NOVEL BENZAMIDE DERIVATIVES AND PROCESS FOR THE PREPARTION THEREOF

• US 20100105727A1
• Filed: 03/14/2008
• Published: 04/29/2010
• Est. Priority Date: 03/16/2007
• Status: Abandoned Application

• Current Assignee: Dong-A Pharm Company Limited
• Original Assignee: Dong-A Pharm Company Limited
• Inventors: Choi, Sung-Hak, Shon, Ju-Hee, Kim, Ja-Young, Rhee, Jae-Keol, Park, Jung-Sang, Choi, Sun-Ho, Im, Weon-Bin, Sung, Hyun-Jung, Shon, Tae-Kyoung, Kim, Eun-Jung, Yoo, Moo-Hi
• Application Number:
  US12/531,677
• Publication Number:
  US 20100105727A1
• Time in Patent Office: Days
• US Class Current: 514/311
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 25/28 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 211/58 attached in position 4
• 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 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a novel benzamide derivative represented by formula 1 and an isomer, a pharmaceutically acceptable salt or hydrate thereof, and a composition for activating a 5-HT<sb>4</sb> receptor comprising the same, as an active ingredient. Benzamide derivatives of the present invention has superior affinity for 5-HT<sb>4</sb> receptors, capability to reduce the gastric evacuation time, capability to alleviate ventricular tachycardia, ventricular fibrillation, torsades de pointes and QT prolongation, and low toxicity. Therefore, benzamide derivatives of the present invention are therapeutically effective for digestive system diseases.

Claims

1. A compound represented by formula 1:

wherein;

R¹ is hydrogen or C_1-6 alkyl;

R² is hydrogen or C_1-6 alkyl;

R³, R⁴ and R⁵ are independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, amino, hydroxy, cyano, nitro, or halogen; and

L is

wherein m is an integer of 1 to 5;

X is —

(C═

O)—

, —

(C═

S)—

, or —

SO₂—

;

R⁶ is C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkoxy, C_1-10 thioalkoxy, or NR⁷R⁸ wherein R⁷ and R⁸, which are identical or different, are independently hydrogen or C_1-10 alkyl;

Q is pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, or benzofuran, each of which being optionally substituted by C_3-10 cycloalkyl, C_1-6 alkyl or nitro; and

R⁹ and R¹⁰, which are identical or different, are independently pyridine, indole, or quinoline, each of which being optionally substituted by hydrogen or C_1-6 alkyl;

or an isomer, a pharmaceutically acceptable salt or a hydrate thereof.

2. The compound according to claim 1, wherein the position 3 and position 4 in formula 1 are in a cis configuration, a (3S,4R) configuration, or a (3R,4S) configuration.

3. The compound according to claim 1, wherein R¹ is methyl.

4. The compound according to claim 1, wherein R² is hydrogen.

5. The compound according to claim 1, wherein R³, R⁴, and R⁵ are independently chloro, amino or methoxy.

6. The compound according to claim 5, wherein R³ is 2-methoxy, R⁴ is 4-amino, and R⁵ is chloro.

7. The compound according to claim 1, wherein L is

8. The compound according to claim 1, wherein L is

9. The compound according to claim 1, wherein L is

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

ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

ethyl 4-[((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

ethyl 4-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate,

ethyl 2-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate,

methyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

propyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

isopropyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

isobutyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

allyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

2-ethylhexyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

3-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

4-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1-propionylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-butyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(1-butyrylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pentanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-hexanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(2-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-acetylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(2-methylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-ethanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pentanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-hexanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-butanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(1-(2,2-dimethylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

S-ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

S-propyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

S-butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

cis-4-amino-5-chloro-N-[1-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-(1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-tetrazol-2-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,3-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-pyrrol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(bicyclo[2.2.1]heptan-2-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(benzofuran-2-ylmethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-6-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(quinolin-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(4,6-dimethylpyridin-2-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(4,6-dimethylpyridin-2-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(1H-indol-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(1H-indol-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid dimethylamide,

(3R,4S)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride,

cis-4-amino-5-chloro-N-[1-(1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate,

cis-4-amino-5-chloro-N-[1-(1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride,

cis-4-amino-5-chloro-N-[1-(1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide hydrochloride, and

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide maleate.

11. A process for preparing a compound represented by formula 1, comprising:

(1) introducing a substituent at the amine of a compound of formula III to form a compound of formula IV;

(2) substituting hydroxy of the compound of formula IV by halogen or sulfonate to form a compound of formula V; and

(3) reacting the resulting compound of formula V with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-1;

wherein L, X, R¹, R², R³, R⁴, R⁵, R⁶, and m are as defined in claim 1, and Y is a halogen atom or sulfonate.

12. A process for preparing a compound represented by formula 1, comprising:

(1) substituting Y² of a compound of formula VI with Q to form a compound of formula VII; and

(2) reacting the resulting compound of formula VII with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-2;

wherein L, R¹, R², R³, R⁴, R⁵, R⁶, m and Q are as defined in claim 1, and Y¹ and Y² are independently a halogen atom.

13. A process for preparing a compound represented by formula 1, comprising:

(1) reacting an acid chloride compound of formula VIII or XI with an amine compound of formula X to form an amide compound of formula IX or XII, and

(2) reacting the resulting compound of formula IX or XII with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-3;

wherein L, R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, and m are as defined in claim 1, and Y is a halogen atom.

19. A method for treating a disease condition mediated by 5-HT₄ receptor activity, comprising administering a compound of claim 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof to a mammalian subject in need thereof.

20. A method for treating a disease condition, comprising administering a compound of claim 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof to a mammalian subject in need thereof, wherein the disease condition is selected from the group consisting of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, post-operative ileus, gastroparesis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer'"'"'s disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes and apnea syndrome.

21. A use of a compound of claim 1, an isomer, a pharmaceutically acceptable salt or a hydrate thereof, for the preparation of a medicament for treating a disease condition mediated by 5-HT₄ receptor activity in a mammalian subject.

22. A use of a compound of claim 1, an isomer, a pharmaceutically acceptable salt or a hydrate thereof, for the preparation of a medicament for treating a disease condition in a mammalian subject, wherein the disease condition is selected from the group consisting of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, post-operative ileus, gastroparesis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer'"'"'s disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes and apnea syndrome.

14. A composition for activating a 5-HT₄ receptor, comprising a compound represented by formula 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof, as an active ingredient.

wherein:

R¹ is hydrogen or C_1-6 alkyl;

R² is hydrogen or C_1-6 alkyl;

R³, R⁴ and R⁵ are independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, amino, hydroxy, cyano, nitro, or halogen; and

L is

wherein m is an integer of 1 to 5;

X is —

(C═

O)—

, —

(C═

S)—

, or —

SO₂—

;

R⁶ is C_1-10 alkyl, C_1-10 alkenyl, C_1-10 alkoxy, C_1-10 thioalkoxy, or NR⁷R⁸ wherein R⁷ and R⁸, which are identical or different, are independently hydrogen or C_1-10 alkyl;

Q is pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, or benzofuran, each of which being optionally substituted by C_3-10 cycloalkyl, C_1-6 alkyl or nitro; and

R⁹ and R¹⁰, which are identical or different, are independently pyridine, indole, or quinoline, each of which being optionally substituted by hydrogen or C_1-6 alkyl.

15. The composition according to claim 14, wherein the compound is selected from the group consisting of:

ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

ethyl 4-[((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

ethyl 4-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate,

ethyl 2-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate,

methyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

propyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

isopropyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

isobutyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

allyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

2-ethylhexyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

3-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

4-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate,

cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1-isobutyrylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1-propionylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-butyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-butyrylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pentanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-hexanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(2-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-acetylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(2-methylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-ethanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-propanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-pentanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-hexanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-butanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(2,2-dimethylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

S-ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

S-propyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

S-butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate,

cis-4-amino-5-chloro-N-[1-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1 (2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-tetrazol-2-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,3-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-(1H-pyrrol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(bicyclo[2.2.1]heptan-2-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(benzofuran-2-ylmethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

(3S,4R)-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-6-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(quinolin-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(4,6-dimethylpyridin-2-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(4,6-dimethylpyridin-2-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(3-oxo-3-(1H-indol-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-(6-oxo-6-(1H-indol-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid dimethylamide,

(3R,4S)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide,

cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride,

cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate,

cis-4-amino-5-chloro-N-[1-((1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride,

cis-4-amino-5-chloro-N-[1-((1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate,

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide hydrochloride, and

4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide maleate.

16. The composition according to claim 14, wherein the composition for the treatment of one or more disease conditions selected from the group consisting of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, post-operative ileus, gastroparesis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer'"'"'s disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes and apnea syndrome.

17. A method for activating a 5-HT₄ receptor, comprising administering a composition of claim 14 to a mammalian subject.

18. A use of a composition of claim 14 for activating a 5-HT₄ receptor.