Fused heterocyclic compounds
View Patent ↗Compounds, compositions and methods are provided that are useful in the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor. In particular, the compounds of the invention are useful in the treatment and/or prevention of eating disorders, obesity, anxiety disorders and mood disorders.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt, thereof, wherein
represents a single or fused aryl or heteroaryl ring;
Q is —N(R) (C 1 )alkylene-;
R is
L 1 is a bond, (C 1 -C 4 )alkylene, (C 1 -C 4 )alkylenoxy and (C 1 -C 4 )alkylenamino;
L 2 is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 2 -C 4 )alkynylene, (C 1 -C 4 )alkylenoxy (e.g. —OCH 2 CH 2 —) or (C 1 -C 4 )alkylenamino (e.g. —NH—CH 2 CH 2 —);
R″ is hydrogen or (C 1 -C 8 )alkyl;
each R 1 is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 4 )alkyl, —OR 5 , —SR 5 , fluoro(C 1 -C 4 )alkoxy, aryl, aryl(C 1 -C 4 )alkyl, —NO 2 , —NR 5 R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —N(R 6 )C(O)R 5 , —N(R 6 )CO 2 R 5 , —N(R 7 )C(O)NR 5 R 6 , —S(O) m NR 5 R 6 , —S(O) m R 5 , —CN and —N(R 6 )S(O) m R 5 ;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 4 )alkyl, —OR 8 , —SR 8 , fluoro(C 1 -C 4 )alkoxy, aryl, aryl(C 1 -C 4 )alkyl, —NO 2 , —NR 8 R 9 , ═O, —C(O)R 8 , —CO 2 R 8 , —C(O)NR 8 R 9 , —N(R 9 )C(O)R 8 , —N(R 9 )CO 2 R 8 , —N(R 10 )C(O)NR 8 R 9 , —S(O) m NR 8 R 9 , —S(O) m R 8 , —CN and —N(R 9 )S(O) m R 8 ;
R 4 is selected from the group consisting of hydrogen, —OR 11 , —C(O)R 11 , —CO 2 R 11 , —C(O)NR 11 R 12 , —CN, (C 1 -C 4 )alkyl and aryl;
X and Y are independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —CO 2 R 13 and —C(O)NR 13 R 14 ;
optionally, X and Y may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from 0 to 2 heteroatoms independently selected from the group consisting of N, O and S;
Z is selected from the group consisting of —OR 15 , —NR 15 R 16 , —NR 15 R 18 , —C(O)R 15 , —CO 2 R 15 , —R 18 , —C(O)NR 15 R 16 , —C(O)NR 15 R 18 , —SO 2 NR 15 R 16 , —SO 2 NR 15 R 18 , —NR 16 SO 2 R 15 , —N(R 15 )N(R 16 )SO 2 R 17 , —C(O)N(R 16 )OR 15 , hydroxy(C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, heteroaryl, —C(═NOR 15 )NR 16 R 17 , —C(R 16 ))═NOR 15 , —NR 16 (OR 15 ), —C(O)NR 17 C(O)NR 15 R 16 , —NR 17 C(O)NR 16 C(O)R 15 and —NR 17 C(O)NR 15 R 16 ;
R 5 , R 6 , R 7 , R 8 ,R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, cyclo(C 3 -C 6 )alkyl, fluoro(C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, cyclohetero(C 3 -C 6 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 18 is a 5- or 6-membered ring containing from 0 to 4 heteroatoms selected from the group consisting of N, O and S;
optionally, when two variables selected from the group of variables consisting of R 5 , R 6 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are attached to the same nitrogen atom, the two variables may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2.
2. The compound of claim 1 wherein
represents a benzene ring.
3. The compound of claim 1 wherein R 3 is hydrogen or ═O.
4. The compound of claim 1 wherein
represents a benzene ring, R″ is hydrogen and R 3 is hydrogen.
5. A compound having the formula (II):
or a pharmaceutically acceptable salt, thereof, wherein
L 1 is a bond, (C 1 -C 4 )alkylene, (C 1 -C 4 )alkylenoxy or (C 1 -C 4 )alkylenamino;
L 2 is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 2 -C 4 )alkynylene, (C 1 -C 4 )alkylenoxy or (C 1 -C 4 )alkylenamino;
R″ is hydrogen or (C 1 -C 8 )alkyl;
each R 1 is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 4 )alkyl, —OR 5 , —SR 5 , fluoro(C 1 -C 4 )alkoxy, aryl, aryl(C 1 -C 4 )alkyl, —NO 2 , —NR 5 R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —N(R 6 )C(O)R 5 , —N(R 6 )CO 2 R 5 , —N(R 7 )C(O)NR 5 R 6 , —S(O) m NR 5 R 6 , —S(O) m R 5 , —CN and —N(R 6 )S(O) m R 5 ;
R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 4 )alkyl, —OR 8 , —SR 8 , fluoro(C 1 -C 4 )alkoxy, aryl, aryl(C 1 -C 4 )alkyl, —NO 2 , —NR 8 R 9 , ═O, —C(O)R 8 , —CO 2 R 8 , —C(O)NR 8 R 9 , —N(R 9 )C(O)R 8 , —N(R 9 )CO 2 R 8 , —N(R 10 )C(O)NR 8 R 9 , —S(O) m NR 8 R 9 , —S(O) m R 8 , —CN and —N(R 9 )S(O) m R 8 ;
R 4 is selected from the group consisting of hydrogen, —OR 11 , —C(O)R 11 , —CO 2 R 11 , —C(O)NR 11 R 12 , —CN, (C 1 -C 4 )alkyl and aryl;
X and Y are independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —CO 2 R 13 and —C(O)NR 13 R 14 ;
optionally, X and Y may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from 0 to 2 heteroatoms selected from the group consisting of N, O and S;
Z is selected from the group consisting of —OR 15 , —NR 15 R 16 , —CO 2 R 15 , —R 18 , —C(O)NR 15 R 16 , —C(O)NR 5 R 18 , —SO 2 NR 15 R 16 , —SO 2 NR 15 R 18 , —NR 16 SO 2 R 15 , —N(R 15 )N(R 16 )SO 2 R 17 , —C(O)N(R 16 )OR 15 , fluoro(C 1 -C 4 )alkyl, heteroaryl, —C(═NOR 15 )NR 16 R 17 , —C(R 16 )═NOR 15 , —NR 16 (OR 15 ), —C(O)NR 17 C(O)NR 15 R 16 , —NR 17 C(O)NR 16 C(O)R 15 and —NR 17 C(O)NR 15 R 16 ;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 18 is a 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S;
optionally, when two variables selected from the group of variables consisting of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are attached to the same nitrogen atom, the two groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2.
6. The compound of claim 5 , wherein R 4 is hydrogen.
7. The compound of claim 5 , wherein R″ is hydrogen.
8. The compound of claim 7 , wherein R 2 is (C 1 -C 4 )alkyl or aryl.
9. The compound of claim 8 , wherein R 1 is independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, —OR 5 , fluoro(C 1 -C 4 )alkoxy, —CO 2 R 5 , —S(O) m NR 5 R 6 , —S(O) m R 5 and —CN.
10. The compound of claim 9 , wherein R 1 is halogen or fluoro(C 1 -C 4 )alkyl.
11. The compound of claim 9 , wherein n is 0 or 1.
12. The compound of claim 11 , wherein L 1 is (C 1 -C 4 )alkylene.
13. The compound of claim 12 , having the formula (III):
wherein the subscript p is an integer of from 1 to 4.
14. The compound of claim 13 , wherein p is 1, 2 or 3.
15. The compound of claim 14 , wherein L 2 is a bond.
16. The compound of claim 15 , wherein Z is —CO 2 R 15 or —CO 2 NR 15 R 16 .
17. The compound of claim 14 , wherein X and Y are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from 0 to 2 heteroatoms selected from the group consisting of O, N and S.
18. The compound of claim 17 , wherein X and Y are combined to form a 5- or 6-membered ring containing from 0 to 2 heteroatoms selected from the group consisting of O, N and S.
19. The compound of claim 18 , wherein X and Y are combined to form a 5- or 6-membered ring containing 0 heteroatoms, 1 nitrogen atom or 1 oxygen atom.
20. The compound of claim 5 , having the formula (IV):
wherein the subscript p is an integer of from 1 to 4.
21. The compound of claim 20 , wherein p is 1, 2 or 3.
22. The compound of claim 21 , wherein p is 2.
23. The compound of claim 22 , wherein Y is —CO 2 H.
24. The compound of claim 22 , wherein X and Y are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from 0 to 2 heteroatoms selected from the group consisting of O, N and S.
25. The compound of claim 22 , wherein X and Y are combined to form a 5- or 6-membered ring containing from 0 to 2 heteroatoms selected from the group consisting of O, N and S.
26. The compound of claim 22 , wherein X and Y are combined to form a 5- or 6-membered ring containing 0 heteroatoms, 1 nitrogen atom or 1 oxygen atom.
27. The compound of claim 22 , wherein X and Y are combined to form a 5- or 6-membered ring containing 0 heteroatoms, 1 nitrogen atom or 1 oxygen atom and Y is —CO 2 H.
28. The compound of claim 22 , wherein R 2 is methyl.
29. The compound of claim 22 , wherein R 1 is CF 3 .
30. The compound of claim 29 , wherein R 1 is 9-trifluoromethyl.
31. The compound of claim 22 , wherein R 1 is CF 3 and R 2 is methyl.
32. The compound of claim 22 , wherein R 1 is CF 3 , R 2 is methyl and Y is —CO 2 H.
33. The compound of claim 32 , wherein said compound is selected from the group consisting of:
34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of claims 1 , 2 or 33 .
35. The compound of claim 1 , wherein R 18 is tetrazole.