IP Library › Granted Patent US 7,244,727

Granted Patent B2

US 7,244,727 · App. 10/720,844 · Granted Jul 17, 2007

Fused bicyclic nitrogen-containing heterocycles

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Quick Facts

Patent No.: US 7,244,727
App. No.: 10/720,844
Granted: Jul 17, 2007
Kind: B2

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Abstract

Compounds, pharmaceutical compositions and methods that are useful in the treatment or prevention of metabolic and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the activity of proteins involved in lipid metabolism and cell proliferation.

Claims (137)

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

X is N;

Y is selected from the group consisting of N and N(R 2 );

Z is O;

W 1 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

W 2 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

L 1 is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);

L 2 is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);

the subscript m is 0 or 1;

optionally, when m is 1 and L 2 is a bond, a substituent on W 2 may be combined with a substituent on W 1 to form a 5-, 6- or 7-membered ring fused to W 1 and spiro or fused to W 2 , wherein said ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from the group consisting of N, O and S as ring members;

each R 1 is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, C(O)R a , CO 2 R a and C(O)NR a R b ;

each R 2 is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, C(O)R a , CO 2 R a , C(O)NR a R b , aryl and aryl(C 1 -C 4 )alkyl;

R 3 and R 4 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R a , C(O)NR a R b and (C 1 -C 4 )alkylene-OR a ;

optionally, R 3 and R 4 may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;

optionally, R 2 , R 3 or R 4 may be combined with W 1 to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;

R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a and CO 2 R a ;

optionally, R 5 and R 6 may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;

optionally, when X is C(R 1 ) or when Y includes an R 1 or R 2 group, R 5 or R 6 may be combined with R 1 or R 2 to form a 5-, 6- or 7-membered fused ring containing the nitrogen atom to which R 5 or R 6 is attached;

R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, and C(O)R a ,

optionally, when X is C(R 1 ), R 7 may be combined with R 1 to form a 5-, 6- or 7-membered fused ring;

each R a and R b is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and the dotted line indicates an optional bond.

2. A compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 is a bond and W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.

3. A compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine , thiophene, 1,2,3,4-tetrahydronaphthalene and indane.

4. A compound of claim 3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the subscript m is 1.

5. A compound of claim 3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the subscript m is 1 and L 2 is a bond.

6. A compound of claim 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W 2 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.

7. A compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a and CO 2 R a .

8. A compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 and R 6 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

9. A compound of claim 8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

10. A compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.

11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

X is N;

Y is selected from the group consisting of N and N(R 2 );

Z is O;

W 1 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

W 2 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

L 1 is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);

L 2 is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);

the subscript m is 0 or 1;

R 3 and R 4 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R a , C(O)NR a R b and (C 1 -C 4 )alkylene-OR a ;

optionally, R 3 and R 4 may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;

optionally, R 2 , R 3 or R 4 may be combined with W 1 to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;

R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a and CO 2 R a ;

optionally, R 5 and R 6 may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;

R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, and C(O)R a ,

optionally, when X is C(R 1 ), R 7 may be combined with R 1 to form a 5-, 6- or 7-membered fused ring;

each R a and R b is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and

the dotted line indicates an optional bond.

12. A pharmaceutical composition of claim 11 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, L 1 is a bond and W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.

13. A pharmaceutical composition of claim 12 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane.

14. A pharmaceutical composition of claim 13 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, the subscript m is 1.

15. A pharmaceutical composition of claim 13 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, the subscript m is 1 and L 2 is a bond.

16. A pharmaceutical composition of claim 15 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, W 2 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.

17. A pharmaceutical composition of claim 12 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a and CO 2 R a .

18. A pharmaceutical composition of claim 17 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 5 and R 6 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

19. A pharmaceutical composition of claim 18 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 3 and R 4 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

20. A pharmaceutical composition of claim 19 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 7 is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.

21. A method of treating a disease or condition selected from the group consisting of obesity and insulin resistance, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

X is N;

Y is selected from the group consisting of N and N(R 2 );

Z is O;

W 1 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

W 2 is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;

L 1 is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);

L 2 is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);

the subscript m is 0 or 1;

R 3 and R 4 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R a , C(O)NR a R b and (C 1 -C 4 )alkylene-OR a ;

optionally, R 3 and R 4 may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;

optionally, R 2 , R 3 or R 4 may be combined with W 1 to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;

R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a and CO 2 R a ;

optionally, R 5 and R 6 may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;

R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , OR a and NR a R b ;

optionally, when X is C(R 1 ), R 7 may be combined with R 1 to form a 5-, 6- or 7-membered fused ring;

each R a and R b is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and

the dotted line indicates an optional bond.

22. A method in accordance with claim 21 , wherein said compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof is administered orally.

23. A method in accordance with claim 21 , wherein said compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof is administered in combination with an additional active agent.

24. A method in accordance with claim 23 , wherein said additional active agent is selected from the group consisting of an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a pancreatic lipase inhibitor, SNRI, appetite suppressive agent, a PPAR modulator, a MTP inhibitor, a CETP inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an acyl-coenzyme A cholesterol acyltransferase inhibitor, vitamin B 3 , a cholesterol absorption inhibitor, a bile acid sequestrant anion exchange resin, a low density lipoprotein receptor inducer, a fibrate, probucol, vitamin B 6 , vitamin B 12 , an anti-oxidant vitamin, a β-blocker, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, a platelet aggregation inhibitor, a fibrinogen receptor antagonist, aspirin, phentiramines, β 3 adrenergic receptor agonists, sulfonylureas, biguanides, α-glucosidase inhibitors, insulin secretogogues, insulin and a hepatoprotective agent.

25. A method in accordance with claim 21 , wherein said disease or condition is obesity.

26. A method in accordance with claim 21 , wherein said disease is associated with DGAT.

27. A method in accordance with claim 21 , wherein said disease is mediated by DGAT.

28. A method in accordance with claim 21 , wherein said compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof interferes with the interaction between DGAT and a ligand.

29. A method in accordance with claim 21 , wherein said subject is selected from the group consisting of human, rat, dog, cow, horse and mouse.

30. A method in accordance with claim 21 , wherein said subject is human.

31. A method in accordance with claim 21 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, L 1 is a bond and W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.

32. A method in accordance with claim 31 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, W 1 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane.

33. A method in accordance with claim 32 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, the subscript m is 1.

34. A method in accordance with claim 32 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, the subscript m is 1 and L 2 is a bond.

35. A method in accordance with claim 34 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, W 2 is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.

36. A method in accordance with claim 31 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 5 and R 6 are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a and CO 2 R a .

37. A method in accordance with claim 36 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 5 and R 6 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

38. A method in accordance with claim 37 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 3 and R 4 are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

39. A method in accordance with claim 38 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 7 is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, OH and NR a R b wherein R a and R b are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.

40. A method in accordance with claim 38 , wherein in the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, R 7 is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.

41. A compound of claim 1 , selected from the group consisting of: