N-aroyl cyclic amine derivatives as orexin receptor antagonists

1. A compound of formula (I):

wherein

X represents a CH 2 ;

Y represents CH 2 or CH(OH);

Het is an optionally substituted bicyclic heteroaryl group selected from benzofuranyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indolyl, and benzothienyl;

Ar 2 represents a thiazolyl group, wherein the thiazolyl group is substituted by R 1 and is further optionally substituted;

R 1 represents hydrogen, halo, cyano, an optionally substituted(C 1-4 )alkoxy group, an optionally substituted(C 1-6 )alkyl group, or an optionally substituted phenyl group;

wherein said optionally substituted Het, Ar 2 , and R 1 groups are optionally substituted by halogen, hydroxy, oxo, cyano, nitro, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy(C 1-4 )alkyl, hydroxy(C 1-4 )alkoxy, halo(C 1-4 )alkyl, halo(C 1-4 )alkoxy, aryl(C 1-4 )alkoxy, (C 1-4 )alkylthio, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 3-6 )cycloalkyl(C 1-4 )alkoxy, (C 1-4 )alkanoyl, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylsulfonyl, (C 1-4 )alkylsulfonyloxy, (C 1-4 )alkylsulfonyl(C 1-4 )alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(C 1-4 )alkyl, (C 1-4 )alkylsulfonamido, (C 1-4 )alkylamido, (C 1-4 )alkylsulfonamido(C 1-4 )alkyl, (C 1-4 )alkylamido(C 1-4 )alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(C 1-4 )alkyl, arylcarboxamido(C 1-4 )alkyl, aroyl, aroyl(C 1-4 )alkyl, aryl(C 1-4 )alkanoyl, (C 1-4 )acyl, aryl, aryl(C 1-4 )alkyl, (C 1-4 )alkylamino(C 1-4 )alkyl, or R a R b N—, R a OCO(CH 2 ) r , R a CON(R a )(CH 2 ) r , R a R b NCO(CH 2 ) r , R a R b NSO 2 (CH 2 ) r , R a SO 2 NR b (CH 2 ) r , R a R b N(CH 2 ) n —, R a R b N(CH 2 ) n O—, wherein r represents zero or an integer from 1 to 4, n represents an integer from 1 to 4, each of R a and R b independently represents a hydrogen atom or a (C 1-4 )alkyl group or where appropriate R a R b forms part of a (C 3-6 )azacycloalkane or (C 3-6 )(2-oxo)azacycloalkane ring, or when the substituent is R a R b N(CH 2 ) n — or R a R b N(CH 2 ) n O, R a with at least one CH 2 of the (CH 2 ) n portion of the group optionally forms a (C 3-6 )azacycloalkane and R b represents hydrogen, a (C 1-4 )alkyl group or with the nitrogen to which it is attached forms a second (C 3-6 )azacycloalkane fused to the first (C 3-6 )azacycloalkane,

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein optional substituents for said Ar 2 group are selected from (C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy, halo(C 1-4 )alkoxy, R a R b N, R a R b N(CH 2 ) n O, R a R b N(CH 2 ) n and (C 1-4 )acyl.

3. A compound according to claim 1 , wherein Y represents CH 2 .

4. A compound according to claim 1 , wherein Het is an optionally substituted benzimidazolyl, benzofuranyl or benzoxazolyl group.

5. A compound according to claim 1 , wherein optional substituents for said optionally substituted Het group are selected from halogen, cyano, (C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-4 )alkyl, and CF 3 .

6. A compound according to claim 1 , wherein optional substituents for said optionally substituted R 1 group are selected from halogen, (C 1-4 )alkoxy(C 1-4 )alkyl, R a R b N, R a R b N(CH 2 ) n O, R a R b N(CH 2 ) n , (C 1-4 )alkyl, (C 1-4 )alkoxy and (C 1-4 )acyl.

7. A compound according to claim 1 , wherein optional substituents for said optionally substituted R 1 group are selected from halogen, R a R b N(CH 2 ) n O, (C 1-4 )alkyl, and (C 1-4 )alkoxy.

8. A compound selected from:

(RS)-2-(2-Benzofuranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine;

(RS)-1-(2-Benzoxazol-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(5,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4,5-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(5,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4,5-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(5-Methoxy-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-(2-Benzthiazol-2-ylmethylpiperidin-1-yl)-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanone;

1-[(RS)-2-((RS)-2-Benzofuran-2-yl-2-hydroxy-ethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4-Bromo-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone;

(RS)-1-[2-(4-Cyano-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone;

(RS)-1-[2-(4-Acetyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone;

(RS)-2-(1-{1-[5-(4-Fluoro-phenyl )-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-1H-benzimidazole-5-carbonitrile;

(RS)-1-[2-(5,6-Difluoro-1-propyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol -4-yl]-methanone;

(RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-{2-[1-(2-Dimethylamino-ethyl)-5,6-difluoro-1H-benzimidazol-2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-{2-[5,6-difluoro-1-(2-hydroxy-ethyl)-1 H-benzimidazol -2-ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(6,7-Difluoro-1-methyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl )-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4,5-Difluoro-1-methyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-2-[1-{1-[5-(4-Fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-carboxylic acid amide;

(RS)-1-[2-(3-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3 -carbonitrile;

(RS)-1-[2-(1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-benzofuran-3-yl]-ethanone;

(R)-1-[2-(5,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(S)-1-[2-(5,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[4-(1-hydroxy-ethyl)-1H-benzimidazol-2-ylmethyl]-piperidin-1-yl}-methanone;

(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone;

(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(1H-indol-2-ylmethyl) -piperidin-1-yl]-methanone;

(RS)-1-[2-(5-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol -4-yl]-methanone;

(RS)-1-[2-(5-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(3-methyl-benzofuran-2-ylmethyl)-piperidin-1-yl]-methanone;

(RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4- yl]-methanone;

(RS)-1-(2-Benzo[b]thiophen-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

(RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;

(R)-1-[2-(4,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone; and

(S)-1-[2-(4,6-Difluoro-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;

and a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 , having the formula:

Ar 2

R

F

F

F

H

H

H

H

H

wherein Ar 2 and R are selected from:

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 , having the formula:

wherein X is selected from 5-Cl; 5-F; 5-Cl,6-F; 4-Me; 4,6-di-F; 4-CH 2 NMe 2 ; and 5-Br; or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 , having the formula:

wherein Ar 2 is selected from:

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 , having the formula:

wherein Ar 2 is selected from:

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 , having the formula:

wherein Ar is selected from

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method of treating a disease or disorder where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said disease or disorder is selected from obesity and obesity associated with Type II diabetes.

16. A method of treating insomnia which comprises administering to a subject in need thereof an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1 , wherein

Y is CH 2 ;

Het is optionally substituted benzimidazolyl, benzofuranyl or benzoxazolyl;

R 1 is optionally substituted phenyl;

optional substituents for said Ar 2 thiazolyl group are selected from (C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy, R a R b N, R a R b N(CH 2 ) n and (C 1-4 )acyl;

optional substituents for said optionally substituted Het benzimidazolyl, benzofuranyl or benzoxazolyl group are selected from halogen, cyano, (C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy, and (C 1-4 )alkoxy(C 1-4 )alkyl; and

optional substituents for said optionally substituted R 1 phenyl group are selected from halogen, R a R b N(CH 2 ) n O, (C 1-4 )alkyl, and (C 1-4 )alkoxy;

or a pharmaceutically acceptable salt thereof.