Heteroaryl urea neuropeptide Y Y5 receptor antagonists

1. A compound of Formula I:

or a pharmaceutically acceptable salt of said compound, wherein

=A-B= is ═N—C(R 5 )═ and —X═Y— is —N═C(R 7 ) or

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

Z is

R 1 is H or —(C 1 - 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;

R 3 is

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;

n is 0 to 6;

p is 1, 2 or 3;

q is 1 or 2;

R 4 , R 5 , R 6 and R 7 may be the same or different, and are independently selected from H, —OH, halogen, haloalkyl, —(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 )cycloalkyl, —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 may be the same or different, and is independently selected from H, halogen, —OH, haloalkyl, haloalkoxy, —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 )haloalkyl, —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 )haloalkyl, —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 )haloalkyl, —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 may be the same or different, and is 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.

2. A compound as defined in claim 1 wherein

R 1 is hydrogen,

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

R 4 , R 5 , R 6 and R 7 are hydrogen or halogen,

R 8 may be the same or different, and is independently selected from H, halogen, —O(C 1 -C 6 )alkyl, —OH, haloalkyl and haloalkoxy,

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;

the sum of l and m is 2 or 3; and

n is 0 to 6.

3. A compound as defined in claim 1 wherein

R 15 is H and 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.

4. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt of said compound,

wherein R 9 is as shown in the table below:

Exa

R 9

19

—SO 2 CH 3

19A

19B

19C

19D

19E

19F

19G

19H

19I

19J

19K

19L

19M

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

or a pharmaceutically acceptable salt of said compound,

wherein R 9 is as shown in the table below:

Exa

R 9

24

24A

—SO 2 CH 3

24B

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

7. A method of treating an eating disorder 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.

8. The method of claim 7 wherein said eating disorder is hyperphagia.

9. The method of claim 7 wherein said metabolic disorder is obesity.

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

11. The method of claim 10 wherein the disorder associated with obesity is type II diabetes, insulin resistance, hyperlipidemia or hypertension.

12. 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 , thereof, 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.

13. 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.

14. 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.

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