring system denoted by “B” is
5. The compound according to claim 1 , wherein J is —NR 13 — or —NR 13 C(O)—.
6. The compound according to claim 1 , wherein J is —C(O)NR 13 — or —C(O)—.
7. The compound according to claim 1 , having the structural formula
8. The compound according to claim 1 , having the structural formula
in which J is absent, —NR 13 —, —NR 13 C(O)— or —C(O)NR 13 —.
9. The compound according to claim 1 , wherein the
moiety is
the moiety is
10. The compound according to claim 1 , wherein the
moiety is
11. The compound according to claim 1 , wherein the
moiety is
12. The compound according to claim 1 , wherein the
moiety is
13. A compound according to claim 1 , wherein the the
moiety is
14. A compound according claim 13 , 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, unsubstituted (C 1 -C 6 alkoxy), —(C 1 -C 6 haloalkoxy), —SH, —S(unsubstituted C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), —N(unsubstituted C 1 -C 4 alkyl) 2 , —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(unsubstituted C 1 -C 4 alkyl), C(O)N(unsubstituted C 1 -C 4 alkyl) 2 , —C(O)OH, C(O)O(unsubstituted C 1 -C 6 alkyl), —(NH) 0-1 SO 2 R 33 , —(NH) 0-1 COR 33 , in which each R 33 is (unsubstituted C 1 -C 6 alkyl) or (C 1 -C 6 haloalkyl).
15. The compound according to claim 1 , having the structural formula
16. The compound according to claim 1 , having the structural formula
17. The compound according to claim 1 , having the structural formula
18. A compound according to claim 1 , having structural formula
19. A compound according to claim 1 , having structural formula
20. 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.
21. The compound according to claim 13 , wherein
each R 3 is independently selected from the group consisting of —(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 4 is independently selected from the group consisting of —(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 R4 optionally combine to form oxo;
each R 5 is independently selected from the group consisting of —(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, —N 3 , —SF 5 , —NO 2 and —CN,
R 17 is aryl or heteroaryl, optionally substituted 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,
wherein 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).
22. The compound according to claim 1 , wherein
each R 3 is independently selected from the group consisting of —(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 4 is independently selected from the group consisting of —(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 R4 optionally combine to form oxo;
each R 5 is independently selected from the group consisting of —(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, —N 3 , —SF 5 , —NO 2 and —CN,
R 17 is aryl or heteroaryl, optionally substituted 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,
wherein 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).
23. A compound according to claim 1 , wherein w is 0.
24. A compound according to claim 1 , wherein x is 0 and w is 0.
25. A compound according to claim 1 , 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 30 ;
each R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, trfluoromethyl, pentafluoroethyl, acetyl, —NH 2 , —OH, methoxy, ethoxy, trifluoromethoxy, —SO 2 Me, -halogen, —NO 2 and —CN;
w is 0 or 1;
J is absent, —C(O)—, —NH—, —NHC(O) —or —C(O)NH—;
the ring system denoted by “B” is
wherein each of Y 1 and Y 2 is N, C or CH, provided that at least one of Y 1 and Y 2 is N;
T is
wherein
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 30 is independently selected from halogen, unsubstituted (C 1 -C 6 alkoxy), —(C 1 -C 6 haloalkoxy), —SH, —S(unsubstituted C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), —N(unsubstituted C 1 -C 4 alkyl) 2 , —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(unsubstituted C 1 -C 4 alkyl), C(O)N(unsubstituted C 1 -C 4 alkyl) 2 , —C(O)OH, C(O)O(unsubstituted C 1 -C 6 alkyl), —(NH) 0-1 SO 2 R 33 and —(NH) 0-1 COR 33 , in which each R 33 is (unsubstituted C 1 -C 6 alkyl) or (C 1 -C 6 haloalkyl).
26. A compound according to claim 25 , wherein w is 0.
27. A compound according to claim 4 , wherein R 17 is aryl optionally substituted with 1, 2 or 3 substituents 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, —N 3 , —SF S , —NO 2 and —CN.