N-substituted piperidine derivatives as serotonin receptor agents

• US 7,538,222 B2
• Filed: 12/12/2005
• Issued: 05/26/2009
• Est. Priority Date: 06/24/2002
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Andersson, Carl-Magnus, Schlienger, Nathalie, Fejzic, Alma, Hansen, Eva Louise, Pawlas, Jan
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US11/299,566
• Publication Number:
  US 20060094758A1
• Time in Patent Office: 1,261 Days
• Field of Search: 546/207, 546/208, 546/209, 546/210, 546/211, 546/190, 544/129, 544/283
• US Class Current: 546/190
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

Disclosed herein are compounds of Formula I,

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof. Also disclosed are methods of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Disclosed are also methods of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Furthermore, methods of treating psychotic disease using a compound of Formula I are disclosed.

Claims

1. A compound of Formula I

2. The compound of claim 1, wherein said (heterocyclyl)C_1-6-alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, alkyl, and amino.

3. The compound of claim 1, wherein said heterocyclyl is selected from the group consisting of tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, benzimidazolidone, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-1,3-oxathiolane.

4. The compound of claim 1, wherein R¹ is selected from the group consisting of an optionally substituted (heterocyclyl)methyl, an optionally substituted (heterocyclyl)ethyl, or an optionally substituted (heterocyclyl)propyl.

5. The compound of claim 1, wherein R² and R³ are hydrogen, m is 1, n is 1, and W is oxygen.

6. The compound of claim 1, wherein Ar¹ is an optionally substituted aryl, selected from the group consisting of alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl and amino-substituted phenyl, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl and tert-butyl, and said alkoxy is selected from the group consisting of methoxy, ethoxy, propxy, n-butoxy, sec-butoxy, and tert-butoxy.

7. The compound of claim 1, wherein Ar¹ is 4-substituted aryl.

8. The compound of claim 6, wherein Ar¹ is halogen-substituted phenyl.

9. The compound of claim 1, wherein X is selected from the group consisting of optionally substituted methylene and optionally substituted ethylene.

10. The compound of claim 1, wherein X is CH₂N(R^N).

11. The compound of claim 1, wherein Ar² is an aryl optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heteroaryl, and heterocyclyl.

12. The compound of claim 1, wherein Ar² is 4-substituted aryl.

13. The compound of claim 11, wherein said substituent on Ar² is selected from the group consisting of chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, N-morpholinyl, N-pyrrolidinyl, N-pyrazolyl, N-triazolyl and 2-oxopyrrolidinyl.

14. The compound of claim 1, wherein said compound is selected from the group consisting of:

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide;

N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl }-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino }piperidin-1-yl)propyl]piperidine-4-carboxylic acid methyl ester;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl)ethyl]piperidin-4-yl}acetamide;

N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl }-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-pyrrolidin-1-yl-propyl)piperidin-4-yl ]acetamide;

N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide;

N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide;

N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-propoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-tolylacetamide;

2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide;

N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethylphenyl)acetamide;

2-(4-Cyanophenyl)-N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide;

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyphenyl)-N-(4-methylbenzyl)acetamide;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-ylmethyl)piperidin-4-yl]acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl]acetamide;

N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hydroxyphenyl)-acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-methoxyphenyl)-acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropylphenyl))-acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxy-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)-acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-phenylacetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-fluoroethoxy)-phenyl]acetamide;

N-{1-[2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide;

N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isopropylphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)piperidin-4-yl)}-acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-piperidin-1-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)ethyl]piperidin-4-yl}acetamide;

2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylamino-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propylamino-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1-nitropropyl)-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-oxopyrrolidin-1-yl)phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylsulfanyl-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iodophenyl)-acetamide;

2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)acetamide;

2-[4-(1-Hydroxyiminoethyl)phenyl]-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-morpholin-4-yl-phenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(pyrazol-1-y)lphenyl)acetamide;

N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-acetamide;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-ylphenyl)acetamide;

N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide; and

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(1,2,4-triazol-4-yl)phenyl]acetamide.

15. The compound of claim 1, wherein the (heterocyclyl)C_1-6-alkyl is optionally substituted with one or more substituents selected from the group consisting of C_1-6-alkyl, C_1-6-alkoxy, oxo, carboxyl, amino, hydroxy, nitro, alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, amino, mono- and di(C_1-6-alkyl)amino, carbamoyl, mono- and di(C_1-6-alkyl)aminocarbonyl, amino-C_{1 -6}-alkyl-aminocarbonyl, mono- and di(C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, C_1-6-alkylcarbonylamino, C_1-6-alkylhydroxyimino, cyano, guanidino, carbamido, C_1-6-alkanoyloxy, C_1-6-alkylsulphonyloxy, dihalogen-C_1-6-alkyl, trihalogen-C_1-6-alkyl, heterocyclyl, heteroaryl, halo, alkylamido, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, and sulfamoyl.

16. The compound of claim 1, wherein said heterocyclyl is selected from the group consisting of tetrahydrothiopyran, 4H-pyran, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, 1,3-oxathiane, 1,4-oxathin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazolidine, oxazolidinone and 1,3-oxathiolane.

17. The compound of claim 1, wherein said heterocyclyl is selected from the group consisting of tetrahydropyran, piperidine, piperazine, morpholine, tetrahydrofuran, pyrroline, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, isoxazoline, oxazoline, oxazolidine, thiazoline and thiazolidine.

18. The compound of claim 1, wherein said compound is selected from the group consisting of:

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide;

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide; and

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide.

19. The compound of claim 1, wherein Ar¹ is an aryl, optionally substituted with a substituent selected from the group consisting of C_1-6-alkyl, C_1-6-alkoxy, oxo, carboxyl, hydroxy, nitro, alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, amino, mono-(C_1-6-alkyl)amino, di(C_1-6-alkyl)amino, carbamoyl, mono-(C_1-6alkyl)aminocarbonyl, di(C_1-6-alkyl)aminocarbonyl, amino-C_1-6-alkyl-aminocarbonyl, mono-(C_1-6-alkyl)amino-C_1-6 -alkyl-aminocarbonyl, di(C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, C_1-6alkylcarbonylamino, C_1-6-alkylhydroxyimino, cyano, guanidino, carbamido, C_1-6-alkanoyloxy, C_1-6alkylsulphonyloxy, dihalogen-C_1-6-alkyl, trihalogen-C_1-6-alkyl, trifluoromethoxy, heterocyclyl, halo, alkylamido, hydroxy-C_1-6-alkyl, amino-C_1-6-alkyl, and sulfamoyl.

20. The compound of claim 1 selected from the group consisting of:

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′

-(4-isobutoxybenzyl)carbamide;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′

-(4-isobutoxybenzyl)carbamide;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′

-(4-isopropoxy-benzyl)carbamide;

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidin-4-yl}carbamide;

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]carbamide;

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)piperidin-4-yl]carbamide;

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinon-1-yl-propyl)piperidin-4-yl]carbamide;

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]}piperidin-4-yl]carbamide;

N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′

-(4-isopropoxybenzyl)carbamide; and

N-(4-Fluorobenzyl)-N′

-(4-isopropoxybenzyl)-N-{[2-(1-methyl pyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide.

21. The compound of claim 1, wherein:

R² and R³are hydrogen;

n is 1;

Ar¹ is an aryl optionally substituted with a substituent selected from the group consisting of C_1-6-alkyl, C_1-6-alkoxy, oxo, carboxyl, amino, hydroxy, nitro, alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, amino, mono- and di(C_1-6-alkyl)amino, carbamoyl, mono- and di(C_1-6-alkyl)aminocarbonyl, amino-C_1-6-alkyl-aminocarbonyl, mono- and di(C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, C_1-6-alkylcarbonylamino, C_1-6-alkylhydroxyimino, cyano, guanidino, carbamido, C_1-6-alkanoyloxy, C_1-6-alkylsulphonyloxy, dihalogen-C_1-6-alkyl, trihalogen-C_1-6-alkyl, haloalkoxy, heterocyclyl, halo, alkylamido, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, and sulfamoyl;

W is selected from the group consisting of oxygen and sulfur;

X is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted vinylene, and CH₂N(R^N), wherein R^N is selected from hydrogen and C_1-6-alkyl; and

Ar² is an optionally substituted aryl.

22. The compound of claim 1, wherein Ar¹is an aryl, optionally substituted with a substituent selected from the group consisting of C₁₆-alkyl, C₁₆-alkoxy, oxo, carboxyl, hydroxy, nitro, C_1-6-alkylsulfonyl, C_1-6-alkylsulfenyl, C_1-6-alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, amino, mono-(C_1-6-alkyl)amino, di(C_1-6-alkyl)amino, carbamoyl, mono-(C_1-6-alkyl)aminocarbonyl, di(C_1-6-alkyl)aminocarbonyl, amino-C_1-6-alkyl-aminocarbonyl, mono-(C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, di(C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, C_1-6-alkylcarbonylamino, C_1-6-alkylhydroxyimino, cyano, guanidino, carbamido, C_1-6-alkanoyloxy, C_1-6-alkylsulphonyloxy, dihalogen-C_1-6-alkyl, trihalogen-C_1-6-alkyl, trifluoromethoxy, heterocyclyl, halo, alkylamido, hydroxy-C_1-6-alkyl, amino-C_1-6-alkyl, and sulfamoyl.

23. The compound of claim 1, wherein Ar² is an aryl, optionally substituted with a substituent selected from the group consisting of C_1-6-alkyl, C_1-6-alkoxy, oxo, carboxyl, hydroxy, nitro, C_1-6-alkylsulfonyl, C_1-6-alkylsulfenyl, C_1-6-alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, amino, mono-(C_1-6-alkyl)amino, di(C_1-6-alkyl)amino, carbamoyl, mono-(C_1-6-alkyl)aminocarbonyl, di(C_1-6-alkyl)aminocarbonyl, amino(C_1-6-alkyl-aminocarbonyl, mono-C_1-6-alkyl)amino-C_1-6-alkyl-aminocarbonyl, di(C_1-6-alkyl)amino-C_l-6-alkyl-aminocarbonyl, C_1-6-alkylcarbonylamino, C_1-6-alkylhydroxyimino, cyano, guanidino, carbamido, C_1-6-alkanoyloxy, C_1-6-alkylsulphonyloxy, dihalogen-C_1-6-alkyl, trihalogen-C_1-6-alkyl, trifluoromethoxy, heterocyclyl, halo, alkylamido, hydroxy-C_1-6-alkyl, amino-C_1-6-alkyl, and sulfamoyl.

24. The compound of claim 1, wherein said heterocyclyl is 1,3-dioxane or 1,3-dioxolane.