IP Library › Patent Application 11881805
Patent Application
App. No. 11/881,805

Fused heterocyclic compounds

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Patent No.
US None
App. No.
11/881,805
Abstract

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.

Claims (71)

1 - 35 . (canceled)

36 . A method for treating a condition or disorder is selected from the group consisting of obesity, an eating disorder, an anxiety disorder and a mood disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I):

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 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 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 (e.g. tetrazole);

optionally, when two R groups selected from the group 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 R 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.

37 . The method of claim 36 , wherein said compound condition or disorder is selected from the group consisting of obesity, anorexia nervosa, anxiety, panic disorder and obsessive-compulsive disorder and depression.

38 . The method of claim 36 , wherein said compound is administered in combination with an anti-obesity agent, an antidepressant or an anxiolytic agent.

39 . The method of claim 36 , wherein said compound is administered orally.

40 . The method of claim 36 , wherein said compound is administered parenterally.

41 . The method of claim 36 , wherein said compound modulates MCHR.

42 . A method for modifying eating behavior, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I):

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 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 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 (e.g. tetrazole);

optionally when two R groups selected from the group 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 R 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.

43 . The method of claim 42 , wherein food intake is decreased.

44 . The method of claim 42 , wherein food intake is increased.

45 . A method for treating a condition or disorder mediated by MCHR, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I):

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 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 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 (e.g. tetrazole);

optionally, when two R groups selected from the group 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 R 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.

46 . The method of claim 45 , wherein said condition or disorder is selected from the group consisting of obesity, an eating disorder, an anxiety disorder and a mood disorder.

47 . The method of claim 46 , wherein said eating disorder is anorexia nervosa.

48 . The method of claim 46 , wherein said anxiety disorder is selected from the group consisting of anxiety, panic disorder and obsessive-compulsive disorder.

49 . The method of claim 46 , wherein said mood disorder is depression.

50 - 52 . (canceled)

53 . The method of claim 36 , wherein said compound is selected from the group consisting of: