Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators

• US 20030207875A1
• Filed: 01/07/2003
• Published: 11/06/2003
• Est. Priority Date: 01/07/2002
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Kawamura, Kiyoshi, Mihara, Sachiko, Morita, Mikio, Nukui, Seiji, Uchida, Chikara, Stobie, Alan, Gymer, Geoffrey
• Granted Patent: US 6,979,690 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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

Abstract

This invention provides compounds of the formula (I) and (II):

or the pharmaceutically acceptable esters thereof, and the pharmaceutically acceptable salts thereof: wherein R¹ is hydrogen or halo; R² and R³ are independently hydrogen or C_1-6 alkyl; R⁴ and R⁵ are independently hydrogen or C_1-6 alkyl; R⁶ is hydrogen, C_1-12 alkyl, C_1-6 alkoxy (C_1-6)alkyl or C_1-12 alkyl substituted by up to 3 substituents selected from the groups consisting of C_3-8 cycloalkyl, aryl, heteroaryl and heterocyclic; R⁷ and R⁸ are hydrogen or taken together may form alkylene chain having one or two carbon atoms; R⁹ is C_1-6 alkyl or C_3-8 cycloalkyl; R¹⁰ is C_1-6 alkyl or NR¹¹R¹²; L is (CR¹¹R¹²)_n or NR¹¹; M is NR¹¹ or (CR¹¹R¹²)_n; R¹¹ and R¹² are independently hydrogen or C_1-6 alkyl; n is an integer from 0 to 5; and m is an integer from 0 to 2; said heterocyclic, aryl and heteroaryl are unsubstituted or are substituted by at least one substituent selected from the group consisting of halo and C_1-6 alkyl; with the proviso that when R⁹ is C_1-6 alkyl, L is not NR¹¹.

These compounds have 5-HT₄ receptor binding activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans. This invention also provides a pharmaceutical composition comprising the above compound.

Claims

1. Compounds of formula (I) and (II):

2. A compound according to claim 1, wherein

R¹ is hydrogen, halo, C_1-6 alkyl or heteroaryl;

R² and R³ are independently hydrogen or C_1-6 alkyl;

or two of R² and R³, or R³ and R⁴ taken together with the nitrogen atoms to which they are attached may form nitrogen-containing hetrocyclic;

R⁴ and R⁵ are independently hydrogen, C_1-6 alkyl, aryl, C_1-6 alkyl substituted with 1 to 6 halogen atom(s);

said aryl is unsubstituted or is substituted by at least one substituent selected from the groups consisting of halo, C_1-6 alkyl, amino, hydroxy, cyano, mono- or di-(C_1-6) alkylamino, C_1-6 alkoxy, aryloxy, aryl (C_1-6)alkoxy, (C_1-6)alkoxy carbonyl(C_1-6)alkoxy, di-(C1-6) alkylaminocarbonyl, di-(C_1-6) alkylamino(C_1-6) alkoxy, (C_1-6) alkylsulfonylamino(C_1-6) alkoxy and (C_1-6) alkoxy(C_1-6) alkyl;

R⁶ is C_1-12 alkyl, C_3-8 alkenyl or C_1-12 alkyl substituted by up to 3 substituents selected from the groups consisting of C(═

O)R¹⁰, C_3-8 cycloalkyl, hydroxy, cyano, oxo, phenyl, naphthyl, phenyl-S and 5-12 membered monocyclic or bicyclic aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from O, N and S;

said phenyl, naphthyl and 5-12 membered monocyclic or bicyclic aromatic or non-aromatic ring are unsubstituted or are substituted by at least one substituent selected from the groups consisting of halo, cyano, C_1-6 alkyl, C_1-6 alkyl substituted by 1 to 6 halogen atom(s), C_1-6 alkoxy, C_1-6 alkoxy substituted by 1 to 6 halogen atom(s), mono- or di-(C_1-6)alkyl amino and C_1-6 alkoxy(C_1-6) alkyl; and

R⁷ and R⁸ are hydrogen;

R⁹ is C_1-6 alkyl;

R¹⁰ is C_1-6alkyl, OR¹¹ or NR¹¹R¹² wherein R¹¹ and R¹² are independently hydrogen, C_3-8 cycloalkyl or C_1-6 alkyl;

L is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or C_1-6 alkyl, and n is an integer from 0 to 3; and

M is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or C_1-6 alkyl, and n is an integer from 0 to 3;

said heterocyclic, aryl and heteroaryl are unsubstituted or are substituted by at least one substituent selected from the group consisting of halo, C_1-6 alkyl, amino, hydroxy, cyano, mono- or di-(C_1-6) alkylamino, C_1-6 alkoxy, aryloxy, aryl (C_1-6)alkoxy, (C_1-6)alkoxy carbonyl(C_1-6)alkoxy, di-(C1-6) alkylaminocarbonyl, di-(C_1-6) alkylamino(C_1-6) alkoxy, (C_1-6) alkylsulfonylamino(C_1-6) alkoxy and (C_1-6) alkoxy(C_1-6) alkyl.

3. A compound according to claim 1, wherein

R¹ is hydrogen, halo or heteroaryl;

R² and R³ are independently hydrogen or C_1-6 alkyl;

R⁴ and R⁵ are independently hydrogen, C_1-6 alkyl or C_1-6 alkyl substituted by 1 to 6 halogen atom(s);

R⁶ is C_1-10 alkyl, C_3-8 alkenyl or C_1-10 alkyl substituted with up to 3 substituents selected from the groups consisting of C(═

O)R¹⁰, C_5-7 cycloalkyl, hydroxy, cyano, oxo, phenyl, naphthyl, phenyl-S, NR¹¹R¹² and heteroaryl selected from the groups consisting of indolyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl and quinolyl, and heterocyclic selected from the groups consisting of pyrazolino, pyrazolidino, imidazolinyl, piperidino, morpholino, thiamorpholino, pyrrolidino, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and phthalimidolyl;

said phenyl, naphthyl, heteroaryl and heterocyclic are unsubstituted or are substituted by at least one substituent selected from the groups consisting of halo, cyano, C_1-6 alkyl, C_1-6 alkyl substituted by 1 to 6 halogen atom(s), C_1-6 alkoxy, C_1-6 alkoxy substituted by 1 to 6 halogen atom(s), mono- or di-(C_1-6)alkyl amino and C_1-6 alkoxy(C_1-6) alkyl;

R¹⁰ is C_1-6alkyl or C_1-6 alkoxy;

R¹¹ and R¹² are independently hydrogen, C_3-8 cycloalkyl or C_1-6 alkyl;

L is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2; and

M is (CR¹¹R¹²)_n, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2.

4. A compound according to claim 1, wherein

R¹ is hydrogen or halo;

R² and R³ are hydrogen;

R⁴ and R⁵ are independently hydrogen or C_1-6 alkyl;

R⁶ is C_1-10 alkyl, C_3-8 alkenyl or C_1-10 alkyl substituted with up to 3 substituents selected from the groups consisting of C(═

O)R¹⁰, C_5-7 cycloalkyl, oxo, phenyl, naphthyl, phenyl-S, NR¹¹R¹² and heteroaryl selected from the groups consisting of indolyl, furyl, thienyl, oxazolyl, pyridyl, pyrrolyl and quinolyl, and heterocyclic selected from the groups consisting of piperidino, morpholino, pyrrolidino, piperazinyl, phthalimidolyl, pyrrolidinyl and tetrahydropyaranyl;

said phenyl, naphthyl, heteroaryl and heterocyclic are unsubstituted or are substituted by at least one substituent selected from the groups consisting of halo, cyano, C_1-6 alkyl, C_1-6 alkyl substituted by 1 to 6 halogen atom(s), C_1-6 alkoxy, C_1-6 alkoxy substituted by 1 to 6 halogen atom(s), mono- or di-(C_1-6)alkyl amino and C_1-6 alkoxy(C_1-6) alkyl;

R¹⁰ is C_1-6 alkoxy;

R¹¹ and R¹² are independently C_3-8 cycloalkyl or C_1-6 alkyl;

L is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2; and

M is (CR¹¹R¹²)_n, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2

5. A compound according to claim 1, wherein

R¹ is hydrogen or halo;

R²and R³ are hydrogen;

R⁴ and R⁵ are hydrogen;

R⁶ is C_1-10 alkyl, C_3-8 alkenyl or C_1-10 alkyl substituted with up to 3 substituents selected from the groups consisting of C_1-6 alkoxycarbonyl, C_5-7 cycloalkyl, oxo, phenyl, naphthyl, phenyl-S and heteroaryl selected from the groups consisting of indolyl and pyridyl, and heterocyclic selected from the groups consisting of pyrrolyl, piperidino, phthalimidolyl and tetrahydropyranyl;

said phenyl, naphthyl, heteroaryl and heterocyclic are unsubstituted or are substituted by at least one substituent selected from the groups consisting of halo, C_1-6 alkyl, C_1-6 alkyl substituted by 1 to 6 halogen atom(s), C_1-6 alkoxy and C_1-6 alkoxy substituted by 1 to 6 halogen atom(s);

R¹⁰ is C_1-6alkoxy;

L is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2; and

M is (CR¹¹R¹²)_n, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2

6. A compound according to claim 1, wherein

R¹ is hydrogen or halo;

R² and R³ are hydrogen;

R⁴ and R⁵ are hydrogen;

R⁶ is isobutyl, cyclohexylmethyl, n-butyl, indolylethyl, phenylethyl, fluorophenylethyl, ethoxycarbonyl(n-propyl)methyl, methoxycarbonyl(phenyl)methyl, naphthylethyl, trifuluoromethoxyphenylmethyl, n-heptyl, n-butyl(ethoxycarbonyl)methyl, (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl, isopentyl, n-hexyl, hexenyl, chlorophenylmethyl, dichlorophenylmethyl, pyrrolylethyl, ethoxycarbonyl(ethyl)methyl, cyclohexylethyl, ethoxycarbonyl(isopropyl)methyl, ethylhexyl, phenylthioethyl, methylpentyl, (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl, bromofluorophenylmethyl, butylmethyl, bromophenylmethyl, dimethoxyphenyl-oxoethyl, benzoylethyl, 3,3-dimethyl-2-oxobutyl, 1,3,3-trimethyl-2-oxobutyl-2-oxobutyl, 2-hydroxy-3,3-dimethylbutyl, 4-methoxycarbonyl-3,3-dimethyl-2-oxo-butyl, 3,3-dimethyl-2-oxobutyl, neopentyl, [(dimethylamino)carbonyl]pentyl, (piperidinylcarbonyl)pentyl or {[cyclohexyl(methyl)amino]carbonyl}pentyl;

R¹⁰ is C_1-6alkoxy;

L is (CR¹¹R¹²)_n or NR¹¹, wherein R¹¹ and R¹² are independently hydrogen or methyl, and n is an integer from 0 to 2; and

M is chemical bond or methylene.

7. A compound according to claim 1, wherein

R¹ is hydrogen or halo;

R² and R³ are hydrogen;

R⁴ and R⁵ are hydrogen;

R⁶ is isobutyl, cyclohexylmethyl, n-butyl, indolylethyl, phenylethyl, fluorophenylethyl, ethoxycarbonyl(n-propyl)methyl, methoxycarbonyl(phenyl)methyl, naphthylethyl, 4-methoxycarbonyl-3,3-dimethyl-2-oxo-butyl, 3,3-dimethyl-2-oxobutyl, neopentyl, [(dimethylamino)carbonyl]pentyl, (piperidinylcarbonyl)pentyl or {[cyclohexyl(methyl)amino]carbonyl}pentyl;

R¹⁰ is C_1-6alkoxy;

L is NR¹¹; and

M is chemical bond or methylene.

8. A compound according to claim 1 selected from

6-amino-5-chloro-2-oxo-N-({1-[4-(trifluoromethoxy)benzyl]-4-piperidinyl}methyl)-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-[(1-heptyl-4-piperidinyl)methyl]-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

ethyl 2-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl]hexanoate;

6-amino-5-chloro-N-({1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-{[1-(3-methylbutyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-[(1-hexyl-4-piperidinyl)methyl]-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-{[1-(5-hexenyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-{[1-(3-chlorobenzyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-{[1-(2,6-dichlorobenzyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-2-oxo-N-({1-[2-(1H-pyrrol-1-yl)ethyl]-4-piperidinyl}methyl)-1,2-dihydro-3-pyridinecarboxamide;

ethyl 2-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl]butanoate;

6-amino-5-chloro-N-{[1-(2-cyclohexylethyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

ethyl 2-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl]-3-methylbutanoate;

6-amino-5-chloro-N-{[1-(2-ethylhexyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-2-oxo-N-({1-[2-(phenylthio)ethyl]-4-piperidinyl}methyl)-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-{[1-(4-methylpentyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-N-{[1-(4-bromo-2-fluorobenzyl)-4-piperidinyl]methyl}-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide di-hydrochloride;

6-amino-5-chloro-N-{[1-(2-methylbutyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-N-{[1-(2-bromobenzyl)-4-piperidinyl]methyl}-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-N-{[1-(3-bromobenzyl)-4-piperidinyl]methyl}-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

1-(6-amino-5-chloro-2-methoxy-3-pyridinyl)-3-(1-isobutyl-4-piperidinyl)-1-propanone;

6-amino-5-chloro-N-{[1-(cyclohexylmethyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1H-indol-2-yl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-2-oxo-N-{[1-(2-phenylethyl)-4-piperidinyl]methyl}-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

ethyl 2-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl]pentanoate;

methyl [4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl](phenyl)acetate;

6-amino-5-chloro-N-{[1-(2-methylpropyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1-naphthyl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]piperidin-4-yl}methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-Amino-5-chloro-N-{[1-(1-methyl-2-oxo-2-phenylethyl)piperidin-4-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-3-{3-[1-(3,3-dimethyl-2-oxobutyl)piperidine-4-yl]prpanoyl}pyridin-2(1H)-one;

6-amino-5-chloro-3-{3-[1-(1,3,3-trimethyl-2-oxobutyl-2-oxobutyl)piperidine-4-yl]propanoyl}pyridin-2(1H)-one;

6-amino-5-chloro-3-{3-[1-(cyclohexylmethyl)piperidine-4-yl]propanoyl}pyridin-2(1H)-one;

6-amino-5-chloro-3-{3-[1-(2-hydroxy-3,3-dimethylbutyl)piperidine-4-yl]propanoyl}pyridin-2(1H)-one;

methyl 5-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydropyridin-3-yl)carbonyl]-amino}methyl)piperidin-1-yl]-3,3-dimethyl-4-oxopentanoate;

6-amino-5-chloro-N-{[1-(3,3-dimethyl-2-oxobutyl)piperidin-4-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-N-[(1-neopentylpiperidin-4-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-N-[(1-{1-[(methylamino)carbonyl]pentyl}piperidin-4-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-2-oxo-N-({1-[1-(piperidin-1-ylcarbonyl)pentyl]piperidin-4-yl}methyl)-1,2-dihydropyridine-3-carboxaimde;

or

6-amino-5-chloro-N-{[1-(1-{[cyclohexyl(methyl)amino]carbonyl}pentyl)-piperidine-4-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxamide; and

salts thereof.

9. A compound according to claim 1 selected from

1-(6-amino-5-chloro-2-methoxy-3-pyridinyl)-3-(1-isobutyl-4-piperidinyl)-1-propanone;

6-amino-5-chloro-N-{[1-(cyclohexylmethyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1H-indol-2-yl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-2-oxo-N-{[1(2-phenylethyl)-4-piperidinyl]methyl}-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

ethyl 2-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl]pentanoate;

methyl [4-({[(6-amino-5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)carbonyl]-amino}methyl)-1-piperidinyl](phenyl)acetate;

6-amino-5-chloro-N-{[1-(2-methylpropyl)-4-piperidinyl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-N-({1-[2-(1-naphthyl)ethyl]-4-piperidinyl}methyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide;

6-amino-5-chloro-2-oxo-N-({1-[4-(trifluoromethoxy)benzyl]-4-piperidinyl}methyl)-1,2-dihydro-3-pyridinecarboxamide;

methyl 5-[4-({[(6-amino-5-chloro-2-oxo-1,2-dihydropyridin-3-yl)carbonyl]-amino}methyl)piperidin-1-yl]-3,3-dimethyl-4-oxopentanoate;

6-amino-5-chloro-N-{[1-(3,3-dimethyl-2-oxobutyl-2-oxobutyl)piperidin-4-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-N-[(1-neopentylpiperidin-4-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-N-[(1-{1-[(methylamino)carbonyl]pentyl}piperidin-4-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;

6-amino-5-chloro-2-oxo-N-({1-[1-(piperidin-1-ylcarbonyl)pentyl]piperidin-4-yl}methyl)-1,2-dihydropyridine-3-carboxaimde;

or

6-amino-5-chloro-N-{[1-(1-{[cyclohexyl(methyl)amino]carbonyl}pentyl)-piperidine-4-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxamide; and

salts thereof.

10. A pharmaceutical composition for the treatment or prevention of disease conditions mediated by 5-HT₄ receptor activity, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to any of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder, which comprises a therapeutically effective amount of a compound according to any of claims 1 to 9 and a pharmaceutically acceptable carrier.

12. A method for the treatment or prevention of disease conditions mediated by 5-HT₄ receptor activity, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to any of claims 1 to 9.

13. A method for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder, which comprises administering to said subject a therapeutically effective amount of a compound according to any of claims 1 to 9.

14. Use of a compound according to any of claims 1 to 9 in the manufacture of a medicament for the treatment or prevention of disease conditions mediated by 5-HT₄ receptor activity, in a mammalian subject.

15. Use of a compound according to any of claims 1 to 9, wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety or cardiovascular disorder.