Heteroaryl urea neuropeptide Y Y5 receptor antagonists

1. A compound of Formula I:

or a pharmaceutically acceptable salt of said compound, or where applicable, a geometric or optical isomer or racemic mixture thereof,

wherein

=A-B= is ═C(R 4 )—N═ and —X═Y— is —N═C(R 6 )—,

or =A-B= is —N—C(R 6 )—, and —X═Y— is —C(R 4 )═N—

Z is

R 1 is H or —(C 1 -C 6 )alkyl;

R 2 is H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl or —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl;

Q is —OR 13 , or —NR 13 R 14 ;

j is 1 or 2;

k is 0, 1 or 2;

l is 0, 1 or 2;

m is 0, 1 or 2;

R 4 , R 5 , R 6 and R 7 may be the same or different, and are independently selected from the group consisting of H, —OH, halogen, polyhaloalkyl, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —CN, NR 10 R 11 , NR 13 R 14 , —O(C 1 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl(C 3 -C 7 )cycolalkyl, —S(C 1 -C 6 )alkyl, —S(C 3 -C 7 )cycloalkyl and —S(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl;

R 8 is 1 to 3 substituents, which may be the same or different, and are independently selected from the group consisting of H, halogen, —OH, polyhaloalkyl, polyhaloalkoxy, —CN, —NO 2 , —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl,—(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, NR 10 R 11 , NR 13 R 14 , —O(C 1 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl and —CONR 13 R 14 ;

R 9 is —SO 2 (C 1 -C 6 )alkyl, —SO 2 (C 3 -C 7 )cycloalkyl, —SO 2 (C 1 -C 6 )alkyl (C 3 -C 7 )cycloalkyl, —SO 2 (C 1 -C 6 )polyhaloalkyl, —SO 2 [hydroxy(C 2 -C 6 )alkyl], —SO 2 [amino(C 2 -C 6 )alkyl], —SO 2 [alkoxy(C 2 -C 6 )alkyl], —SO 2 [alkylamino(C 2 -C 6 )alkyl], —SO 2 [dialkylamino(C 2 -C 6 )alkyl], —SO 2 (aryl), —SO 2 (heteroaryl), —SO 2 [aryl(C 1 -C 6 ) alkyl], —SO 2 NR 13 R 14 , —CO(C 1 -C 6 )alkyl, —CO(C 3 -C 7 )cycloalkyl, —CO(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, CO(C 1 -C 6 )polyhaloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR 13 R 14 , —C(S)NR 13 R 14 , aryl, heteroaryl, —(CH 2 )CONR 13 R 14 , —C(═NCN)alkylthio, —C(═NCN)NR 13 R 14 , —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylaryl, —(C 1 -C 6 )alkylheteroaryl or —COOR 12 ;

R 10 is H or alkyl;

R 11 is H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 (C 3 -C 7 )cycloalkyl, —SO 2 (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —SO 2 (C 1 -C 6 )polyhaloalkyl, —SO 2 (aryl), —SO 2 (heteroaryl), —CO(C 1 -C 6 )alkyl, —CO(C 3 -C 7 )cycloalkyl, —CO(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR 13 R 14 or —COOR 12 ;

R 12 is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylaryl, —(C 1 -C 6 )alkylheteroaryl, aryl or heteroaryl;

R 13 and R 14 may be the same or different and are independently H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkylaryl, aryl or heteroaryl; and,

R 15 is one or two substituents, which may be the same or different, and are independently H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, —CN, —CONR 13 R 14 , —COOR 13 , —OH, —O(C 1 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —NR 10 R 11 , —NR 13 R 14 , or a —(C 1 -C 6 )alkyl group substituted by an aryl, heteroaryl, hydroxy, alkoxy, —NR 10 R 11 , —NR 13 R 14 , —CONR 13 R 14 , or —COOR 13 group, provided that a chemically stable compound results from substitution by R 15 .

2. A compound as defined in claim 1 wherein the heterocyclic group attached to Z is

3. A compound as defined in claim 2 wherein

R 1 is hydrogen,

R 2 is hydrogen or (C 1 -C 6 )alkyl,

R 5 and R 6 are hydrogen or halogen,

R 6 is 1 to 3 substituents, which may be the same or different, and are independently selected from the group consisting of H, halogen, —O(C 1 -C 6 )alkyl, —OH, polyhaloalkyl and polyhaloalkoxy,

R 9 is —SO 2 (C 1 -C 6 )alkyl, —SO 2 (C 3 -C 7 )cycloalkyl, —SO 2 (C 1 -C 6 )alkyl (C 3 -C 7 )cycloalkyl, —SO 2 aryl, —SO 2 heteroaryl, —SO 2 NR 13 R 14 , —CO(C 1 -C 6 )alkyl, —CO(C 3 -C 7 )cycloalkyl, —CO(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —C(O)aryl, —C(O)heteroaryl, aryl, heteroaryl,

R 10 is H or —(C 1 -C 6 )alkyl,

R 11 is —SO 2 (C 1 -C 6 )alkyl, Q is —OR 13 or —NR 13 R 14 ;

R 13 and R 14 may be the same or different, and are independently H or —(C 1 -C 6 )alkyl;

the sum of j and k is 2 or 3; and,

the sum of l and m is 2 or 3.

4. A compound as defined in claim 3 wherein R 3 is

R 9 is —SO 2 (C 1 -C 6 )alkyl, —SO 2 (C 3 -C 7 )cycloalkyl, —SO 2 aryl, —SO 2 heteroaryl, —CO(C 1 -C 6 )alkyl, —CO(C 3 -C 7 )cycloalkyl, —CO(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl, —C(O)aryl, —C(O)heteroaryl, aryl, or heteroaryl, and

the sum of j and k is 2 or 3.

5. The compound as defined in claim 1 of the formula:

or a pharmaceutically acceptable salt of said compound or where applicable, a geometric or optical isomer or racemic mixture thereof,

wherein R 9 is as shown in the table below:

R 9

0

0A

0B

0C

0D

0E

0F

0G

0H

0I

0J

0K

0L

0M

0N

0O

0P

0Q

0W

—SO 2 CH 3 .

6. The compound as defined in claim 1 of the formula:

or a pharmaceutically acceptable salt of said compound, or where applicable, a geometric or optical isomer or racemic mixture thereof,

wherein R 9 is as shown in the table below:

R 9

0S

—SO 2 CH 3

0T

0U

0V

.

7. The compound as defined in claim 1 of the formula:

or a pharmaceutically acceptable salt of said compound, or where applicable, a geometric or optical isomer or racemic mixture thereof,

wherein Z and R 9 are as shown in the table below:

Z

R 9

0X

—SO 2 CH 3

0Y

0Z

0AA

0BB

0CC

0DD

0EE

0FF

0GG

0HH

0II

0JJ

0KK

0LL

0MM

0NN

0OO

0PP

0QQ

0RR

1

—SO 2 CH 3

1A

—SO 2 CH 3

1B

—SO 2 CH 3

1C

—SO 2 CH 3

1D

—SO 2 CH 3

1E

—SO 2 CH 3 .

8. A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

9. A method of treating eating disorders, obesity and disorders related to obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.

10. The method of claim 9 wherein said eating disorder is hyperphagia.

11. A method of treating disorders associated with obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.

12. The method of claim 11 wherein said disorders associated with obesity are type II diabetes, insulin resistance, hyperlipidemia and hypertension.

13. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising:

a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

a second compound, said second compound being a β 3 agonist, a thryomimetic agent, an eating behavior modifying agent or an NPY antagonist; and

a pharmaceutically acceptable carrier therefor.

14. A method of treating an eating disorder which comprises administering to a mammal in need of such treatment

an amount of a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

a second compound, said second compound being a β 3 agonist, a thryomimetic agent, an eating behavior modifying agent or an NPY antagonist;

wherein the amounts of the first and second compounds result in a therapeutic effect.

15. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising

a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound;

a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, insulin, metformin, acarbose, a thiazolidinedione such as troglitazone or rezulin; a glitazone such as rosaglitazone or pioglitazone; a sulfonylurea, glipazide, glyburide, or chlorpropamide; and

a pharmaceutically acceptable carrier therefor.

16. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.