GABA-B RECEPTOR MODULATORS

• US 20090149474A1
• Filed: 12/21/2006
• Published: 06/11/2009
• Est. Priority Date: 12/23/2005
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Gustafsson, Linda, Bauer, Udo, Svensson, Tor, Brailsford, Wayne
• Granted Patent: US 7,812,026 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to novel imidazole derivatives having a positive allosteric GABA_B receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use, optionally in combination with a GABA_B agonist, for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS). The compounds are represented by the general formula (I) wherein R¹, R², R³ and R⁴ are as defined in the description. For example, R¹ may be phenyl, R² may be dimethylamino pyrrolidin-1-yl, R³ may be alkoxy and R⁴ may be alkyl, ai arylalkyl, aryloxyalkyl, aryloxy or heterocyclylalkyl.

Claims

1. A compound of the general formula (I) an enantiomer of the compound, or a pharmaceutically acceptable salt of the compound or the enantiomer,

2. The compound according to claim 1, wherein R¹ represents C₁-C₄ alkyl, optionally substituted by one aryl or two heteroaryl groups.

3. The compound according to claim 1, wherein R¹ represents heteroaryl, optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, SO₂R⁷, halogen(s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

4. The compound according to claim 1, wherein R¹ represents aryl, optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, SO₂R⁷, halogen(s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

5. The compound according to claim 4, wherein R¹ represents unsubstituted phenyl.

6. The compound according to claim 1, wherein R³ represents C₁-C₄ alkoxy, optionally substituted by one or more of C₁-C₁₀ thioalkoxy, C₃-C₁₀ cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

7. The compound according to claim 6, wherein R³ represents tertiary butyl.

8. The compound according to claim 1, wherein R³ represents C₁-C₁₀ alkyl, optionally substituted by one or more of C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, C₃-C₁₀ cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

9. The compound according to claim 8, wherein R³ represents C_1-4 alkyl substituted by one C_1-4 alkoxy.

10. The compound according to claim 9, wherein said C_1-4 alkoxy is methoxy.

11. The compound according to claim 1, wherein R⁴ represents C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₇ cycloalkyl, optionally substituted by one or more of C₁-C₁₀ alkoxy, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide, nitrile, SO₂NR⁸R⁹, NR⁸SO₂R⁹, NR⁸C═

ONR⁹ or one or two aryl or heteroaryl groups.

12. The compound according to claim 11, wherein R⁴ represents C₁-C₄ alkyl, optionally substituted by one or two aryl or heteroaryl groups.

13. The compound according to claim 12, wherein R⁴ represents C₁-C₄ alkyl, substituted by one or two aryl or heteroaryl groups.

14. The compound according to claim 1, wherein R⁴ represents aryl or heteroaryl, optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

15. The compound according to claim 14, wherein R⁴ represents phenyl optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

16. The compound according to claim 14, wherein R⁴ represents phenyl and said phenyl is substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, nitrile, or one or two aryl or heteroaryl groups.

17. The compound according to claim 1, wherein R⁵ represents C_1-4 alkyl.

18. The compound according to claim 17, wherein R⁵ represents methyl.

19. The compound according to claim 1, wherein R⁶ represents C_1-4 alkyl.

20. The compound according to claim 19, wherein R⁶ represents methyl.

21. The compound according to claim 1, wherein R⁵ and R⁶ together form a ring consisting of 5 or 6 atoms selected from the group consisting of C, O and N atoms.

22. The compound according to claim 1, wherein:

R¹ represents aryl;

R² represents NR⁵R⁶;

R³ represents C₁-C₁₀ alkoxy, or

R³ represents C₁-C₁₀ alkyl optionally substituted by one or more of C₁-C₁₀ alkoxy;

R⁴ represents C₁-C₁₀ alkyl, optionally substituted by one or more of C₁-C₁₀ alkoxy, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, keto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, COR¹⁰, nitrile, SO₂NR⁸R⁹, SO₂R¹¹, NR⁸SO₂R⁹, NR⁸C═

ONR⁹ or one or two aryl or heteroaryl groups;

or

R⁴ represents aryl or heteroaryl, each optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁹, CO₂R¹⁰, SO₂R⁷, nitrile, or one or two aryl or heteroaryl groups;

R⁵ represents C₁-C₁₀ alkyl;

R⁶ represents C₁-C₁₀ alkyl;

R⁷ each and independently represents C₁-C₁₀ alkyl;

R⁸ each and independently represents hydrogen, C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

R⁹ each and independently represents hydrogen, C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

R¹⁰ each and independently represents C₁-C₁₀ alkyl;

R¹¹ represents C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

wherein each alkyl group may independently have one or more carbon atom(s) replaced by an O, N or S atom, wherein none of the O, N or S atoms is in a position adjacent to any other O, N or S atom; and

wherein each alkyl group may independently have one or more carbon atom(s) substituted with fluoro.

23. The compound according to claim 1, wherein

R¹ represents phenyl;

R² represents NR⁵R⁶;

R³ represents C₁-C₁₀ alkoxy;

or

R³ represents C₁-C₁₀ alkyl optionally substituted by one or more of C₁-C₁₀ alkoxy;

R⁴ represents C₁-C₁₀ alkyl optionally substituted by one or more of C₁-C₁₀ alkoxy, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, keto, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, CO₂R¹⁰, COR¹⁰, nitrile, SO₂NR⁸R⁹, SO₂R¹¹, NR⁸SO₂R⁹, NR⁸C═

ONR⁹ or one or two aryl or heteroaryl groups;

or

R⁴ represents aryl or heteroaryl, each optionally substituted by one or more of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR⁸R⁹, NR⁸COR⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁹, CO₂R¹⁰, SO₂R⁷, nitrile, or one or two aryl or heteroaryl groups;

R⁵ represents methyl;

R⁶ represents methyl;

R⁷ each and independently represents C₁-C₁₀ alkyl;

R⁸ each and independently represents hydrogen, C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

R⁹ each and independently represents hydrogen, C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

R¹⁰ each and independently represents C₁-C₁₀ alkyl;

R¹¹ represents C₁-C₁₀ alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy or C₁-C₁₀ thioalkoxy;

wherein each alkyl group may independently have one or more carbon atom(s) replaced by an O, N or S atom, wherein none of the O, N or S atoms is in a position adjacent to any other O, N or S atom; and

wherein each alkyl group may independently have one or more carbon atom(s) substituted with fluoro.

24. The compound according to claim 1, wherein the compound is selected from the group consisting of:

tert-butyl 4-[(4-chlorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[(2-phenylbutanoyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(methoxyacetyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[(phenylacetyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(benzyloxy)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(phenoxyacetyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[4-(benzyloxy)phenyl]acetyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[(2-thienylacetyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2,4-dimethoxybenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(4-chlorophenyl)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(2-phenoxypropanoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(3-chlorophenoxy)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(2,5-dichloro-3-thienyl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[5-(4-chlorophenyl)-2-methyl-3-furoyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2,1,3-benzoxadiazol-5-ylcarbonyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(acetyloxy)(phenyl)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(3,4-difluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(3-chloro-1-benzothien-2-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(1-benzothien-2-ylcarbonyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(4-chlorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-{[(3-chlorophenoxy)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-4-[(4-methylbenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(3,4-dichlorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-{[(acetyloxy)(phenyl)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-{[(2,5-dichloro-3-thienyl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2-chloro-4-fluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(3-chloro-4-fluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(4-butoxybenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-({N-[(4-methylphenyl)sulfonyl]-L-phenylalanyl}amino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(3,4-dimethylbenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-({[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(2,4-dichlorophenoxy)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-{[(1-phenyl-5-propyl-1H-pyrazol-4-yl)carbonyl]amino}-1H-imidazole-5-carboxylate;

tert-butyl 4-[(5-tert-butyl-2-methyl-3-furoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[3-chloro-4-(isopropylsulfonyl)-2-thienyl]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furoyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[3-tert-butyl-1-(2,4-dichlorobenzyl)-1H-pyrazol-5-yl]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(4-methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(6-phenoxypyridin-3-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(3,4-difluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(4-bromo-2-chlorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(4-bromo-2-methylbenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(4-chloro-2-methylbenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2-chloro-4,5-dimethylbenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2,4-difluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2-chloro-4-fluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-1-phenyl-4-[(3-phenylpropanoyl)amino]-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2-chloro-6-methoxyisonicotinoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-4-[(2,4-dimethylbenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2-chlorobenzoyl)amino]-1-phenyl-2-pyrrolidin-1-yl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(2-bromo-4-fluorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-4-{[4-fluoro-2-(trifluoromethyl)benzoyl]-amino}-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-4-[(4-fluoro-2-methoxybenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(4-chloro-2-methoxybenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-{[2-(trifluoromethyl)benzoyl]amino}-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2-chlorobenzoyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(2-methoxybenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(3-chloro-2-thienyl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-{[(benzyloxy)acetyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[4-chloro-2-(methylsulfonyl)benzoyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(4-ethoxybenzoyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(2-phenoxypyridin-3-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-({[2-(4-chlorophenoxy)pyridin-3-yl]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(4-bromo-1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(5-chloro-1-methyl-1H-pyrazol-4-yl)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

1H-imidazole-5-carboxylic acid, 4-[[[2-(2,3-dihydro-5-benzofuranyl)-4-thiazolyl]carbonyl]-amino]-2-(dimethylamino)-1-phenyl-, 1,1-dimethylethyl ester;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}carbonyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(6-phenoxypyridin-3-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-{[(4-methyl-2-pyrazin-2-yl-1,3-thiazol-5-yl)carbonyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-({[1-(4-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]carbonyl}amino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-[(N-phenylglycyl)amino]-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(N-methyl-N-phenylglycyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 4-[(2,3-dihydro-1H-indol-1-ylacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-4-[(1H-indol-1-ylacetyl)amino]-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 4-[(1H-benzimidazol-1-ylacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

2-methoxy-1,1-dimethylethyl 2-(dimethylamino)-4-{[(2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]amino}-1-phenyl-1H-imidazole-5-carboxylate;

tert-butyl 2-(dimethylamino)-1-phenyl-4-{[(2-thienylamino)carbonyl]amino}-1H-imidazole-5-carboxylate;

tert-butyl 4-{[(benzylamino)carbonyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate; and

tert-butyl 4-({[(4-chlorophenyl)amino]carbonyl}amino)-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate.

25. A pharmaceutical composition comprising a compound of the general formula (I) an enantiomer of the compound or a pharmaceutically acceptable salt of the compound or the enantiomer,

37. A method for the treatment of gastroesophageal reflux disease (GERD), the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 25, optionally in combination with a GABA_B receptor agonist, to a patient in need thereof.

38. A method for the treatment of a functional gastrointestinal disorder, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 25, optionally in combination with a GABA_B receptor agonist, to a patient in need thereof.

39. A method for the treatment of irritable bowel syndrome (IBS), the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 25, optionally in combination with a GABA_B receptor agonist, to a patient in need thereof.

42. A method for the prevention of reflux, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 25, optionally in combination with a GABA_B receptor agonist, to a patient in need thereof.

43. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 25, optionally in combination with a GABA_B receptor agonist, to a patient in need thereof.

44. The method according to claim 39, wherein the IBS is constipation predominant IBS, diarrhea predominant IBS, or alternating bowel movement predominant IBS.

45. The method according to claim 38, wherein the functional gastrointestinal disorder is functional dyspepsia.

26-36. -36. (canceled)

40. A compound selected from the group consisting of:

tert-butyl 4-amino-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;

methyl N″

-cyano-N′

-phenyl-N,N-dimethylguanidine;

methyl N-cyano-N′

-phenylimidothiocarbamate; and

2-methoxy-1,1-dimethylethyl 4-amino-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate.

41. (canceled)