HK1225375A1

HK1225375A1 - Piperidine compounds, pharmaceutical composition comprising the same and its use

Info

Publication number: HK1225375A1
Application number: HK16113549.1A
Authority: HK
Inventors: 郑求民; 全亨珍; 金辰圣; 金羲浩; 闵惠景; 金用吉; 崔锺吉; 金弘彧
Original assignee: 爱思开生物制药株式会社
Priority date: 2008-10-14
Filing date: 2016-11-28
Publication date: 2017-09-08

Abstract

Piperidine compounds and pharmaceutically useful salts thereof, a pharmaceutical composition including an effective amount of the racemic or enantiomerically enriched piperidine compounds to treat gastrointestinal diseases, and a method of treating gastrointestinal diseases in a mammal are provided.

Description

Piperidine compounds, pharmaceutical compositions containing the same and uses thereof

This application claims priority from U.S. patent application No.61/105070 filed on 14/10/2008; the present application is a divisional application of chinese patent application No.200980140895.6(No.201410234573.0) entitled "piperidine compound, pharmaceutical composition containing the same, and use thereof", filed on 14/4/2011, 2009, 13/13.

Technical Field

The present invention relates generally to a piperidine compound and pharmaceutically acceptable salts thereof, a pharmaceutical composition for treating gastrointestinal disorders comprising an effective amount of a racemic or enantiomerically enriched piperidine compound, and a method of treating gastrointestinal disorders in a mammal. More particularly, the present invention relates to racemic or enantiomerically enriched O-carbamoyl (O-carbamoyl) and hydroxypiperidine compounds and pharmaceutically acceptable salts thereof, which are useful in the treatment of Irritable Bowel Syndrome (IBS), gastric motility disorder (gastromotility disorder) and visceral pain.

Background

Numerous reports have disclosed that piperidine compounds are useful in the control of various gastrointestinal disorders, particularly irritable bowel syndrome and gastric motility disorders.

For example, cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) -propyl ] -3-methoxy-4-piperidinyl ] -2-methoxybenzamide (common name: Cisapride) has been widely used in the clinical field as a gastrointestinal motility enhancer or gastrointestinal motility agent, and other piperidine compounds as therapeutic drugs for solving gastrointestinal diseases are disclosed in many patents (WO2005/092882, WO1999/055674, WO2005/021539, WO04/026868, WO04/094418, WO 99/02494).

Active research and development efforts on the use of piperidine compounds for the treatment of gastrointestinal disorders continue.

Disclosure of Invention

Certain embodiments provide a piperidine compound and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising an effective amount of a piperidine compound and/or a pharmaceutically acceptable salt thereof for treating gastrointestinal disorders, and a method of treating a disease in a mammal, such as Irritable Bowel Syndrome (IBS), gastric motility disorder, and/or visceral pain.

Certain embodiments provide a method of treating a disease in a mammal in need of treatment for Irritable Bowel Syndrome (IBS) or gastric motility disorder by administering to the mammal an effective amount of a racemic or enantiomerically enriched piperidine compound represented by the following structural formula (I), particularly compounds represented by the following structural formulae (IV) and (V), and a pharmaceutically acceptable carrier.

Certain embodiments provide the use of a piperidine compound and/or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of gastrointestinal disorders (e.g., Irritable Bowel Syndrome (IBS), gastric motility disorder, constipation, and/or visceral pain) in a mammal.

Certain embodiments provide the use of a piperidine compound and/or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention and/or treatment of gastrointestinal disorders, such as Irritable Bowel Syndrome (IBS), gastric motility disorders, constipation and/or visceral pain, in a mammal.

Detailed Description

The present invention may be better understood, and its numerous advantages made apparent by the following detailed description.

In one embodiment, provided are piperidine compounds represented by the following structural formula (I),

wherein:

m is an integer of 1 or 2;

n is an integer from 0 to 2, preferably 0;

a is selected from the group consisting of phenyl and benzimidazolyl, wherein the phenyl may be substituted with one or more of the same or different groups independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, amino, and halogen, and the benzimidazolyl may be substituted with one or more of the same or different groups independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, C3-C7 cycloalkyl, amino, halogen, and oxo (oxo).

X is hydroxy or OCONR₁R₂Wherein R is₁And R₂May be the same or different and are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, benzyl, and a 5-7 membered ring or heterocyclic compound which may be substituted with one or more of the same or different groups independently selected from C1-C6 alkyl, or R₁And R₂May form a 5-7 membered heterocyclic compound together with the nitrogen atom to which they are attached; and is

B is selected from phenyl, phenoxy, thienyl and naphthyl, wherein the phenyl, phenoxy, thienyl or naphthyl may be substituted by one or more same or different groups independently selected from hydrogen, halogen, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 linear or branched alkyl and C1-C6 linear or branched alkoxy.

In the definition of the substituents, the alkyl group may be selected from methyl, ethyl, linear or branched propyl, linear or branched butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and benzyl. The halogen is selected from fluorine, chlorine, bromine and iodine atoms.

In one embodiment, substituent A in structural formula (I) may be phenyl, which may be substituted with one or more groups which may be the same or different and are independently selected from hydrogen, halogen, amino, C1-C6 linear or branched alkyl, or C1-C6 linear and branched alkoxy.

Substituent A may be represented by structural formula (II):

wherein R3 is a substituted or unsubstituted C1-C6 straight or branched chain alkyl group.

When substituent a in structural formula (I) has structural formula (II), the piperidine compound is represented by the following structural formula (IV):

wherein m, n, X, B and R3 are as defined above.

Examples of the compound of formula (IV) may include 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide;

4-amino-5-chloro-N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-methylphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [2- (4-chlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [2- (3, 4-dichlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- [4- (trifluoromethyl) phenyl ] ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [2- (3, 4-difluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1-phenylethyl ] carbamate: a hydrochloride salt;

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) ethyl ] carbamate: a hydrochloride salt;

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-dichlorophenyl) ethyl ] carbamate: a hydrochloride salt;

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-difluorophenyl) ethyl ] carbamate: a hydrochloride salt;

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- [4- (trifluoromethyl) phenyl ] ethyl ] carbamate: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [3- (3, 4-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- (3-hydroxy-3-thiophen-2-ylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride (4-amino-5-chloro-N- [ [1- (3-hydroxy-3-thiophen-2-ylpropyll) piperidine-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride);

4-amino-5-chloro-N- [ [1- [4- (4-fluorophenyl) -3-hydroxybutyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [5- (4-fluorophenyl) -3-hydroxypentyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-chlorophenyl) propyl ] carbamate: a hydrochloride salt;

[4- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) but-2-yl ] carbamate: a hydrochloride salt;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -5- (4-fluorophenyl) pent-3-yl ] carbamate: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

4-amino-5-chloro-N- [ [1- [2-hydroxy-3- [4- (trifluoromethyl) phenoxy ] propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: a hydrochloride salt;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: a hydrochloride salt;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-fluorophenoxy) propan-2-yl ]3, 5-dimethylpiperidine-1-carboxylate: a hydrochloride salt;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-methoxyphenoxy) propan-2-yl ] carbamate: a hydrochloride salt;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2,3-dichlorophenoxy) propan-2-yl ] azepan-1-carboxylate: a hydrochloride salt; ([1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidine-1-yl ] -3- (2, 3-dichlorphenoxy) propan-2-yl ] azepane-1-carboxylate: hydrochloride)

4-amino-5-chloro-N- [ [1- [ (2S) -2-hydroxy-2-phenylethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide;

4-amino-5-chloro-N- [ [1- [ (2R) -2-hydroxy-2-phenylethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide;

4-amino-5-chloro-N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide;

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate;

(R) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate;

(S) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate;

4-amino-5-chloro-N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide;

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxypropan-2-yl ] piperidine-1-carboxylic acid ester; and

4-amino-5-chloro-N- [ [1- [3- (2, 5-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide.

In another embodiment, substituent A may be a benzimidazolyl group, which may be substituted by one or more of the same or different groups independently selected from hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, C3-C7 cycloalkyl, amino, halogen, and oxo.

The substituent A in the structural formula (I) is represented by the structural formula (III):

wherein R4 is a C1-C6 straight or branched chain alkyl group, or a C3-C7 cycloalkyl group which may be substituted or unsubstituted.

When substituent a in structural formula (I) has structural formula (III), the piperidine compound is represented by the following structural formula (V):

examples of the compound of formula (V) may include [1- (2-methylphenoxy) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate ([1- (2-methylphenoxy) -3- [4- [ [ (2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] pididin-1-yl ] propan-2-yl ] carbamate);

n- [ [1- (2-hydroxy-3- (4-nitrophenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide hydrochloride (N- [ [1- [2-hydroxy-3- (4-nitrophenoxy) propyl ] piperidine-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide: hydrochloride);

n- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide hydrochloride;

n- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide hydrochloride (N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypyrol ] piperidine-4-yl ] methyl ] -3-methyl-2-oxobenzamide: hydrochloride);

3-ethyl-N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride;

[1- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: a hydrochloride salt;

[1- (4-fluorophenoxy) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate: a hydrochloride salt;

[1- (4-methoxyphenoxy) -3- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] prop-2-yl ] carbamate: a hydrochloride salt;

[1- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: a hydrochloride salt;

[1- (4-chlorophenoxy) -3- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] propan-2-yl ] carbamate: a hydrochloride salt;

3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride;

3-cyclopropyl-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide hydrochloride;

[3- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1-phenylpropyl ] carbamate: a hydrochloride salt;

[1- (4-fluorophenyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: a hydrochloride salt;

[1- (4-methoxyphenyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: a hydrochloride salt;

n- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride;

[1- (4-fluorophenyl) -2- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] ethyl ] carbamate: a hydrochloride salt;

[ [2- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1- (3-methoxyphenyl) ethyl ] carbamate: a hydrochloride salt;

[1- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxypropan-2-yl ] carbamate;

n- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide; and

[3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -1-phenylpropyl ] carbamate.

According to one embodiment of the present invention, the compound represented by structural formula (I) and pharmaceutically acceptable salts thereof can be prepared by starting from an amino alcohol compound represented by general structural formula (VI):

wherein A, B, m and n are as described above.

The process for producing an O-carbamoyl compound represented by the following general structural formula (VII) will be described in detail below:

wherein A, B, R1, R2, m and n are as described above.

An O-carbamoyl compound represented by the general structural formula (VII) is prepared by: reacting an amino alcohol represented by the general structural formula (VI) with 1, 1' -Carbonyldiimidazole (CDI) and then with an amine base represented by the general structural formula (VIII):

NHR1R2(VIII)

wherein R1 and R2 are as described above.

An overview of this process is shown in reaction scheme 1 below.

Reaction scheme I

The reaction conditions described in reaction scheme I are described in detail below. For the conversion of compound (VI) to compound (VII), the concentration of starting material (VI) is about 0.005-0.1 molar and 1, 1' -Carbonyldiimidazole (CDI) is about 2.0-3.0 equivalents. The reaction is preferably carried out at a temperature of from 10 to 30 ℃. The resulting intermediate is treated, without purification, with 1-1000 equivalents of an amine base represented by general structural formula (VIII) at a temperature of 10-30 ℃ to produce the compound of general structural formula (VII). For the carbamoylation reaction, an ether solvent such as diethyl ether and tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane and chloroform, or a mixture thereof may be used.

In reaction scheme I, HX represents an acid capable of forming a pharmaceutically acceptable salt with the nitrogen atom of the base. Specific examples of the acid used for preparing compound (IX) from compound (VII) include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid (ethanesulfonic acid), hydroxymethylsulfonic acid, isethionic acid and the like. Other acids can be obtained by reference to "pharmaceutical salts", j.pharm.sci., 1977; 66(1) 1-19. The preparation can be carried out in a reaction medium such as: ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents, and mixtures thereof. The ether solvent is preferably an addition solution (addition) comprising diethyl ether, propyl ether, isopropyl ether, dibutyl ether and isobutyl ether. The concentration of compound (VII) is of the order of about 0.01-5 molar.

For the preparation of a medicament intended for the prevention or treatment of gastrointestinal disorders such as Irritable Bowel Syndrome (IBS), gastric motility disorder and/or visceral pain, the piperidine compound of structural formula (I) may include all the possible isomeric forms, such as the racemic form, the enantiomeric form and the diastereomeric form, and the pharmaceutically acceptable addition salts of said compound of structural formula (I) with inorganic and/or organic acids or with inorganic and/or organic bases.

The process for producing the aminoalcohol benzamide compound represented by the following structural formula (X) will be described in detail below:

wherein B, m and n are as described above.

The aminoalcohol benzamide compound represented by the general structural formula (X) is prepared by: reacting a piperidine benzamide represented by the general structural formula (XI) with an alkyl halide represented by the following general structural formula (XII), an epoxide represented by the following general structural formula (XIII), or a Weinreb amide represented by the following general structural formula (XIV):

wherein m is the integer 1 or 2, Z is halogen, and B is the same as defined above;

wherein n is an integer from 0 to 2, preferably 0, and B is the same as defined above; and

wherein n is an integer from 0 to 2, preferably 0, and B is the same as defined above.

The process is summarized as shown in reaction scheme II below.

Reaction scheme II

Step II-1

In this step, the desired piperidine compound of formula (XV) is prepared by alkylating a compound of formula (XI) with an alkyl halide (XII) and then reducing the resulting ketone. The details of the reaction conditions of step II-1 are as follows. For the conversion of compound (XI) to compound (XV), the concentration of the starting material (XI) is about 0.005 to 0.1 mol, the compound (XII-1) is about 1.1 to 3.0 equivalents, and the base (e.g., potassium carbonate, cesium carbonate, and triethylamine) is about 1.5 to 5.0 equivalents. The reaction is preferably carried out at a temperature of from 20 to 80 ℃. Without purification, the resulting intermediate ketone is treated with 1.0-10.0 equivalents of NaBH at a temperature of 0-30 deg.C₄Processing to obtain the compound with the general structural formula (XV).

For another conversion of compound (XI) to compound (XV) wherein the alkyl halide is represented by formula (XII-2), starting material (XI) is about 0.005-0.1 moles, compound (XII-2) is about 1.1-3.0 equivalents, and base (e.g., potassium carbonate, cesium carbonate and triethylamine) is about 1.5-5.0 equivalents. The reaction is preferably carried out at a temperature of from 20 to 80 ℃. For this reaction, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, alcohol solvents such as methanol, ethanol and isopropanol, or acetonitrile can be used.

Step II-2

In this step, the piperidine compound (XVI) is prepared by a ring-opening reaction of an epoxide.

The reaction conditions described in step II-2 are described in detail below. For the conversion of compound (XI) to compound (XVI), the concentration of starting material (XI) is about 0.005-0.1 molar and compound (XIII) is about 1.1-3.0 equivalents. The reaction is preferably carried out at a temperature of from 20 to 80 ℃. For this reaction, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, alcohol solvents such as methanol, ethanol and isopropanol, or acetonitrile can be used.

Step II-3

In this step, the piperidine compound (XVIII) is prepared by: coupling of a compound of formula (XI) with a Weinreb amide compound of formula (XIV) followed by reduction of the resulting ketone compound of formula (XVII). The reaction conditions described in step II-3 are described in detail below. For the conversion of compound (XI) to compound (XVIII), the concentration of Weinreb amide (XIV) is about 0.005-0.1 molar and the vinyl magnesium bromide is about 1.1-2.0 equivalents. Next, the resulting intermediate is treated with a piperidine compound represented by the general formula (XI) and an excess of water at a temperature of 0 to 30 ℃ to obtain a compound of the general structural formula (XVII). Without purification, the resulting intermediate ketone is treated with 1.0-10.0 equivalents of NaBH at a temperature of 0-30 deg.C₄And (XVIII) to obtain a compound of the general structural formula (XVIII). For this reaction, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, alcohol solvents such as methanol, ethanol and isopropanol, or acetonitrile can be used.

The process for preparing aminoalcohol benzimidazole compounds represented by the following general structural formula (XIX) will be described in detail below:

here, B, R4, m, and n are as defined above.

Aminoalcohol benzimidazole compounds represented by the general structural formula (XIX) are prepared by: reacting piperidine benzimidazole represented by the general structural formula (XX) with an alkyl halide represented by the following general structural formula (XII) or an epoxide represented by the following general structural formula (XIII):

wherein m is the integer 1 or 2, Z is halogen, and B is the same as defined above; and

wherein n is an integer from 0 to 2 and B is the same as defined above.

An overview of this process is shown in reaction scheme III below.

Reaction scheme III

Step III-1

In this step, the piperidine compound of formula (XXI) is prepared by alkylating the compound of formula (XX) with an alkyl halide (XII) followed by reduction. The reaction may be carried out under the same conditions as described in step II-1.

Step III-2

In this step, the piperidine compound of formula (XXII) is prepared by the ring-opening reaction of an epoxide. The reaction may be carried out under the same conditions as described in step II-2.

It should be noted that the stereochemistry of the product (I, IV or V) depends only on the stereochemistry of the starting material (XII or XIII); the starting material (XII or XIII) with the (S) -enantiomer yields only the product with the (S) -enantiomer, and the starting material (XII or XIII) with the (R) -enantiomer yields only the product with the (R) -enantiomer.

Based on the therapeutic activity of the novel piperidine compounds shown in the following examples, another embodiment provides a pharmaceutical composition comprising, as an active ingredient, a piperidine compound represented by structural formula (I), particularly compounds represented by structural formulae (IV) and (V).

In another embodiment, there is provided a pharmaceutical composition comprising an effective amount of a piperidine compound represented by structural formula (I), particularly compounds represented by structural formulae (IV) and (V), for treating gastrointestinal diseases such as irritable bowel syndrome, gastrointestinal motility disorders (such as gastric motility disorder), constipation, visceral pain, and the like.

Another embodiment provides a method of treating gastrointestinal disorders (e.g., Irritable Bowel Syndrome (IBS), gastrointestinal motility disorders (e.g., gastric motility disorder), constipation, and visceral pain) in a mammal, comprising administering to a mammal in need of treatment for a gastrointestinal disorder, a composition of a compound of formula (I).

The compounds of structural formula (I) are useful in the treatment of IBS, particularly constipatory IBS, constipation and other gastrointestinal disorders associated with a disorder of gastrointestinal motility, as these compounds increase gastrointestinal motility.

In addition, the compounds of structural formula (I) are useful for alleviating visceral pain caused by IBS and/or other gastrointestinal disorders because these compounds can alleviate visceral pain and discomfort associated with IBS and the like.

The compounds of structural formula (I) may be administered orally or parenterally, either alone or in combination with conventional pharmaceutical carriers. Suitable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrating agents, or an encapsulating material. In powders, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression characteristics in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to 99% of the active ingredient.

Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine (polyvinylpyrrolidine), low melting waxes and ion exchange resins. Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators (osmo-regulators). Suitable examples of liquid carriers for oral and parenteral administration include water (particularly with additives as described above such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).

For parenteral administration, the carrier may also be an oil or fat such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, may be used by injection, for example, intramuscularly, intraperitoneally, or subcutaneously. Sterile solutions can also be administered intravenously.

Oral administration can be in the form of liquid or solid compositions. Preferably, the pharmaceutical compositions comprising the compounds of the present invention are in unit dosage form, such as tablets or capsules. In this form, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged composition, for example, a packaged powder, vial (visual), ampoule (ampoule), pre-filled syringe, or sachet containing a liquid (sachet). Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate amount of any such composition in packaged form. The therapeutically effective dose to be used may be varied or adjusted by the administering physician according to the particular condition(s) being treated and the size, age and response pattern of the patient, and is typically from 0.5mg to 750 mg.

The compound of formula (I) may be administered to a patient at a dose of 0.7 to 7000mg per day. For a normal adult human weighing about 70kg, the dosage is converted to a daily dose of 0.01-100mg per kg body weight. However, the specific dose administered may vary according to the needs of the patient, the severity of the patient's condition, and the activity of the compound. Determination of the optimal dosage for a particular situation must be performed clinically and is within the ability of those skilled in the art.

Another embodiment provides the use of a piperidine compound and/or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of gastrointestinal disorders, such as Irritable Bowel Syndrome (IBS), gastric motility disorder, constipation and/or visceral pain, in a mammal. Yet another embodiment provides a use of a piperidine compound and/or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of gastrointestinal disorders such as Irritable Bowel Syndrome (IBS), gastric motility disorder, constipation and/or visceral pain in a mammal.

The invention will be better understood by means of the following examples, which are given for the purpose of illustrating the invention and are not to be construed as limiting the invention.

Example 1

4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A mixture of 4-amino-5-chloro-2-methoxy-N- ((piperidin-4-yl) methyl) benzamide (5.0mmol), 2-bromoacetophenone (6.0mmol) and potassium carbonate (7.6mmol) was stirred in 15mL acetonitrile for 2 hours. The solution was then concentrated in a rotary evaporator and diluted with ethyl acetate. The mixture was then washed with brine, and the resulting organic layer was dried and purified by column chromatography. This was dissolved in ethanol (10mL), sodium borohydride (10.0mmol) was added at 0 deg.C and stirred at 25 deg.C for 2 hours. The solution was then concentrated in a rotary evaporator and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography. The resulting 4-amino-5-chloro-N- ((1- (2-hydroxy-2-phenylethyl) piperidin-4-yl) methyl) -2-methoxybenzamide was dissolved in dichloromethane (MC) and the resulting solution was treated with an ethereal solution of HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4-7.2(m,5H),6.35(s,1H),4.95(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.3(m,3H),3.0(m,1H),2.6(m,2H),2.4(m,1H),2.2(m,1H),1.9-1.6(m,3H),1.6-1.4(m,2H)

Example 2

4-amino-5-chloro-N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -fluoroacetophenone instead of 2-bromoacetophenone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.15(m,2H),7.1-6.95(m,2H),6.35(s,1H),4.9(m,1H),4.4(s,2H),3.9(m,3H),3.4-3.2(m,3H),3.1-2.9(m,1H),2.6-2.3(m,3H),2.3-2.1(m,1H),1.9-1.7(m,3H),1.6-1.4(m,2H)

Example 3

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-tolyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -methylacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.1(m,4H),6.35(s,1H),4.9(m,1H),4.4(s,2H),3.9(m,3H),3.5-3.3(m,3H),3.3-3.1(m,1H),2.7(m,2H),2.6-2.5(m,1H),2.4(m,4H),1.9-1.7(m,3H),1.6-1.5(m,2H)

Example 4

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -methoxyacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1HNMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.2(m,2H),6.95-6.85(m,2H),6.35(s,1H),4.9(m,1H),4.4(s,2H),3.9(m,3H),3.8(s,3H),3.4-3.2(m,3H),3.1-3.0(m,1H),2.6(m,2H),2.5(m,1H),2.3-2.1(m,1H),1.9-1.7(m,3H),1.6-1.4(m,2H)

Example 5

4-amino-5-chloro-N- [ [1- [2- (4-cyanophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -cyanoacetophenone as the reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.65(m,2H),7.55(m,2H),6.35(s,1H),4.9(m,1H),4.45(s,2H),3.9(m,3H),3.4(m,2H),3.2(m,1H),2.95(m,1H),2.7-2.33(m,3H),2.2(m,1H),1.9-1.7(m,3H),1.6-1.4(m,2H)

Example 6

4-amino-5-chloro-N- [ [1- [2- (4-chlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -chloroacetophenone instead of 2-bromoacetophenone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.8(m,1H),7.3(m,4H),6.35(s,1H),4.8(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.2(m,3H),3.05-2.9(m,1H),2.6-2.3(m,3H),2.2(m,1H),1.9-1.6(m,3H),1.6-1.4(m,2H)

Example 7

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-phenylphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -phenylacetophenone instead of 2-bromoacetophenone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.85(m,1H),7.6-7.3(m,9H),6.35(s,1H),5.3(m,1H),4.4(s,2H),3.9(s,3H),3.8-3.4(m,4H),3.2-3.0(m,2H),3.0-2.7(m,2H),2.4-1.6(m,3H),1.6-1.4(m,2H)

Example 8

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (2-methoxyphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2' -methoxyacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.85(m,1H),7.6(m,1H),7.3(m,1H),7.0(m,1H),6.9(m,1H),6.35(s,1H),5.25(m,1H),4.4(s,2H),3.9(s,3H),3.8(s,3H),3.6(m,2H),3.1-3.0(m,2H),2.9-2.7(m,4H),1.9-1.7(m,3H),1.7-1.4(m,2H)

Example 9

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-3' -methoxyacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.85(m,1H),7.3-7.2(m,1H),7.0-6.9(m,2H),6.85(m,1H),6.35(s,1H),4.8(m,1H),4.4(s,2H),3.9(s,3H),3.8(s,3H),3.4-3.2(m,3H),3.0(m,1H),2.6(m,2H),2.4(m,1H),2.2(m,1H),1.9-1.6(m,3H),1.6-1.4(m,2H)

Example 10

4-amino-5-chloro-N- [ [1- [2- (3, 4-dichlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-3 ', 4' -dichloroacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.5(s,1H),7.45(m,1H),7.2(m,1H),6.35(s,1H),4.8(m,1H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.3-3.2(m,1H),3.0(m,1H),2.6-2.3(m,3H),2.2(m,1H),1.9-1.6(m,3H),1.6-1.3(m,2H)

Example 11

4-amino-5-chloro-N- [ [1- [2- (2, 4-difluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2 ', 4' -difluoroacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.85(m,1H),7.65(m,1H),7.0-6.7(m,2H),6.35(s,1H),5.3(m,1H),4.4(s,2H),3.9(s,3H),3.5(m,1H),3.4(m,2H),3.2(m,2H),2.9-2.2(m,4H),2.7-2.4(m,2H),2.0-1.8(m,3H),1.8-1.6(m,2H)

Example 12

4-amino-N- [ [1- [2- (4-tert-butylphenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -5-chloro-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' -tert-butylbenzophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.45-7.3(m,4H),6.35(s,1H),4.8(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.2(m,3H),3.0(m,1H),2.6(m,2H),2.4(m,1H),2.15(m,1H),1.9-1.6(m,3H),1.55(m,2H),1.3(s,9H)

Example 13

4-amino-5-chloro-N- [ [1- [2- (2-chlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2' -chloroacetophenone instead of 2-bromoacetophenone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.85(m,1H),7.75(m,1H),7.3(m,3H),6.35(s,1H),5.3(m,1H),4.4(s,2H),3.9(s,3H),3.4(m,3H),3.05(m,1H),2.85(m,1H),2.5(m,2H),2.3(m,1H),1.9-1.7(m,3H),1.6(m,2H)

Example 14

4-amino-5-chloro-N- [ [1- [2- (2, 4-xylyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2 ', 4' -dimethylacetophenone instead of 2-bromoacetophenone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.45(m,1H),7.05(m,1H),6.95(m,1H),6.35(m,1H),5.05(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.3(m,3H),3.0(m,1H),2.6-2.4(m3H),2.35(m,6H),2.2(m,1H),1.9-1.6(m,3H),1.55(m,2H)

Example 15

4-amino-5-chloro-N- [ [1- [2- (2, 5-dimethoxyphenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2 ', 5' -dimethoxyacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.2(m,1H),6.8(s,2H),6.35(m,1H),5.2(m,1H),4.45(s,2H),3.9(s,3H),3.8(m,6H),3.35(m,2H),3.0(m,1H),2.8(m,1H),2.55(m2H),2.2(m,1H),1.9-1.7(m,3H),1.5(m2H)

Example 16

4-amino-5-chloro-N- [ [1- [2- (4-difluoromethoxy) phenyl-2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' - (difluoromethoxy) acetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4(m,2H),7.1(m,2H),6.35(m,1H),4.85(m,1H),4.45(s,2H),3.9(s,3H),3.4-3.2(m,3H),3.0(m,1H),2.7-2.4(m,3H),2.2(m1H),1.9-1.7(m,3H),1.5(m2H)

Example 17

4-amino-5-chloro-N- [ [1- [2- (3, 4-difluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-3 ', 4' -difluoroacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.3-7.1(m,3H),6.35(m,1H),4.85(m,1H),4.45(s,2H),3.9(s,3H),3.5-3.2(m,3H),3.0(m,1H),2.7-2.4(m,3H),2.2(m1H),1.9-1.7(m,3H),1.5(m2H)

Example 18

4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- [4- (trifluoromethyl) phenyl ] ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-4' - (trifluoromethyl) acetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.6(m,2H),7.5(m,2H),6.35(m,1H),4.9(m,1H),4.45(s,2H),3.9(s,3H),3.4(m,2H),3.3(m,1H),3.0(m,1H),2.7-2.3(m,3H),2.2(m1H),1.9-1.7(m,3H),1.5(m2H)

Example 19

4-amino-5-chloro-N- [ [1- [2- (2, 4-dichlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 1 was followed using 2-bromo-2 ', 4' -dichloroacetophenone as a reactant, instead of 2-bromoacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.65(m,2H),7.35(m,2H),6.35(m,1H),5.25(m,1H),4.45(s,2H),3.9(s,3H),3.4(m,2H),3.0(m,1H),2.8(m,1H),2.6-2.2(m,3H),1.9-1.7(m,3H),1.5(m2H)

Example 20

4-amino-5-chloro-N- [ [1- [ (2S) -2-hydroxy-2-phenylethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A mixture of 4-amino-5-chloro-2-methoxy-N- ((piperidin-4-yl) methyl) benzamide (5.0mmol) and (S) -styrene oxide (6.0mmol) was refluxed in 30mL of isopropanol for 4 hours. The solution was then concentrated in a rotary evaporator and diluted with ethyl acetate. The mixture was then washed with brine, and the resulting organic layer was dried and purified by column chromatography. The resulting 4-amino-5-chloro-N- [ [1- [ (2S) -2-hydroxy-2-phenylethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide is dissolved in MC and the resulting solution is treated with an ethereal solution of HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),8.0-7.9(br,1H),7.5-7.3(m,5H),6.35(s,1H),5.45(br,1H),4.4(s,2H),3.9(s,3H),3.5-2.7(m,6H),2.2-2.0(m,2H),1.9-1.4(m,5H)

Example 21

4-amino-5-chloro-N- [ [1- [ (2R) -2-hydroxy-2-phenylethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 20 was followed using (R) -styrene oxide as a reactant, instead of (S) -styrene oxide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(,1H),8.0-7.9(br,1H),7.5-7.3(m,5H),6.35(s,1H),5.2(br,1H),4.4(s,2H),3.9(s,3H),3.5-2.7(m,6H),2.2-2.0(m,2H),1.9-1.4(m,5H)

Example 22

[2- [4- [ [ (4-amino-5-chloro-2- (methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1-phenethyl ] carbamate: hydrochloride

4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 1 (1.5mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (12mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then excess ammonium hydroxide (3ml) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.2(m,5H),6.35(s,1H),5.9(m,1H),4.7(m,2H),4.4(s,2H),3.9(m,3H),3.3(m,2H),3.1-2.8(m,3H),2.6-2.5(m,1H),2.2-2.0(m,2H),1.8-1.3(m,5H)

Example 23

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 2 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.2(m,2H),7.15-7.0(m,2H),6.35(s,1H),5.9-5.8(m,1H),5.1-4.8(br,2H),4.4(s,2H),3.9(m,3H),3.4(m,2H),3.3-3.0(m,3H),2.8-2.6(m,2H),2.5-2.3(m,2H),1.9-1.5(m,5H)

Example 24

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-tolyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-tolyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 3 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.1(m,4H),6.35(s,1H),5.9-5.8(m,1H),4.9(m,2H),4.4(s,2H),3.9(m,3H),3.4(m,2H),3.2-2.9(m,3H),2.6(m,1H),2.35(s,3H),2.3-2.1(m,2H),1.9-1.5(m,5H)

Example 25

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-cyanophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (4-cyanophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 5 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.7(m,2H),7.5(m,2H),6.35(s,1H),5.9-5.8(m,1H),5.0-4.8(br,2H),4.4(s,2H),3.9(m,3H),3.4(m,2H),3.1-2.9(m,3H),2.7-2.6(m,1H),2.4-2.2(m,2H),1.9-1.7(m,3H),1.5(m,2H)

Example 26

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-phenylphenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (4-phenylphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 7 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(DMSO-d6,200MHz)10.2(br,1H),8.05(s,1H),7.7(m,5H),7.5-7.3(m,4H),6.9-6.8(m,2H),6.5(s,1H),6.05(m,1H),3.9(s,3H),3.6(m,2H),3.4(m,3H),3.2(m,1H),3.0(m,2H),1.9-1.4(m,5H)

Example 27

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-methoxyphenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 9 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(DMSO-d6,200MHz)10.1(br,1H),8.05(s,1H),7.65(m,1H),7.4-7.3(m,1H),7.0-6.8(m,5H),6.5(s,1H),6.0(m,1H),3.9(s,3H),3.85(s,3H),3.6(m,2H),3.4(m,3H),3.2(m,1H),3.0(m,2H),1.9-1.4(m,5H)

Example 28

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-dichlorophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (3, 4-dichlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 10 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.85(m,1H),7.5(m,2H),7.3(m,1H),6.35(s,1H),5.95(m,1H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.3-3.0(m,3H),2.7(m,1H),2.6-2.3(m,2H),1.9-1.6(m,5H)

Example 29

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-chlorophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (2-chlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 13 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.5-7.2(m,4H),6.35(m,1H),6.3(m,1H),5.1(m,2H),4.45(s,2H),3.9(s,3H),3.4-3.2(m,3H),3.0(m,1H),2.9(m1H),2.7(m,1H),2.3(m,2H),1.9-1.6(m,3H),1.55(m,2H)

Example 30

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 4-xylyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (2, 4-xylyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 14 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.05(m,1H),7.0(m,2H),6.35(s,1H),6.1(m,1H),4.9(br,2H),4.45(s,2H),3.9(s,3H),3.4(m,2H),3.2(m,1H),3.05-2.9(m,2H),2.6(m,2H),2.5-2.1(m,7H),1.9-1.5(m,5H)

Example 31

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 5-dimethoxyphenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (2, 5-dimethoxyphenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 15 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),6.95(s,1H),6.8(s,2H),6.35(s,1H),6.3(m,1H),4.95(br,2H),4.45(s,2H),3.9(s,3H),3.8(d,6H),3.4-3.2(m,3H),3.0(m,1H),2.9(m,1H),2.7(m,1H),2.4-2.2(m,2H),1.9-1.7(m,3H),1.5(m2H)

Example 32

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- [4- (difluoromethoxy) phenyl ] ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- [4- (difluoromethoxy) phenyl ] -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 16 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4(m,2H),7.15(m,2H),6.65(s,1H),6.35(s,1H),5.9(m,1H),5.1-4.8(br,2H),4.45(s,2H),3.9(s,3H),3.4-3.2(m,2H),3.3-3.0(m,3H),2.7(m,1H),2.5-2.2(m,2H),1.9-1.5(m,5H)

Example 33

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-difluorophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (3, 4-difluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 17 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.3-7.0(m,3H),6.35(s,1H),5.8(m,1H),5.1-4.8(br,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),3.2-2.9(m,2H),2.6(m,H),2.4-2.1(m,3H),1.9-1.4(m,5H)

Example 34

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- [4- (trifluoromethyl) phenyl ] ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [ 2-hydroxy-2- [4- (trifluoromethyl) phenyl ] ethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 18 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.65(m,2H),7.5(m,2H),6.35(s,1H),5.9(m,1H),5.1-4.8(br,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),3.2-2.9(m,3H),2.6(m,H),2.4-2.1(m,2H),1.9-1.4(m,5H)

Example 35

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 4-dichlorophenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 22 was followed using 4-amino-5-chloro-N- [ [1- [2- (2, 4-dichlorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 19 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenylethyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.5-7.2(m,3H),6.35(s,1H),6.2(m,1H),5.1-4.8(br,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),3.2(m,1H),3.0(m,1H),2.8(m,1H),2.65(m,1H),2.35(m,2H),1.9-1.4(m,5H)

Example 36

4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A mixture of 4-amino-5-chloro-2-methoxy-N- ((piperidin-4-yl) methyl) benzamide (5.0mmol), 3-chlorophenylacetone (6.0mmol), potassium carbonate (7.6mmol) and potassium iodide (7.6mmol) was refluxed in 15mL acetonitrile for 12 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was then washed with brine, and the resulting organic layer was dried and purified by column chromatography. This was dissolved in ethanol (10mL), sodium borohydride (10.0mmol) was added at 0 deg.C and stirred at 25 deg.C for 2 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography. The resulting 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide is dissolved in MC and the resulting solution is treated with an ethereal HCl solution. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4-7.2(m,5H),6.35(s,1H),4.95(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.1(m,4H),2.75(m,2H),2.3-1.7(m,7H),1.5(m,2H)

Example 37

4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 36 was followed using 3-chloro-4' -fluorophenylacetone instead of 3-chlorophenylacetone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.3(m,2H),7.1-7.0(m,2H),6.35(s,1H),4.9(m,1H),4.4(s,2H),3.9(s,3H),3.4-3.1(m,4H),2.9-2.7(m,2H),2.4-2.0(m,2H),1.9-1.7(m,5H),1.7-1.5(m,2H)

Example 38

4-amino-5-chloro-N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 36 was followed using 3-chloro-4' -chlorophenylacetone instead of 3-chlorophenylacetone as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4-7.35(m,2H),7.1-6.9(m,2H),6.35(s,1H),4.9(m,1H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.3-3.1(m,2H),2.8-2.6(m,2H),2.3-1.7(m,7H),1.5(m,2H)

Example 39

4-amino-5-chloro-N- [ [1- [ 3-hydroxy-3- (4-tolyl) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 36 was followed using 3-chloro-4' -methylpropiophenone as a reactant, instead of 3-chlorophenylacetone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.85(m,1H),7.3(m,2H),7.2(m,2H),6.35(s,1H),4.95(t,1H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.2(m,2H),2.8-2.7(m,2H),2.4(s,3H),2.2(m,1H),2.05-1.7(m,6H),1.4-1.2(m,2H)

Example 40

4-amino-5-chloro-N- [ [1- [ 3-hydroxy-3- (4-methoxyphenyl) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 36 was followed using 3-chloro-4' -methoxypropiophenone as a reactant, instead of 3-chlorophenylacetone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.85(m,1H),7.3(m,2H),6.9(m,2H),6.35(s,1H),4.95(t,1H),4.4(s,2H),3.9(s,3H),3.8(s,3H),3.4(m,2H),3.3-3.1(m,2H),2.8-2.6(m,2H),2.2(m,1H),2.2-1.7(m,6H),1.6-1.4(m,2H)

EXAMPLE 41

4-amino-5-chloro-N- [ [1- [3- (2-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A mixture of 2-chlorobenzoic acid (5mmol) and 1, 1' -carbonyldiimidazole was stirred in 30ml of THF for 30 minutes, then N, O-dimethylhydroxylamine hydrochloride (6.5mmol) and triethylamine (5mmol) were added. After stirring at room temperature for 12 hours, the reaction was terminated by adding water. The organic layer was extracted 2 times with ethyl acetate, then washed with 5% HCl solution and brine, dried and concentrated in vacuo. The crude product was dissolved in THF (30ml) and a 1M solution of vinylmagnesium bromide (5.5mmol) in THF was added at 0 ℃. After stirring for 10 min, the mixture was warmed to room temperature and stirred for 1h, then 4-amino-5-chloro-2-methoxy-N- ((piperidin-4-yl) methyl) benzamide (7.5mmol) and water (7.5ml) were added at room temperature. After stirring at room temperature for 30 minutes, water and ethyl acetate were added, and the organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography. This was dissolved in ethanol (10mL), sodium borohydride (10.0mmol) was added at 0 deg.C and stirred at 25 deg.C for 2 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated in vacuo. The resulting 4-amino-5-chloro-N- [ [1- [3- (2-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide is dissolved in MC and the resulting solution is treated with an ethereal solution of HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.05(s,1H),7.8(m,1H),7.7(m,1H),7.4-7.1(m,3H),5.3(s,1H),4.5(s,2H),3.9(s,3H),3.35(m,2H),3.1(m,2H),2.6(m,2H),2.2-1.6(m,7H),1.5-1.3(m,2H)

Example 42

4-amino-5-chloro-N- [ [1- [3- (3-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 3-chlorobenzoic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.05(s,1H),7.8(m,1H),7.4(s,1H),7.3-7.1(m,3H),6.3(s,1H),4.9(m,1H),4.4(s,2H),3.9(s,3H),3.35(m,2H),3.1(m,2H),2.6(m,2H),2.1-1.9(m,1H),1.9-1.5(m,6H),1.5-1.3(m,2H)

Example 43

4-amino-5-chloro-N- [ [1- [3- (2-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 2-fluorobenzoic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.05(s,1H),7.8(m,1H),7.6(m,1H),7.2(m,2H),6.95(m,1H),6.3(s,1H),5.2(m,1H),4.4(s,2H),3.9(s,3H),3.3(m,2H),3.1(m,2H),2.6(m,2H),2.2-1.5(m,7H),1.5-1.1(m,2H)

Example 44

4-amino-5-chloro-N- [ [1- [3- (3-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 3-fluorobenzoic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.05(s,1H),7.8(m,1H),7.3(m,1H),7.1(m,2H),6.9(m,1H),6.3(s,1H),4.9(m,1H),4.6(s,2H),3.9(s,3H),3.3(m,2H),3.1(m,2H),2.6(m,2H),2.2-1.5(m,7H),1.5-1.2(m,2H)

Example 45

4-amino-5-chloro-N- [ [1- [3- (2, 3-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 2, 3-dichlorobenzoic acid as a reactant, instead of 2-chlorobenzoic acid, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.6(m,1H),7.3(m,4H),6.35(s,1H),5.2(m,1H),4.5(m,2H),3.9(s,3H),3.35(m,2H),3.1(m,2H),2.8-2.5(m,2H),2.2-1.6(m,7H),1.4(m,2H)

Example 46

4-amino-5-chloro-N- [ [1- [3- (2, 4-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 2, 4-dichlorobenzoic acid as a reactant, instead of 2-chlorobenzoic acid, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.6(m,1H),7.4-7.2(m,2H),6.35(s,1H),5.3(m,1H),4.5(s,2H),3.9(s,3H),3.35(m,2H),3.1(m,2H),2.8-2.5(m,2H),2.2-1.6(m,7H),1.4(m,2H)

Example 47

4-amino-5-chloro-N- [ [1- [3- (3, 4-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 3, 4-dichlorobenzoic acid as a reactant, instead of 2-chlorobenzoic acid, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.5-7.3(m,2H),7.2(m,1H),6.35(s,1H),4.95(m,1H),4.5(s,2H),3.9(s,3H),3.35(m,2H),3.2(m,2H),2.8-2.6(m,2H),2.2-1.6(m,7H),1.5(m,2H)

Example 48

4-amino-5-chloro-N- [ [1- [3- (4-isopropylphenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 4-isopropylbenzoic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.15(m,4H),7.2(m,2H),6.3(s,1H),4.9(m,1H),4.5(s,2H),3.9(s,3H),3.35(m,2H),3.2(m,2H),2.9(m,1H),2.6(m,2H),2.2-1.6(m,7H),1.4(m,2H),1.3(m,6H)

Example 49

4-amino-5-chloro-N- [ [1- [3- (3-methoxyphenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 3-methoxybenzoic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.2(m,1H),6.9(m,2H),6.8(m,1H),6.3(s,1H),5.7(br,1H),4.9(m,1H),4.55(s,2H),3.9(s,3H),3.85(s,3H),3.3(m,2H),3.1(m,2H),2.65(m,2H),2.1(m,2H),2.0(m,1H),1.9-1.6(m,3H),1.45(m,2H)

Example 50

4-amino-5-chloro-N- [ [1- (3-hydroxy-3-thiophen-2-ylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 2-thiophenecarboxylic acid as a reactant, instead of 2-chlorobenzoic acid, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.2(m,1H),6.9(m,2H),6.8(m,1H),6.3(s,1H),5.2(m,1H),4.9(br,1H),4.55(s,2H),3.9(s,3H),3.35(m,2H),3.2(m,2H),2.7(m,2H),2.2(m,1H),2.1(m,3H),1.9-1.6(m,3H),1.45(m,2H)

Example 51

4-amino-5-chloro-N- [ [1- [4- (4-fluorophenyl) -3-hydroxybutyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 4-fluorophenylacetic acid as a reactant instead of 2-chlorobenzoic acid to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.2(m,2H),7.0(m,2H),6.3(s,1H),4.4(s,2H),4.0(m,1H),3.9(s,3H),3.3(m,2H),3.0(m,1H),2.9-2.6(m,4H),2.3-1.3(m,11H)

Example 52

4-amino-5-chloro-N- [ [1- [5- (4-fluorophenyl) -3-hydroxypentyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 41 was followed using 3- (4-fluorophenyl) propionic acid instead of 2-chlorobenzoic acid as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.75(m,1H),7.15(m,2H),7.0(m,2H),6.3(s,1H),4.4(s,2H),3.85(s,3H),3.8(m,4H),3.3(m,H),3.2(m,1H),3.0-2.6(m,6H),2.1(m,1H),2.0-1.6(m,4H),1.6-1.3(m,2H)

Example 53

[3- [4- [ [ (4-amino-5-chloro-2- (methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1-phenylpropyl ] carbamate: hydrochloride

4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 34 (1.5mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (12mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 4 hours, then excess ammonium hydroxide (3ml) was added at 0 ℃. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in dichloromethane and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.75(m,1H),7.4-7.3(m,5H),6.3(s,1H),5.7(m,1H),4.6(m,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),2.9(m,2H),2.4-2.3(m,2H),2.0-1.8(m,2H),1.8-1.5(m,3H),1.4-1.2(m,2H)

Example 54

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 35 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.2(m,2H),7.1-7.0(m,2H),6.35(s,1H),5.7(m,1H),4.6(m,2H),4.4(s,2H),3.9(s,3H),3.4-3.2(m,2H),3.0-2.8(m,2H),2.4-2.1(m,4H),2.0-1.5(m,5H),1.5-1.3(m,2H)

Example 55

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-chlorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 36 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.4-7.2(m,2H),7.1-7.0(m,2H),6.35(s,1H),5.7(m,1H),4.7(m,2H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.1-2.9(m,2H),2.4(m,2H),2.3-1.6(m,7H),1.5-1.3(m,2H)

Example 56

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-chlorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (2-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 39 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.5-7.1(m,4H),6.3(s,1H),6.05(m,1H),5.0(m,2H),4.5(m,2H),3.9(s,3H),3.3(m,2H),3.0(m,2H),2.55(m,2H),2.1(m,2H),1.8-1.2(m,5H),0.9(m,2H)

Example 57

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-fluorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (2-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 41 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-6.9(m,4H),6.3(s,1H),5.95(m,1H),5.0(s,2H),4.5(m,2H),3.85(s,3H),3.3(m,2H),2.95(m,2H),2.45(m,2H),2.1(m,2H),1.8-1.2(m,5H),0.9(m,2H)

Example 58

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-fluorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (3-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 42 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3(m,1H),7.1-6.9(m,3H),6.3(s,1H),5.65(m,1H),4.9(s,2H),4.5(s,2H),3.85(s,3H),3.3(m,2H),2.9(m,2H),2.35(m,2H),2.2-1.8(m,2H),1.8-1.2(m,5H),0.9(m,2H)

Example 59

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 3-dichlorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (2, 3-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 43 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.15(m,3H),6.3(s,1H),6.05(m,1H),5.05(m,2H),4.5(s,2H),3.9(s,3H),3.3(m,2H),2.95(m,2H),2.5(m,2H),2.1-1.8(m,4H),1.8-1.5(m,3H),1.3(m,2H)

Example 60

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 4-dichlorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (2, 4-dichlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 44 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.15(m,3H),6.3(s,1H),6.05(m,1H),5.05(br,2H),4.5(s,2H),3.9(s,3H),3.35(m,2H),3.05(m,2H),2.6(m,2H),2.1-1.8(m,4H),1.8-1.5(m,3H),1.3(m,2H)

Example 61

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-dichlorophenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (3, 4-chlorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 45 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.45(m,2H),7.2(m,1H),6.3(s,1H),5.6(m,1H),4.95(br,2H),4.45(s,2H),3.9(s,3H),3.53(m,2H),2.9(m,2H),2.3(m,4H),2.2-1.5(m,5H),1.3(m,2H)

Example 62

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-cumyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (4-cumyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 46 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.1(m,4H),6.3(s,1H),5.65(s,1H),4.95(s,2H),4.5(s,2H),3.85(s,3H),3.3(m,2H),3.1-2.8(m,3H),2.4(m,2H),2.2-1.8(m,4H),1.8-1.5(m,3H),1.4-1.2(m,8H)

Example 63

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-methoxyphenyl) propyl ] carbamate hydrochloride

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [3- (3-methoxyphenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 47 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.25(m,1H),6.9(m,3H),6.3(s,1H),5.7(m,1H),4.9(s,2H),4.55(s,2H),3.9(s,3H),3.8(s,3H),3.35(m,2H),2.95(m,2H),2.4(m,2H),2.2-1.9(m,4H),1.8-1.5(m,3H),1.45-1.2(m,2H)

Example 64

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1-thiophen-2-ylpropyl ] carbamate: hydrochloride salt

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [ 3-hydroxy-3-thiophen-2-ylpropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 48 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3(m,1H),7.1-6.9(m,2H),6.35(s,1H),4.75(s,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),3.1(m,2H),2.55(m,1H),2.5-2.0(m,5H),1.9-1.2(m,5H)

Example 65

[4- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) but-2-yl ] carbamate: hydrochloride salt

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [4- (4-fluorophenyl) -3-hydroxybutyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 51 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.75(m,1H),7.15(m,2H),7.0(m,2H),6.3(s,1H),4.9(m,1H),4.8(s,2H),4.5(s,2H),3.85(s,3H),3.3(m,2H),2.9-2.8(m,4H),2.4(m,2H),1.9(m,2H),1.8-1.5(m,5H),1.3(m,2H)

Example 66

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -5- (4-fluorophenyl) pent-3-yl ] carbamate: hydrochloride salt

The procedure given in example 53 was followed using 4-amino-5-chloro-N- [ [1- [5- (4-fluorophenyl) -3-hydroxybutyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 52 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.75(m,1H),7.15(m,2H),6.95(m,2H),6.3(s,1H),4.8(m,1H),4.75(s,2H),4.45(s,2H),3.85(s,3H),3.35(m,2H),2.95(m,2H),2.65(m,2H),2.4(m,2H),2.0-1.5(m,9H),1.3(m,2H)

Example 67

(S) -4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A solution of 3-chloro-4' -fluorophenylacetone (5.4mmol) was slowly added to a 1.6M solution of (-) -chlorodiisopinocampheylborane (8.1mmol) in hexane at-25 ℃. The reaction mixture was stirred at room temperature for 16 hours. After stirring at-25 ℃ for 16 h, MeOH was added to stop the reaction, which was then washed with brine, and the resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in 20mL acetonitrile and 4-amino-5-chloro-2-methoxy-N- [ (piperidin-4-yl) methyl ] benzamide (3.6mmol), potassium carbonate (5.4mmol) and potassium iodide (5.4mmol) were added at 25 ℃. The reaction mixture was refluxed for 12 hours. The solution was then concentrated in a rotary evaporator and diluted with ethyl acetate, washed with brine, and the resulting organic layer was dried and purified by column chromatography. The resulting (S) -4-amino-5-chloro-N- [ [1- (3- (4-fluorophenyl) -3-hydroxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide is dissolved in MC and the resulting solution is treated with an etheric solution of HCl. The resulting precipitate was filtered off to give the title compound.

Example 68

(S) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate: hydrochloride salt

(S) -4-amino-5-chloro-N- [ [1- (3- (4-fluorophenyl) -3-hydroxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 62 (1.5mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (12mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 4 hours, then excess ammonium hydroxide (3ml) was added at 0 ℃. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting (S) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate is dissolved in MC and the solution is treated with etheric HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.4-7.2(m,2H),7.1-7.0(m,2H),6.3(s,1H),5.7(m,1H),4.6(m,2H),4.4(s,2H),3.9(s,3H),3.4-3.1(m,4H),2.8-2.6(m,2H),2.3-2.0(m,2H),2.0-1.6(m,5H),1.5-1.3(m,2H)

Example 69

(R) -4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 67 was followed using (+) -chlorodiisopinocampheylborane as a reactant, instead of (-) -chlorodiisopinocampheylborane, to give the title compound.

Example 70

(R) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate: hydrochloride salt

The procedure given in example 68 was followed using (R) -4-amino-5-chloro-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide as a reactant, instead of (S) -4-amino-5-chloro-N- [ [1- (3- (4-fluorophenyl) -3-hydroxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.8(m,1H),7.4-7.3(m,4H),6.35(s,1H),4.9(m,2H),4.4(s,2H),3.9(s,3H),3.4(m,2H),3.3-3.1(m,2H),2.7(m,2H),2.2(m,1H),2.1-1.6(m,6H),1.5-1.3(m,2H)

Example 71

4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

A mixture of 4-amino-5-chloro-2-methoxy-N- [ (piperidin-4-yl) methyl ] benzamide (3mmol) and 1, 2-epoxy-3-phenoxypropane (3mmol) was heated at reflux in 10mL of isopropanol for 3 hours. The solution was concentrated in a rotary evaporator and the mixture was purified by column chromatography. The resulting 4-amino-5-chloro-N- ((1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide is dissolved in MC and the resulting solution is treated with ethereal HCl.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.75(br,1H),8.0(m,1H),7.66(s,1H),7.30(m,2H),6.96(m,3H),6.48(s,1H),5.96(s,2H),4.35(m,1H),3.95(m,2H),3.83(m,3H),3.54(m,2H),3.17(m,4H),3.0(m,2H),1.9-1.5(m,5H)

Example 72

4-amino-5-chloro-N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 4-fluorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1HNMR (DMSO,500MHz), ppm (): hydrochloride form)

9.3(m,1H),8.0(s,1H),7.67(s,1H),7.13(m,2H),6.96(m,2H),6.48(s,1H),5.93(s,2H),4.3(m,1H),3.92(s,2H),3.83(s,3H),3.55(m,2H),3.3-3.2(m,4H),3.0(m,2H),1.77(m,3H),1.6(m,1H),1.5(m,1H)

Example 73

4-amino-5-chloro-N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 4-chlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1HNMR (DMSO,200MHz), ppm () (free amine form) 7.9(m,1H),7.65(s,1H),7.3(m,2H),6.95(m,2H),6.46(s,1H),5.93(s,2H),4.85(m,1H),4.0-3.8(m,5H),3.3-3.1(m,4H),2.9(m,2H),2.4(m,1H),2.0(m,2H),1.7-1.4(m,3H),1.2(m,2H)

Example 74

4-amino-5-chloro-N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using glycidyl 4-methoxyphenyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,500MHz), ppm () (hydrochloride form) 9.4(m,1H),8.00(m,1H),7.67(s,1H),6.86(m,4H),6.48(m,1H),5.91(m,2H),4.29(m,1H),3.9) m,2H),3.83(s,3H),3.52(m,2H),3.21(m,4H),2.90(m,2H),1.75(m,3H),1.56(m,1H),1.47(m,1H)

Example 75

4-amino-5-chloro-N- [ [1- [3- (2,3-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 2, 3-dichlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7,9-7.85(m,1H),7.25(s,1H),7.20-7.05(m,2H),6.95(m,1H),6.35(s,1H),4.4(m,2H),4.2(m,1H),4.05(m,2H),3.9(s,3H),3.3(m,2H),3.1(m,1H),3.0(m,1H),2.7(m,2H),2.4(m,1H),2.2(m,1H),1.97-1.8(m,3H),1.6-1.4(m,2H)

Example 76

4-amino-5-chloro-N- [ [1- [3- (2, 4-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 2, 4-dichlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7,9-7.85(m,1H),7.4(s,1H),7.20(m,1H),6.9(m,1H),6.35(s,1H),4.4(m,2H),4.2(m,1H),4.05(m,2H),3.9(s,3H),3.4(m,2H),3.1(m,1H),2.9(m,1H),2.65(m,2H),2.4(m,1H),2.1(m,1H),1.9-1.65(m,3H),1.6-1.25(m,2H)

Example 77

4-amino-5-chloro-N- [ [1- [3- (2, 5-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 2, 5-dichlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3(M,1H),6.95(m,2H),6.3(s,1H),4.4(s,2H),4.2(m,1H),4.0(m,2H),3.9(s,3H),3.4(t,2H),3.1(m,1H),2.9(m,1H),2.6(t,2H),2.4(m,1H),2.1(m,1H),1.9-1.8(m,3H),1.5-1.3(m,2H)

Example 78

4-amino-5-chloro-N- [ [1- [3- (2, 6-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 2, 6-dichlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.8(m,1H),8.1(s,1H),7.3(2H),7.0(t,1H),6.35(s,1H),4.4(s,2H),4.2(s,1H),4.1(t,2H),3.95(s,3H),3.4(t,2H),3.15(m,1H),3.0(m,1H),2.75(m,2H),2.4(m,1H),2.2(m,1H),1.8(m,3H),1.6-1.3(m,2H)

Example 79

4-amino-5-chloro-N- [ [1- [3- (3, 4-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 3, 4-dichlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.8(m,1H),7.4-7.3(m,1H),7.1(m,1H),6.9(m,1H),6.3(m,1H),4.4(s,2H),4.1(m,1H),4.0-3.9(m,5H),3.4(m,2H),3.1(m,1H),2.9(m,1H),2.6(m,2H),2.4(m,1H),2.2-2.05(m,1H),1.9-1.6(m,3H),1.5-1.3(m,2H)

Example 80

4-amino-5-chloro-N- [ [1- [3- (2-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 2-chlorophenyl glycidyl ether as a reactant instead of 1, 2-epoxy-3-phenoxypropane to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(m,1H),7.8(m,1H),7.4-7.2(m,2H),7.0-6.9(m,2H),6.9-6.8(m,1H),6.4(s,1H),4.5-4.4(m,2H),4.3-4.1(m,3H),3.9(m,3H),3.4(m,2H),3.1(m,1H0),2.9(m,1H),2.6(m,2H),2.4(m,1H),2.1(m,1H)1,9-1.6(m,3H),1.5-1.3(m,2H)

Example 81

4-amino-5-chloro-N- [ [1- [3- (4-methylphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using glycidyl 4-tolyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(m,1H),7.8(m,1H),7.1(m,2H),6.8(m,2H),6.4(s,1H),4.4(m,2H),4.1(m,1H),4.0-3.9(m,5H),3.4(m,2H),3.1(m,1H),2.9(m,1H),2.6(m,2H),2.3(m,4H),2.1(m,1H),1.9-1.6(m,3H),1.4(m,2H)

Example 82

4-amino-5-chloro-N- [ [1- [3- (3, 4-difluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using 3, 4-difluorophenyl glycidyl ether instead of 1, 2-epoxy-3-phenoxypropane as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.2-7.0(m,1H),6.9-6.6(m,2H),6.35(s,1H),4.4(s,2H),4.1(m,1H),3.9(m,5H),3.4(m,2H),3.1-2.9(m,2H),2.6(m,2H),2.4(m,1H),2.1(m,1H),1.9-1.6(m,3H),1.5-1.3(m,2H)

Example 83

4-amino-5-chloro-N- [ [1- [2-hydroxy-3- [4- (trifluoromethyl) phenoxy ] propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using glycidyl 4-trifluoromethylphenyl ether instead of 1, 2-epoxy-3-phenoxypropane as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.75(m,1H),7.6-7.5(m,2H),7.0(m,2H),6.3(s,1H),4.4(s,2H),4.2-4.0(m,3H),3.9(s,3H),3.35(m,2H),3.1(m,1H),2.9(m,1H),2.5(m,2H),2.35(m,1H),2.1(m,1H),1.9-1.6(m,3H),1.5-1.3(m,2H)

Example 84

4-amino-5-chloro-N- [ [1- [2-hydroxy-3- (4-phenylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using glycidyl 4-phenyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.75(m,1H),7.5-6.9(m,9H),6.3(s,1H),5.7(m,1H),4.6(m,2H),4.4(s,2H),3.9(s,3H),3.35(m,2H),2.9(m,2H),2.4-2.3(m,2H),2.0-1.8(m,2H),1.8-1.5(m,3H),1.4-1.2(m,2H)

Example 85

4-amino-5-chloro-N- [ [1- (2-hydroxy-2-3-naphthalen-2-yloxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide hydrochloride

The procedure given in example 71 was followed using 2- (naphthalen-2-yloxymethyl) -oxirane instead of 1, 2-epoxy-3-phenoxypropane as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.6-7.3(m,5H),7.0(m,2H),6.3(s,1H),4.4(s,2H),4.3(m,1H),4.1-4.0(m,2H),3.9(s,3H),3.3(m,1H),3.1(m,1H),2.7(m,2H),2.5(m,1H),2.35(m,1H),1.9-1.6(m,3H),1.6-1.4(m,2H)

Example 86

4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenylpropyl) piperidin-1-ium 4-yl ] methyl ] -2-methoxybenzamide: hydrochloride salt

The procedure given in example 71 was followed using (2, 3-epoxypropyl) benzene as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3(m,5H),6.35(s,1H),4.45(s,2H),4.0(m,1H),3.95(s,3H),3.35(m,2H),3.05(m,1H),2.9(m,2H),2.7(m,1H),2.5-2.3(m,3H),2.0(m,1H),1.8-1.6(m,3H),1.4(m,2H)

Example 87

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: hydrochloride salt

4-amino-5-chloro-N- [ [1- (2-hydroxy-2-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide (1mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (1.5mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then excess ammonium hydroxide (3mL) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 8.0(m,1H),7.66(s,1H),7.29(m,2H),6.96(m,2H),6.90(m,1H),6.48(s,1H),5.98(s,2H),5.35(m,1H),4.15(m,2H),3.83(s,3H),3.3-2.1(m,6H),3.0(m,2H),1.78(m,3H),1.5(m,2H)

Example 88

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxypropan-2-yl ] piperidine-1-carboxylate: hydrochloride salt

The title compound was obtained by the method described in example 87, except that piperidine (2mmol) was used instead of ammonium hydroxide.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.95(m,1H),8.05(m,1H),7.66(s,1H),7.31(m,2H),6.96(m,3H),6.48(s,1H),6.0(br,2H),5.4(m,1H),4.2(m,2H),3.83(s,3H),3.7-3.4(m,6H),3.18(m,4H),3.0(m,2H),1.77(m,3H),1.7-1.3(m,8H)

Example 89

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-fluorophenoxy) propan-2-yl ]3, 5-dimethylpiperidine-1-carbamate: hydrochloride salt

4-amino-5-chloro-N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide (1mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (1.5mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then 3, 5-dimethylpiperidine (2mmol) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 8.0(s,1H),7.66(s,1H),7.09(m,2H),7.01(m,2H),6.48(s,1H),5.96(s,2H),5.35(br,1H),4.17(s,2H),4.0-3.8(m,7H),3.46(m,2H),3.18(m,4H),3.0(m,2H),2.22(m,2H),1.9-1.3(m,7H),0.81(m,6H)

Example 90

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-chlorophenoxy) propan-2-yl ]3, 5-dimethylpiperidin-1-carbamate: hydrochloride salt

The title compound was obtained by the method described in example 89, except that 4-amino-5-chloro-N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide was used as starting material instead of 4-amino-5-chloro-N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 10.1(br,1H),8.0(m,1H),7.66(s,1H),7.34(m,2H),7.00(m,2H),6.48(s,1H),5.96(s,2H),5.35(m,1H),4.2(m,2H),4.0-3.7(m,7H),3.6-3.4(m,2H),3.18(m,4H),3.0(m,2H),2.2(m,2H),1.9-1.2(m,7H),0.9-0.6(m,6H)

Example 91

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-methoxyphenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (4-methoxyphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 74 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.95(m,1H),8.0(m,1H),7.66(s,1H),6.88(m,6H),6.48(s,1H),5.35(m,1H),4.07(m,2H),3.83(s,3H),3.69(s,3H),3.6(m,2H),3.25(m,5H),3.0(m,2H),2.0-1.5(m,5H)

Example 92

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2,3-dichlorophenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (2,3-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 75 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3(m,1H),7.1(m,1H),6.9(m,1H),6.35(s,1H),5.3(m,1H),4.4(m,2H),4.3(m,2H),3.95(m,3H),3.8(m,2H),3.4(m,2H),3.1(m,1H),2.9(m,1H),2.3-2.2(m,2H),1.9-1.3(m,5H)

Example 93

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2,3-dichlorophenoxy) propan-2-yl ] pyrrolidine-1-carboxylic acid ester: hydrochloride salt

4-amino-5-chloro-N- [ [1- [3- (2,3-dichlorophenoxy) -2-hydroxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide (1mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (1.5mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then pyrrolidine (2mmol) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.9(m,1H),7.2-7.1(m,2H),7.0-6.9(m,1H),6.4(s,1H),5.6(m,1H),4.5-4.3(m,2H),3.9(m,3H),3.6(m,1H),3.55-3.3(m,5H),2.8(m,2H),2.55(m,3H),2.1(m,1H),2.0-1.8(m,7H),1.4-1.2(m,2H)

Example 94

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2,3-dichlorophenoxy) propan-2-yl ] piperidine-1-carboxylic acid ester: hydrochloride salt

The title compound was obtained by the method described in example 93, except that piperidine was used instead of pyrrolidine.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.3(s,1H),7.2-7.1(m,2H),7.0(m,1H),6.4(s,1H),5.6(m,1H),4.5(m,1H),4.3(m,1H),3.9(m,3H),33.6(m,1H),3.5-3.3(m,5H),2.9-2.7(m,2H),2.5(m,4H),2.2-1.9(m,4H),1.8-1.5(m,7H)

Example 95

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2,3-dichlorophenoxy) propan-2-yl ] azepan-1-carboxylate: hydrochloride salt

The title compound was obtained by the method described in example 93, except that hexamethyleneamine was used instead of pyrrolidine.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.9(m,1H),7.3(m,1H),7.2-7.1(m,2H),7.0-6.9(m,1H),6.4(s,1H),5.6(m,1H),4.5(m,1H),4.35(m,1H),4.2-4.0(m,2H),3.95(s,3H),3.7-3.3(m,6H),2.8(m,2H),2.7-2.4(m,4H),2.2-1.8(m,4H),1.8-1.5(m,9H)

Example 96

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 4-dichlorophenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (2, 4-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 76 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(m,1H),7.9(m,1H),7.4(m,1H),7.1(m,1H),6.9(m,1H),6.35(m,1H),5.2(m,1H),4.8(m,2H),4.4(m,2H),4.2(m,2H),3.9(m,3H),3.4(m,2H),3.0(m,2H),2.75(m,2H),2.2(m,2H),1.9-1.5(m,3H),1.5-1.3(m,2H)

Example 97

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 5-dichlorophenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (2, 5-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 77 as a reactant instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(m,1H),7.8(m,1H),7.3(m,1H),7.0-6.9(m,2H),6.3(m,1H),5.2(m,1H),4.8(m,2H),4.4(m,2H),4.3-4.1(m,2H),3.9(m,3H),3.3(m,2H),3.0(m,2H),2.7(m,2H),2.2(m,2H),1.9-1.6(m,3H),1.4-1.3(m,2H)

Example 98

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 6-dichlorophenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (2, 6-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 78 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(m,1H),7.9(m,1H),7.4(m,1H),7.05(m,1H),6.8(m,1H),6.4(m,1H),5.2(m,1H),4.8(s,2H),4.4(s,2H),4.2(m,2H),3.9(m,3H),3.4(m,2H),3.0(m,2H),2.8(m,2H),2.1(m,2H),1.8-1.5(m,3H),1.4-1.2(m,2H)

Example 99

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (3, 4-dichlorophenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [3- (3, 4-dichlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 79 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.9(m,1H),7.4-7.3(m,1H),7.1(m,1H),6.9(m,1H),6.35(s,1H),5.2(m,1H),4.8(m2H),4.4(m,2H),4.2-4.0(m,2H),3.95(s,3H),3.35(m,2H),3.1-2.9(m,2H),2.6(m,2H),2.2-2.1(m,2H),1.8-1.5(m,3H),1.4-1.2(m,3H)

Example 100

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- [4- (trifluoromethyl) phenoxy ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [2-hydroxy-3- [4- (trifluoromethyl) phenoxy ] propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 83 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.75(m,1H),7.7-7.5(m,2H),7.0(m,2H),6.3(s,1H),5.2(m,1H),4.7(m,2H),4.4(s,2H),4.2(m,2H),3.9(s,3H),3.35(m,2H),2.9(m,2H),2.7-2.6(m,2H),2.2-2.05(m,2H),1.85(m,2H),1.7(m,1H),1.4-1.2(m,2H)

Example 101

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-phenylphenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [2-hydroxy-3- (4-phenylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 84 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8-7.7(m,5H),7.5-7.1(m,5H),6.3(s,1H),5.25(m,1H),4.7(m,2H),4.4-4.2(m,4H),3.9(s,3H),3.35(m,2H),3.1-2.9(m,2H),2.7(m,2H),2.2-2.1(m,2H),1.8-1.5(m,3H),1.4-1.2(m,2H)

Example 102

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-naphthalen-2-yloxyprop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- [ 2-hydroxy-3-naphthalen-2-yloxypropyl ] piperidin-4-yl ] methyl ] -2-methoxybenzamide from example 85 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.15(s,1H),7.8(m,1H),7.6-7.3(m,5H),7.0(m,2H),6.3(s,1H),5.25(m,1H),4.9-4.7(br,2H),4.4(s,2H),4.2(m,2H),3.9(s,3H),3.4-3.3(m,2H),3.2-3.1(m,2H),2.9-2.8(m,2H),2.4-2.15(m,2H),1.9-1.6(m,3H),1.6-1.4(m,2H)

Example 103

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenylpropan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 87 was followed using 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenylpropyl) piperidin-1-ium-4-yl ] methyl ] -2-methoxybenzamide from example 86 as a reactant, instead of 4-amino-5-chloro-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-methoxybenzamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.1(s,1H),7.8(m,1H),7.3-7.1(m,5H),6.3(s,1H),5.1(m,1H),4.95(s,2H),4.6(s,2H),4.0(m,1H),3.85(s,3H),3.35(m,2H),3.0-2.6(m,4H),2.5-2.2(m,2H),2.1-1.9(m,2H),1.8-1.5(m,3H),1.3(m,2H)

Example 104

N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide; hydrochloride salt

A mixture of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-yl-methyl) -amide (3mmol) and 1, 2-epoxy-3-phenoxypropane (3mmol) was refluxed in 10mL of isopropanol for 3 hours. The solution was concentrated in a rotary evaporator and the mixture was purified by column chromatography. The resulting N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide was dissolved in MC and the solution was treated with an ethereal solution of HCl. The resulting precipitate was filtered off to give the title compound.

1HNMR (DMSO,200MHz), ppm () (free amine form) 8.83(m,1H),8.05(m,1H),7.44(m,1H),7.4-7.1(m,4H),6.93(m,3H),4.84(m,1H),4.67(m,1H),3.88(m,2H),3.22(m,2H),2.92(m,2H),2.4(m,2H),1.99(m,2H),1.64(m,3H),1.48(m,6H),1.22(m,2H)

Example 105

N- [ [1- (2-hydroxy-3- (4-nitrophenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using glycidyl 4-nitrophenyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)9.0(m,1H),8.35-8.2(m,3H),7.2(m,3H),7.0(m,2H),4.75(m,1H),4.2-4.05(m,3H),3.4(t,2H),3.1(m,1H),2.9(m,1H),2.55(m,2H),2.4(m,1H),2.05(m,1H),1.85(m,2H),1.7(m,1H),1.6(d,6H),1.4(m,2H)

Example 106

N- [ [1- (2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using glycidyl 4-methoxyphenyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (free amine form) 8.83(m,1H),8.07(m,1H),7.44(m,1H),7.15(m,2H),6.85(m,4H),4.78(m,1H),4.66(m,1H),3.91-3.77(m,2H),3.68(s,3H),3.22(m,2H),2.87(m,2H),2.36(m,2H),1.96(m,2H),1.60(m,2H),1.48(m,7H),1.23(m,2H)

Example 107

N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 4-fluorophenyl glycidyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.65(m,1H),8.88(m,1H),8.07(m,1H),7.45(m,1H),7.16(m,4H),6.96(m,2H),5.96(m,1H),4.67(m,1H),4.34(m,1H),3.94(m,2H),3.56(m,2H),3.26(m,4H),2.99(m,2H),1.86(m,3H),1.7-1.4(m,8H)

Example 108

N- [ [1- (2-hydroxy-3- (2-methylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using glycidyl 2-methylphenyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.3(m,1H),8.87(m,1H),8.07(m,1H),7.45(m,1H),7.18(m,5H),6.90(m,2H),5.94(m,1H),4.7(m,1H),4.35(m,1H),3.95(m,2H),3.59(m,2H),3.4-2.8(m,6H),2.18(s,3H),1.87(m,3H),1.7-1.4(m,8H)

Example 109

N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 4-chlorophenyl glycidyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.5(m,1H),8.87(m,1H),8.07(m,1H),7.5-6.9(m,6H),5.97(m,1H),4.67(m,1H),4.35(m,1H),3.96(m,2H),3.55(m,2H),3.27(m,4H),2.99(m,2H),1.87(m,3H),1.7-1.4(m,8H)

Example 110

N- [ [1- [3- (4-tert-butylphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 4-tert-butylphenyl glycidyl ether as a reactant, instead of 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.32(m,1H),8.87(m,1H),8.07(m,1H),7.45(m,1H),7.29(m,1H),7.19(m,2H),6.87(m,2H),5.95(m,1H),4.65(m,1H),4.29(m,1H),3.93(m,2H),3.54(m,2H),3.5-3.1(m,4H),2.99(m,2H),1.87(m,3H),1.7-1.47(m,8H),1.25(s,9H)

Example 111

N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide; hydrochloride salt

The procedure given in example 104 was followed using 3-methyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.3(m,1H),8.83(m,1H),8.03(m,1H),7.29-7.16(m,5H),6.97(m,3H),5.98(m,1H),4.30(m,1H),3.96(m,2H),3.61(m,2H),3.5-3.1(m,5H),2.93(m,2H),2.6(m,2H),1.87(m,3H),1.6(m,2H)

Example 112

N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-methyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 4-chlorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.6(m,1H),8.82(m,1H),8.02(m,1H),7.4-6.9(m,7H),5.98(m,1H),4.35(m,1H),3.95(m,2H),3.54(m,2H),3.4-2.9(m,9H),1.87(m,3H),1.63(m,2H)

Example 113

N- [ [1- [3- (4-tert-butylphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-methyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 4-tert-butylphenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.64(m,1H),8.82(m,1H),8.02(m,1H),7.4-7.12(m,5H),6.87(m,2H),5.95(m,1H),4.34(m,1H),3.93(m,2H),3.58(m,2H),3.5-3.1(m,7H),3.0(m,2H),1.87(m,3H),1.53(m,2H),1.25(s,9H)

Example 114

N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-methyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and glycidyl 4-methoxyphenyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.45(m,1H),8.82(m,1H),8.02(m,1H),7.35-7.1(m,3H),6.88(m,4H),5.95(m,1H),4.29(m,1H),3.89(m,2H),3.69(s,3H),3.6-3.1(m,7H),2.99(m,4H),1.87(m,3H),1.6(m,2H)

Example 115

N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-methyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 4-fluorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.5(m,1H),8.82(m,1H),8.02(m,1H),7.35-7.05(m,5H),6.98(m,2H),5.94(m,1H),4.32(m,1H),3.94(m,2H),3.55(m,2H),3.5-3.1(m,7H),2.98(m,2H),1.87(m,3H),1.6(m,2H)

Example 116

3-ethyl-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide: hydrochloride salt

The procedure given in example 104 was followed using 3-ethyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.25(m,1H),7.4-7.15(m,3H),7.1-6.9(m,5H),4.1(m,2H),4.0(m,2H),3.55(m,1H),3.4(t,2H),3.1(m,1H),3.0(m,1H),2.6(m,2H),2.4(m,1H),2.1(m,1H),1.9-1.6(m,3H),1.5-1.3(m,5H)

Example 117

3-Ethyl-N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-ethyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and glycidyl 4-methoxyphenyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.2(m,1H),7.3-7.0(m,3H),6.8(m,4H),4.25(m,1H),4.0(m,4H),3.8(s,3H),3.5-3.3(m,4H),2.9(m,2H),2.6(m,1H),2.4(m,1H),1.9(m,2H),1.8-1.6(m,3H),1.4(t,3H)

Example 118

3-Ethyl-N- [ [1- [2-hydroxy-3- (2-methylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-ethyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and glycidyl 2-tolyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.25(m,1H),7.3-7.0(m,6H),6.85(m,2H),4.3-3,9(m,5H),3.4(m,2H),3.2(m,1H),3.05(m,1H),2.65(m,2H),2.4(m,1H),2.3(s,3H),2.15(m,1H),1.85(m,2H),1.75(m,1H),1.6-1.3(m,5H)

Example 119

N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-ethyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 104 was followed using 3-ethyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 4-chlorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 1, 2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.25(m,1H),7.2-7.0(m,4H),7.05(m,1H),6.9(m,2H),4.2(m,1H),4.0(m,4H),3.4(m,2H),3.2(m,1H),3.05(m,1H),2.65(m,2H),2.4(m,1H),2.0-1.7(m,3H),1.6-1.3(m,5H)

Example 120

n- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide (1mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (1.5mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then excess ammonium hydroxide (3mL) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 10.2(m,1H),8.88(m,1H),8.07(m,1H),7.6-6.8(m,10H),5.34(m,1H),4.66(m,1H),4.15(m,2H),3.55(m,2H),3.26(m,4H),3.04(m,2H),1.85(m,3H),1.59(m,2H),1.48(m,6H)

Example 121

[1- (4-methoxyphenoxy) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 106 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.7(m,1H),8.80(m,1H),8.07(m,1H),7.45(m,1H),7.18(m,2H),6.88(m,4H),5.28(m,1H),4.65(m,1H),4.07(s,2H),3.69(s,3H),3.58(m,2H),3.5-3.2(m,2H),3.03(m,4H),1.86(m,3H),1.49(m,8H)

Example 122

[1- (4-fluorophenoxy) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 107 instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide as a reactant to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.5(m,1H),8.88(m,1H),8.07(m,1H),7.45(m,1H),7.16(m,4H),7.0-6.8(m,4H),5.31(m,1H),4.66(m,1H),4.11(m,2H),3.60(m,2H),3.5-3.2(m,4H),3.00(m,2H),1.87(m,3H),1.7-1.4(m,8H)

Example 123

[1- (2-methylphenoxy) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [2-hydroxy-3- (2-methylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 108 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.8(m,1H),8.88(m,1H),8.04(m,1H),7.45(m,1H),7.18(m,5H),6.90(m,4H),5.35(m,1H),4.7(m,1H),4.15(m,2H),3.56(m,2H),3.4-2.9(m,6H),2.18(s,3H),1.86(m,3H),1.7-1.4(m,8H)

Example 124

[1- (4-chlorophenoxy) -3- [4- [ [ (2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide from example 109 instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide as a reactant to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.35(m,1H),8.88(m,1H),8.07(m,1H),7.5-6.9(m,9H),5.3(m,1H),4.65(m,1H),4.13(m,2H),3.60(m,2H),3.0(m,4H),2.84(m,2H),1.87(m,3H),1.7-1.1(m,8H)

Example 125

[1- (4-tert-butylphenoxy) -3- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-tert-butylphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 110 instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide as a reactant to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.64(m,1H),8.82(m,1H),8.02(m,1H),7.3-7.1(m,5H),6.87(m,4H),5.35(m,1H),4.1(m,2H),3.58(m,2H),3.5-3.1(m,7H),3.0(m,2H),1.87(m,3H),1.53(m,2H),1.25(s,9H)

Example 126

[1- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide from example 111 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.3(m,1H),8.83(m,1H),8.02(m,1H),7.4-6.8(m,8H),5.31(m,1H),4.12(m,2H),3.61(m,2H),3.5-2.81(m,7H),2.4-2.1(m,2H),1.81(m,3H),1.52(m,2H)

Example 127

[1- (4-chlorophenoxy) -3- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide from example 112 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.5(m,1H),8.83(m,1H),8.02(m,1H),7.4-6.9(m,7H),6.87(m,2H),5.3(m,1H),4.14(m,2H),3.6(m,2H),3.4-3.1(m,5H),3.0(m,4H),1.87(m,3H),1.63(m,2H)

Example 128

The procedure given in example 120 was followed using N- [ [1- [3- (4-tert-butylphenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide from example 113 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1H-NMR (DMSO-d6,200MHz, HCl form) 9.64(m,1H),8.82(m,1H),8.02(m,1H),7.3-7.1(m,5H),6.87(m,4H),5.35(m,1H),4.1(m,2H),3.58(m,2H),3.5-3.1(m,7H),3.0(m,2H),1.87(m,3H),1.53(m,2H),1.25(s,9H)

Example 129

[1- (4-methoxyphenoxy) -3- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- (2-hydroxy-3- (4-methoxyphenoxy) propyl) piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide from example 114 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.65(m,1H),8.82(m,1H),8.02(m,1H),7.35-7.1(m,3H),6.88(m,6H),5.35(m,1H),4.06(m,2H),3.69(s,3H),3.6-3.1(m,7H),3.04(m,4H),1.87(m,3H),1.6(m,2H)

Example 130

[1- (4-fluorophenoxy) -3- [4- [ [ (3-methyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-fluorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-methyl-2-oxobenzimidazole-1-carboxamide from example 115 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1HNMR (DMSO,200MHz), ppm () (hydrochloride form) 9.45(m,1H),8.83(m,1H),8.02(m,1H),7.35-7.05(m,5H),6.99(m,2H),6.88(m,2H),5.35(m,1H),4.11(m,2H),3.60(m,2H),3.5-3.1(m,7H),3.04(m,2H),1.87(m,3H),1.49(m,2H)

Example 131

[1- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxyprop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using 3-ethyl-N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 116 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.9(m,1H),8.25(m,1H),7.4-6.9(m,8H),5.3(s,2H),5.2(m,1H),4.15(m,2H),4.0(m,2H),3.35(t,2H),3.0(m,2H),2.65(m,2H),2.1(m,2H),1.75(m,2H),1.6(m,1H),1.5-1.2(m,5H)

Example 132

[1- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -3- (4-methoxyphenoxy) propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using 3-ethyl-N- [ [1- [2-hydroxy-3- (4-methoxyphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 117 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.9(m,1H),8.25(m,1H),7.2(m,2H),7.05(m,1H),6.85(m,4H),5.15(m,1H),5.0(s,2H),4.15(m,2H),4.0(m,2H),3.8(s,3H),3.35(t,2H),3.0(m,2H),2.65(m,2H),2.1(m,2H),1.75(m,2H),1.6(m,1H),1.5-1.2(m,5H)

Example 133

[1- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -3- (2-methylphenoxy) prop-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using 3-ethyl-N- [ [1- [2-hydroxy-3- (2-methylphenoxy) propyl ] piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 118 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.9(m,1H),8.25(m,1H),7.3-7.0(m,5H),6.85(m,2H),5.25(m,1H),5.05(s,2H),4.15(m,2H),4.0(m,2H),3.35(t,2H),3.0(m,2H),2.7(d,2H),2.2(s,3H),2.1(m,2H),1.8(m,2H),1.6(m,1H),1.5-1.2(m,5H)

Example 134

[1- (4-chlorophenoxy) -3- [4- [ [ (3-ethyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] propan-2-yl ] carbamate: hydrochloride salt

The procedure given in example 120 was followed using N- [ [1- [3- (4-chlorophenoxy) -2-hydroxypropyl ] piperidin-4-yl ] methyl ] -3-ethyl-2-oxobenzimidazole-1-carboxamide from example 119 as a reactant, instead of N- [ [1- (2-hydroxy-3-phenoxypropyl) piperidin-4-yl ] methyl ] -2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.9(m,1H),8.25(m,1H),7.3-7.0(m,5H),6.9(m,2H),5.2(m,1H),5.0(s,2H),4.15(m,2H),4.0(m,2H),3.35(t,2H),2.95(m,2H),2.6(d,2H),2.1(m,2H),1.75(m,2H),1.6(m,1H),1.5-1.2(m,5H)

Example 135

3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

A mixture of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide (5.0mmol), 3-chlorophenylacetone (6.0mmol), potassium carbonate (7.6mmol) and potassium iodide (7.6mmol) was refluxed in 15mL acetonitrile for 12 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was then washed with brine, and the resulting organic layer was dried and purified by column chromatography. This was dissolved in ethanol (10mL), sodium borohydride (10.0mmol) was added at 0 deg.C and stirred at 25 deg.C for 2 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography. The resulting 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide was dissolved in MC and the solution was treated with an ethereal HCl solution. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.35(m,1H),7.5-7.1(m,9H),4.95(m,1H),3.35-3.1(m,4H),2.9(m,1H),2.7(m,2H),2.2(m,1H),2.1-1.6(m,5H),1.5(m,2H),1.3-1.0(m,5H)

Example 136

N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide; hydrochloride salt

The procedure given in example 135 was followed using 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide as a reactant, instead of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide, to give the title compound.

1H-NMR(CDCl3,200MHz)9.0(m,1H),8.25(m,1H),7.5-7.1(m,9H),4.95(m,1H),4.75(m,1H),3.35(m,2H),3.15(m,2H),2.8-2.55(m,2H),2.1(m,1H),1.9(m,4H),1.8-1.4(m,10H)

Example 137

N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 135 was followed using 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloro-4' -fluorophenylacetone as a reactant, instead of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chlorophenylacetone, to give the title compound.

1H-NMR(CDCl3,500MHz)9.00(m,1H),8.28(s,1H),7.36(m,2H),7.20(m,3H),7.03(m,2H),4.95(m,1H),4.72(m,1H),3.37(m,2H),3.35(m,1H),3.22(m,1H),2.81(m,1H),2.71(m,1H),2.28(m,1H),2.11(m,1H),1.93(m,4H),1.79(m,1H),1.58(m,8H)

Example 138

3-cyclopropyl-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide hydrochloride

The title compound was obtained by the procedure given in example 135 using 3-chloro-4' -fluorophenylacetone instead of 3-chlorophenylacetone as a reactant.

1H-NMR(CDCl3,500MHz)9.00(m,1H),8.20(s,1H),7.36(m,2H),7.20(m,3H),7.05(m,2H),4.96(m,1H),3.37(m,3H),3.30(m,1H),2.92(m,2H),2.80(m,1H),2.35(m,1H),2.2(m,1H),1.96(m,2H),1.79(m,2H),1.65(m,3H),1.20(m,2H),1.05(m,2H)

Example 139

N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 135 was followed using 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloro-4' -chloropropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloropropiophenone, to give the title compound.

1H-NMR(CDCl3,500MHz)9.00(m,1H),8.27(m,1H),7.33(m,4H),7.18(m,3H),4.96(m,1H),4.72(m,1H),3.37(m,3H),3.25(m,1H),2.87-2.70(m,2H),2.40(m,1H),2.13(m,1H),1.95(m,5H),1.78(m,2H),1.58(m,6H)

Example 140

N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -3-cyclopropyl-2-oxobenzimidazole-1-carboxamide hydrochloride

The title compound was obtained by following the procedure given in example 135, using 3-chloro-4' -chlorophenylacetone instead of 3-chlorophenylacetone as a reactant.

1H-NMR(CDCl3,500MHz)8.94(m,1H),8.20(m,1H),7.33-7.19(m,7H),4.96(m,1H),3.37(m,3H),3.26(m,1H),2.91(m,2H),2.81(m,1H),2.32(m,1H),2.15(m,1H),1.95(m,4H),1.77(m,2H),1.62(m,3H),1.18(m,2H),1.05(m,2H)

Example 141

N- [ [1- [ 3-hydroxy-3- (4-tolyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 135 was followed using 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloro-4' -methylpropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloropropiophenone, to give the title compound.

1H-NMR(CDCl3,500MHz)9.01(m,1H),8.26(m,1H),7.37-7.15(m,7H),4.95(m,1H),4.75(m,1H),3.38(m,4H),2.90(m,2H),2.36(s,3H),2.10-1.65(m,9H),1.60(m,6H)

Example 142

3-cyclopropyl-N- [ [1- [ 3-hydroxy-3- (4-tolyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

The title compound was obtained by following the procedure given in example 135, using 3-chloro-4' -methylpropiophenone instead of 3-chlorophenylacetone as a reactant.

1H-NMR(CDCl3,500MHz)8.95(m,1H),8.20(m,1H),7.42-7.13(m,7H),4.75(m,1H),3.42-3.20(m,4H),2.90(m,1H),2.81(m,2H),2.32(m,3H),2.18(m,1H),1.95(m,3H),1.80(m,2H),1.65(m,3H),1.20(m,2H),1.06(m,2H)

Example 143

N- [ [1- [ 3-hydroxy-3- (4-methoxyphenyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 135 was followed using 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloro-4' -methoxypropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 3-chloropropiophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)9.05(m,1H),8.25(m,1H),7.35(m,3H),7.2(m,3H),6.9(m,2H),6.85(m,1H),5.0(m,1H),4.7(m,1H),3.85(s,3H),3.7(m,1H),3.5(m,1H),3.4(m,2H),3.25(m,2H),3.0(m,3H),2.65(m,2H),2.3(m,2H),2.1(m,2H),1.6(m,6H)

Example 144

3-cyclopropyl-N- [ [1- [ 3-hydroxy-3- (4-methoxyphenyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

The title compound was obtained by the procedure given in example 135, using 3-chloro-4' -methoxypropiophenone instead of 3-chlorophenylacetone as a reactant.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.2(m,1H),7.4-7.2(m,5H),6.9(m,2H),4.9(m,1H),3.8(s,3H),3.35(m,2H),3.2(m,2H),2.9(m,1H),2.75(m,2H),2.3-2.0(m,2H),1.9(m,4H),1.7(m,1H),1.55(m,2H),1.2-1.0(m,4H)

Example 145

[3- [4- [ [ (3-cyclopropyl-2-oxo-benzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -3-phenylpropyl ] carbamate: hydrochloride salt

3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide (1mmol) was dissolved in 10mL THF and 1, 1' -carbonyldiimidazole (1.5mmol) was added at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours, then excess ammonium hydroxide (3mL) was added at room temperature. After stirring at room temperature for 2 hours, the reaction was terminated by adding water. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The resulting carbamate was dissolved in MC and the resulting solution was treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,200MHz)9.00(m,1H),8.20(m,1H),7.31-7.18(m,8H),5.71(m,1H),4.73(br,2H),3.35(m,2H),3.12(br,2H),2.90(m,2H),2.80(m,1H),2.30(m,2H),2.07(m,2H),1.86(m,2H),1.75(m,1H),1.60(m,2H),1.20(m,2H),1.05(m,2H)

Example 146

[3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-yl ] -1-phenylpropyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 136 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)9.0(m,1H),8.3(m,1H),7.8(m,1H),7.4-7.1(m,9H),5.75(m,1H),4.8-4.6(m,3H),3.35(m,2H),3.1(m,2H),2.55(m,3H),2.4-2.0(m,5H),1.9-1.6(m,4H),1.5(m,6H)

Example 147

[1- (4-fluorophenyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 137 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,500MHz)9.00(m,1H),8.25(s,1H),7.36(m,2H),7.20(m,3H),7.05(m,2H),5.69(m,1H),4.72(m,1H),3.36(m,2H),3.20(m,2H),2.65(m,2H),2.3(m,2H),1.93(m,3H),1.79(m,2H),1.65(m,2H),1.58(m,6H)

Example 148

[3- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using 3-cyclopropyl-N- [ [1- [3- (4-fluorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 138 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.89(m,1H),8.20(m,1H),7.35-7.19(m,5H),7.03(m,2H),5.68(m,1H),4.78(br,2H),3.33(m,2H),3.03(m,2H),2.90(m,1H),2.47(m,2H),2.20(m,1H),2.06(m,3H),1.81(m,2H),1.65(m,1H),1.45(m,2H),1.17(m,2H),1.05(m,2H)

Example 149

[1- (4-chlorophenyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 139 as a reactant instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide to give the title compound.

1H-NMR(CDCl3,200MHz)8.98(m,1H),8.26(m,1H),7.34-7.17(m,7H),5.67(m,1H),4.72(m,3H),3.35(m,2H),3.06(m,2H),2.50(m,2H),2.25(m,1H),2.12(m,1H),2.05(m,2H),1.85(m,2H),1.80(m,1H),1.58(m,6H),1.28(m,2H)

Example 150

[1- (4-chlorophenoxy) -3- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [3- (4-chlorophenyl) -3-hydroxypropyl ] piperidin-1-ium-4-yl ] methyl ] -3-cyclopropyl-2-oxobenzimidazole-1-carboxamide from example 140 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,500MHz)8.93(m,1H),8.19(m,1H),7.35-7.20(m,7H),5.68(m,1H),4.78(m,2H),3.36(m,2H),3.18(m,2H),2.91(m,2H),2.65(m,2H),2.31(m,2H),2.15(m,2H),1.89(m,2H),1.75(m,2H),1.63(m,3H),1.19(m,2H),1.06(m,2H)

Example 151

[1- (4-tolyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [ 3-hydroxy-3- (4-tolyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 141 as a reactant in place of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide to give the title compound.

1H-NMR(CDCl3,200MHz)8.97(m,1H),8.25(m,1H),7.30-7.13(m,7H),5.67(m,1H),4.73(m,3H),3.50(m,1H),3.32(m,2H),3.10(m,2H),2.58(m,2H),2.37(m,3H),2.28(m,1H),2.11(m,3H),1.85(m,3H),1.72(m,1H),1.58(m,6H)

Example 152

[3- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1- (4-tolyl) propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using 3-cyclopropyl-N- [ [1- [ 3-hydroxy-3- (4-tolyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 142 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.90(m,1H),8.20(s,1H),7.32-7.13(m,7H),5.66(m,1H),4.73(br,2H),3.35(m,2H),3.12(m,2H),2.91(m,1H),2.60(m,2H),2.40(s,3H),2.27(m,2H),1.61(m,2H),1.87(m,2H),1.72(m,1H),1.59(m,2H),1.20(m,2H),1.06(m,2H)

Example 153

[1- (4-methoxyphenyl) -3- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [ 3-hydroxy-3- (4-methoxyphenyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 143 as a reactant instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide to give the title compound.

1H-NMR(CDCl3,200MHz)9.0(m,1H),8.25(m,1H),7.35(m,3H),7.2(m,3H),6.9(m,2H),5.65(m,1H),4.95(m,2H),4.7(m,1H),3.8(s,3H),3.4(m,2H),3.2(m,2H),2.7(m,2H),2.4-2.1(m,4H),1.9(m,3H),1.7(m,2H),1.6(m,6H)

Example 154

[3- [4- [ [ (3-cyclopropyl-2-oxobenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1- (4-methoxyphenyl) propyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using 3-cyclopropyl-N- [ [1- [ 3-hydroxy-3- (4-methoxyphenyl) propyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 144 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.2(m,1H),7.4-7.2(m,5H),6.95(m,2H),5.65(m,1H),4.8(m,2H),3.8(s,3H),3.4(m,2H),3.2(m,2H),2.9(m,1H),2.7(m,2H),2.5-2.1(m,4H),1.9(m,3H),1.75(m,2H),1.4-1.0(m,4H)

Example 155

N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

A mixture of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide (5.0mmol), 2-bromo-4' -fluoroacetophenone (6.0mmol) and potassium carbonate (7.6mmol) was stirred in 15mL of acetonitrile for 2 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was then washed with brine, and the resulting organic layer was dried and purified by column chromatography. This was dissolved in ethanol (10mL), sodium borohydride (10.0mmol) was added at 0 deg.C and stirred at 25 deg.C for 2 hours. The solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography. The resulting N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide is dissolved in MC and the solution is treated with ethereal HCl. The resulting precipitate was filtered off to give the title compound.

1H-NMR(CDCl3,500MHz)9.01(m,1H),8.26(m,1H),7.37(m,2H),7.20(m,3H),7.05(m,2H),4.90(br,2H),3.38(m,2H),3.30(m,1H),3.08(m,1H),2.63(m,2H),2.50(m,1H),2.25(m,1H),1.91(m,2H),1.80(m,1H),1.59(m,8H)

Example 156

N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide hydrochloride

The procedure given in example 155 was followed using 2-bromo-3 '-methoxyacetophenone as a reactant, instead of 2-bromo-4' -fluoroacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)9.05(m,1H),8.3(m,1H),7.35-7.1(m,5H),7.0(m,2H),6.85(m,1H),4.9(m,1H),4.85(m,1H),3.95(s,3H),3.4(m,3H),3.1(m,1H),2.85(m,2H),2.5(m,1H),2.3(m,1H),1.95-1.8(m,3H),1.6-1.5(m,8H)

Example 157

3-cyclopropyl-N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide hydrochloride

The procedure given in example 155 was followed using 3-cyclopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 2-bromo-3 '-methoxyacetophenone as reactants, instead of 3-isopropyl-2-oxo-2, 3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl) -amide and 2-bromo-4' -fluoroacetophenone, to give the title compound.

1H-NMR(CDCl3,200MHz)8.95(m,1H),8.25(m,1H),7.35-7.2(m,4H),7.0(m,2H),6.85(m,1H),4.85(m,1H),3.95(s,3H),3.35(m,3H),2.95(m,2H),2.6(m,2H),2.45(m,1H),2.2(m,1H),1.9(m,2H),1.85(m,1H),1.5(m,2H),1.3-1.0(m,4H)

Example 158

[1- (4-fluorophenyl) -2- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] ethyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 155 as a reactant, instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxybenzimidazole-1-carboxamide, to give the title compound.

1H-NMR(CDCl3,500MHz)8.97(m,1H),8.26(m,1H),7.37(m,2H),7.18(m,3H),7.05(m,2H),5.82(m,1H),5.00(m,1H),4.72(m,1H),3.35(m,2H),3.15-2.95(m,2H),2.71(m,1H),2.62(m,1H),2.26(m,2H),1.95(m,1H),1.85(m,2H),1.70(m,2H),1.58(m,6H)

Example 159

[1- (3-methoxyphenyl) -2- [4- [ [ (2-oxo-3-prop-2-ylbenzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] ethyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxo-3-prop-2-ylbenzimidazole-1-carboxamide from example 156 as a reactant instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide to give the title compound.

1H-NMR(CDCl3,200MHz)9.05(m,1H),8.25(m,1H),7.35-7.1(m,4H),7.0-6.85(m,3H),5.9(m,1H),4.7(m,1H),3.8(s,3H),3.5-3.1(m,4H),2.8(m,1H),2.5(m,2H),2.1-1.85(m,6H),1.6(m,6H)

Example 160

[ [2- [4- [ [ (3-cyclopropyl-2-oxo-benzimidazole-1-carbonyl) amino ] methyl ] piperidin-1-ium-1-yl ] -1- (3-methoxyphenyl) ethyl ] carbamate: hydrochloride salt

The procedure given in example 145 was followed using 3-cyclopropyl-N- [ [1- [ 2-hydroxy-2- (3-methoxyphenyl) ethyl ] piperidin-1-ium-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide from example 157 instead of 3-cyclopropyl-N- [ [1- (3-hydroxy-3-phenylpropyl) piperidin-4-yl ] methyl ] -2-oxobenzimidazole-1-carboxamide as a reactant to give the title compound.

1H-NMR(CDCl3,200MHz)9.0(m,1H),8.2(m,1H),7.4-7.2(m,4H),7.05-6.9(m,3H),5.95(m,1H),3.85(s,3H),3.6-3.4(m,3H),2.95(m,2H),2.7(m,2H),2.2-1.8(m,5H),1.7(m,2H),1.4-1.0(m,4H)

Example 161 gastric emptying enhancement Activity

Male mice of the ICRCD strain (body weight 25-30 g; 8 mice per group) were fasted for 24 hours but allowed free access to water until 3 hours prior to the test.

The compounds to be tested for promoting gastrointestinal motility are injected intraperitoneally or administered orally, 30 minutes or 60 minutes later with a phenol red meal. 15 minutes after the test diet (0.5% phenol red in 1.5% methylcellulose solution) was given, the mice were sacrificed and the stomach (pylorus to cardia) was removed and collected into vials. The stomach and its contents were homogenized in 0.1n naoh, and the mixture was centrifuged (700 × g) for 20 minutes. 2.5mL of the suspension was added to 0.25mL of trichloroacetic acid solution (20% w/v) to precipitate the protein. After centrifugation (2600 × g) for 20 min, 0.5mL of supernatant was added to 0.25mL of 1n naoh. The mixture was homogenized and its absorbance (Abs) was read at 560 nm.

In each experiment, a group of mice that had just been given the test diet was sacrificed and considered as baseline (0% empty). Gastric Emptying (GE) at 15 minutes was calculated according to the following formula.

GE(％)＝(1-Abs_{Test of}/Abs_Datum)x100

Increased value (%) ═ GE%_{Test of}-GE％_Excipient)/GE％_Excipient*100

As shown in Table 1, most of the compounds of the present invention exhibited an effective gastric emptying enhancement effect at a dose of 3 mg/kg.

As is apparent from the above experimental results, the compound of structural formula (I) and pharmaceutically acceptable salts thereof have excellent gastrointestinal motility enhancing activity and thus are useful for treating gastrointestinal diseases such as Irritable Bowel Syndrome (IBS), particularly constipation-predominant IBS and gastric motility disorder.

5-hydroxytryptamine (5-HT) released by enterochromaffin cells modulates gastrointestinal function in a stimulatory or inhibitory manner. The gastrointestinal motility enhancing activity is characterized by agonists at the 5-HT4 receptor. 5-HT4 receptor agonists stimulate motility in the upper or lower intestinal tract, whereas 5-HT4 antagonists inhibit intestinal motility enhanced by 5-HT4 agonists.

The compounds of structural formula (I) have 5-HT4 receptor binding activity and stimulate intestinal motility (see Table 1). Thus, the enhancement of intestinal motility by compounds of structural formula (I) is believed to be mediated by agonists at the 5-HT4 receptor.

Table 1: gastric emptying enhancement Activity (3.0mg/kg peritoneal)

Hypersensitivity to colorectal distension is common to patients with IBS and may be responsible for the main symptoms that cause visceral pain. Inflammatory and non-inflammatory animal models of visceral versus distending hyperalgesia are described in examples 162 and 163, respectively, and have been developed to study the effects of compounds on visceral pain in IBS.

Example 162 TNBS-induced colorectal hypersensitivity assay

Wistar rats (weight 200-. After laparotomy, three sets of three electrodes were implanted in the striated muscle of the abdomen. The electrodes were exposed at the back of the neck and protected with a glass tube attached to the skin.

Colorectal distension (CRD) was achieved using an inflated balloon inflated from 0 to 60mmHg at 15mmHg steps every 5 minutes by connection to a computer controlled barostat. Rats were subjected to CRD 1 day before (basal conditions) and 3 days after intraduodenal administration of trinitrobenzenesulfonic acid (TNBS80mg/kg intrarectally). Colonic pressure and balloon volume were continuously monitored with a potentiometer recorder (L6514, Linseis, Selb, Germany) at a paper speed of 1 cm/min.

Rats were treated with the test article or its vehicle (0.5% hydroxymethylcellulose, 1mLpo) 5 days after TNBS administration and were dilated after 1 hour. The number of spike bursts corresponding to abdominal contractions was measured every 5 minutes. Values are expressed as mean ± SEM. Statistical analysis was performed using Student's t-test, with a statistical significance (staticilisinglnficance) criterion of p < 0.05.

Table 2 summarizes the results of the activity of the compound obtained in example 68 as a test compound in the TNBS-induced colorectal hypersensitivity model. A significant reduction in abdominal contractions was observed at 10mg/kg and 30mg/kg of test compound. This result indicates that the compound of one embodiment of the present invention has an activity of reducing visceral pain in a rat preclinical model.

Table 2: effect of test Compounds on TNBS-induced colorectal hypersensitivity in rats

^a)Expansion pressure

P <0.05, significantly different from "TNBS + excipient

Example 163 PRS (partial restraint stress) -induced colorectal hypersensitivity assay

Adult female Wistar rats (225-250 g body weight; 6-7 rats per group) were prepared for electromyography. After anesthesia, three pairs of nichrome wire electrodes were implanted into the striated muscle on both sides 3cm from the midline. The free end of the electrode is exposed at the back of the neck and protected by a glass tube attached to the skin.

As previously described in BradesiS, EutameneH, Garcia-villar r, fioramonti j, BuenoL; the PRS, described in 'actunociceptive differential stress devices' neuroastroretrol et. mot. (2002)14,75-82, was performed, a relatively mild stress.

Rats were placed in a plastic tunnel where they could not move or escape for several days prior to colorectal distension (CRD). Balloons connected to a barostat were inflated progressively from 0 to 15, 30, 45 and 60mmHg in 15mmHg steps, each step of inflation lasting 5 minutes. To determine the analgesic effect of test compounds on PRS-induced visceral hypersensitivity, test compounds or excipients (CMC 0.5%) were administered orally (PO) 1 hour 15 minutes after the start of PRS. CRD was performed 3 hours before and 15 minutes after the stress start (stress).

For each volume of distension, the number of spike bursts corresponding to abdominal contractions was measured every 5 minutes. Colonic pressure and balloon volume were continuously monitored with a potentiometer recorder (L6514, Linseis, Selb, Germany). Values are expressed as mean ± SEM.

Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Dunnett's test. p <0.05 was considered significant.

Table 3 summarizes the results of the activity of the compound obtained in example 68 as a test compound in the PRS-induced colorectal hypersensitivity model. A significant reduction in abdominal contractions was observed at 30 mg/kg. This result indicates that the compound of one embodiment of the present invention has an activity of relieving visceral pain.

Table 3: effect of test Compounds on PRS-induced colorectal hypersensitivity in rats

^a)Expansion pressure

P <0.05 compared to "PRS + excipient".

Claims

1. A piperidine compound selected from compounds of structural formula (I):

wherein

m is an integer of 1 or 2;

n is an integer of 0 to 2;

a is selected from phenyl groups represented by structural formula (II):

wherein R is₃Is C1-C6 straight or branched chain alkyl;

x is OCONR₁R₂Wherein R is₁And R₂Independently selected from hydrogen, C1-C6 straight or branched chain alkyl, benzyl, and 5-7 membered cyclic or heterocyclic groups substituted with one or more groups independently selected from C1-C6 alkyl, and R₁And R₂Together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring; and is

B is selected from phenyl, phenoxy, thienyl and naphthyl, wherein the phenyl, phenoxy, thienyl or naphthyl is substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 straight or branched chain alkyl and C1-C6 straight or branched chain alkoxy.

2. The compound of claim 1, wherein X is-O (CO) NH₂。

3. The compound of claim 2, wherein the compound is selected from the group consisting of:

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-methylphenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-methoxyphenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-chlorophenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 5-dimethoxyphenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- [4- (difluoromethoxy) phenyl ] ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-difluorophenyl) ethyl ] carbamate,

[2- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 4-dichlorophenyl) ethyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1-phenylpropyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-chlorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-chlorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2-fluorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-fluorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (2, 3-dichlorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3, 4-dichlorophenyl) propyl ] carbamate,

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (3-methoxyphenyl) propyl ] carbamate,

[4- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) but-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -5- (4-fluorophenyl) pent-3-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 4-dichlorophenoxy) propan-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 5-dichlorophenoxy) propan-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (2, 6-dichlorophenoxy) propan-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (3, 4-dichlorophenoxy) propan-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- [4- (trifluoromethyl) phenoxy ] prop-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenylpropan-2-yl ] carbamate,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenoxypropan-2-yl ] piperidine-1-carboxylic acid ester,

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3- (4-fluorophenoxy) propan-2-yl ]3, 5-dimethylpiperidine-1-carboxylate.

4. The compound of claim 2, wherein the compound is selected from the group consisting of:

[3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate, and

[1- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -3-phenylpropan-2-yl ] carbamate.

5. The compound of claim 4, wherein the compound is selected from the group consisting of:

(S) -3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propylcarbamate, and

(R) - [3- [4- [ [ (4-amino-5-chloro-2-methoxybenzoyl) amino ] methyl ] piperidin-1-yl ] -1- (4-fluorophenyl) propyl ] carbamate.

6. Use of the piperidine compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases.

7. The use of claim 6, wherein the gastrointestinal disease comprises at least one disorder selected from Irritable Bowel Syndrome (IBS), gastric motility disorder, constipation, and visceral pain.