MXPA06005825A - Quinolonecarboxylic acid compounds having 5-ht4 receptor agonistic activity - Google Patents

Abstract

This invention provides a compound of the formula (I):wherein Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents&agr;1;A represents an alkylene group having from 1 to 4 carbon atoms;B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms;Rl represents an isopropyl group, a n-propyl group or a cyclopentyl group;R2 represents a methyl group, a fluorine atom or a chlorine atom;R3 independently represents (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group;(ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents, or (iii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents, and n is 1, 2 or 3, or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

Description

COMPOUNDS OF THE QU1NOLONA-CARBOXILICO ACID THAT HAVE AGONISTA ACTIVITY OF THE 5-HT RECEIVER TECHNICAL FIELD This invention relates to novel quinolone carboxylic acid compounds. These compounds have selective 5-HT receptor agonist activity. The present invention also relates to a pharmaceutical composition, a method of treatment and a use, comprising the above compounds for the treatment of disease conditions mediated by the activity of the 5-HT4 receptor.

ANTECEDENTS OF THE TECHNIQUE In general, 5-HT4 receptor agonists are known to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome. (Sil), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as heart failure and cardiac arrhythmia, and apnea (See TiPs, 1992,13, 141; Ford APDW et al, Med. Res. Rev., 1993, 13, 633; Gullikson GW et al., Drug Dev. Res., 1992, 26, 405; Richard M. Eglen et al, Típs, 1995, 16, 391, Bockaert J. et al., CNS Drugs, 1, 6, Romanelli MN et al, Arzheim Forsch, IDrug Res., 1993, 43, 913, Kaumann A. et al, Naunyn. -Schmiedebergs 1991, 344, 150 and Romanell M. N. et al., Arzheim Forsch.1Drug Res., 1993, 43, 913). Also, it is known that mosaprida is useful for the treatment of diabetes. In addition, cisapride is known to be useful for the treatment of postoperative bowel motility (Tommy A. Brown et al., The American J. of Surgery, 177, p 399 (1999) .A variety of quinolone-carboxylic compounds as 5-HT4 receptor agonists has been described by the Taisho Company, among them, a compound represented by the following formula is specially described, which was selected as a preclinical compound TS-951 in the Japanese publication Kokai H09-194374: BRIEF DESCRIPTION OF THE INVENTION It has now surprisingly been found that the quinolone-carboxylic compounds of this invention have a strong affinity for the 5-HT4 receptor by introducing small size substituents such as a methyl group and a fluorine atom, and thus are useful for the treatment of disease conditions mediated by 5-HT4 activity such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (HS), constipation, dyspepsia, esophagitis, gastroesophageal disease , nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes, apnea syndrome (especially caused by an administration of opioids) , and postoperative bowel motility. In addition, the compounds of the present invention show a prolongation of the reduced QT interval by introducing a polar group in the R3 of the formula (1). The prolongation of the QT interval is known to be a potential cause of producing fatal cardiac arrhythmias of Torsades de Pointes (TdP). The ability to prolong the potential duration of cardiac action was identified as being due to an action in the potassium channel of HERG. For example, drugs withdrawn from the market due to prolongation of the QT interval are known, such as cisapride and terfenadine, which are potent potassium channel blockers of HERG (Expert Opinion of Pharmacotherapy; 2, pp. 947-973, 2000 ). The inhibitory activity in the HERG channel was estimated from the affinity for the potassium channel of the HERG type and was investigated by checking the binding to [3H] -dofetilide, which can predict the inhibitory activity in the HERG channel (Eur, J. Pharmacol., 430, pp. 147-148, 2001). The compounds of the present invention may show a shorter prolongation of the QT interval, less toxicity, good absorption, distribution, good solubility, low affinity of binding proteins, less drug-drug interaction, and good metabolic stability. The present invention provides a compound of the following formula (I): wherein Het represents a heterocyclic group having a nitrogen atom, to which B is directly attached, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected separately from of the group consisting of substituents s1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, an n-propyl group or a cyclopentyl group; R 2 represents a methyl group, a fluorine atom or a chlorine atom; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents selected separately from the group consisting of substituents a2, or (iii) a heterocyclic group having 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents selected separately from the group consisting of β substituents, said substituents being selected separately from a hydroxy group and an amino group; said a2 substituents are selected separately from a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof. Also, the present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by the 5-HT4 receptor, in a mammalian subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or its salts pharmaceutically acceptable In addition, the present invention also provides a pharmaceutical composition for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (Sil), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome, motility postoperative intestine, or the like, comprising a therapeutically effective amount of the quinolone carboxylic acid compound of formula (I) or its pharmaceutically acceptable sai together with a pharmaceutically acceptable carrier.

Also, the present invention provides a method for the treatment of disease conditions mediated by the 5-HT4 receptor, in a mammalian subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or its pharmaceutically salts acceptable In addition, the present invention provides a method for the treatment of the disease conditions mentioned above. In addition, the present invention provides the use of the compound of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicament for the treatment of disease conditions mediated by the activity of the 5-HT receptor, in a mammalian subject. Conditions mediated by 5-HT4 receptor activity include those diseases or disorders described above.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "heterocyclic" of "He." means a heterocyclic group having a nitrogen atom and from 4 to 7 carbon atoms such as: As used herein, the term "alkylene" in "A" means straight or branched chain saturated radicals having from 1 to 4 carbon atoms, including, but not limited to methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene. The "alkylene" in "A" preferably represents a methylene group, an ethylene group or a propylene group; more preferably a methylene group or an ethylene group; more preferably a methyphene group. As used herein, the term "alkylene" in "B" means straight or branched chain saturated radicals having from 1 to 5 carbon atoms, including, but not limited to methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, sec-pentylene, tert-pentylene. "Alkylene" in "B" preferably represents an alkylene group having from 1 to 4 carbon atoms; more preferably an alkylene group having from 1 to 3 carbon atoms; much more preferably a methylene group or an ethylene group; more preferably, a methylene group.

As used herein, the term "alkyl" of "an alkylamino" in "R3"; "alkyl" of "an alkyl group substituted by hydroxy" and "an alkoxy group having from 1 to 4 carbon atoms" in "substituents s2"; "alkyl" in "substituents"; and "alkyl" of "an alkyl group substituted by hydroxy" and "an alkyl group substituted by amino" in "substituents" means straight or branched chain saturated radicals having from 1 to 4 carbon atoms, including, but not limited to to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl. As used herein, the term "cycloalkyl" in "R3" means a cyclic alkyl group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and etc. As used herein, the term "heterocyclic" of "R3" means a heterocyclic ring having one or more heteroatoms in the ring, preferably having 2 to 6 carbon atoms and 1 to 3 heteroatoms, including aziridinyl, azetidinyl , piperidinyl, morpholinyl (including morpholino), pyrrolidinyl, pyrazolidinyl, piperazinyl, tetrahydropyrazolyl, pyrazolinyl, tetrahydropyranyl and etc. The term "treat", as used herein, refers to reversing, alleviating, inhibiting the progress, or preventing a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

The term "treatment" as used herein refers to the act of treating, such as "treating" is defined immediately above.

The substituents "R3" can be attached to the carbon atom linking the "group B" and the "group R3"), such as the formulas that follow: A preferred compound of formula (I) of this invention is one in which Het represents a heterocyclic group selected from: said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected separately from the group consisting of substituents a1. A most preferred compound of formula (I) of this invention is one in which: Het represents a group of formula and this group being unsubstituted or substituted by a substituent selected from the group consisting of substituents s1; A represents an alkylene group having from 1 to 3 carbon atoms; R1 represents an isopropyl group or a cyclopentyl group.

A most preferred compound of formula (I) of this invention is the one in which: Het represents a group of formula: A represents an alkylene group having 1 to 2 carbon atoms; B represents an alkylene group which has from 1 to 5 carbon atoms carbon; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkyl-amino group or a carboxyl group; (ii) a cycloalkyl group having from 5 to 7 carbon atoms, and said cycloalkyl group being substituted by 1 to 3 substituents selected by being stopped from the group consisting of substituents s2 or (iii) a heterocyclic group having from 5 to 7 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected separately from the group consisting of substituents ß, said a2 substituents are selected separately from of a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2 or 3. A highly preferred compound of formula (I) of this invention is one in which: A represents a methylene group; B represents an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group; R3 represents separately: (i) an oxo group or a hydroxy group; (ii) a cycloalkyl group having from 5 to 6 carbon atoms, and said cycloalkyl group being substituted by 1 to 2 substituents selected separately from the group consisting of substituents cr 2, or (iii) a heterocyclic group having from 5 to 6 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents selected separately from the group consisting of β substituents, said substituents s2 are selected separately from a hydroxy group or an amino group; and said β substituents are selected from a hydroxy group, an amino group and an alkyl group having from 1 to 4 group of carbon atoms; and n is 1 or 2. A highly preferred compound of formula (I) of this invention is one in which: B represents an alkylene group having from 1 to 3 carbon atoms; R3 represents separately: (i) an oxo group or a hydroxy group; (ii) a cyclohexyl group substituted by 1 to 2 hydroxy group, or (ii) a heterocyclic group selected from a hydroxytetrahi-dropyranyl, piperidinyl and morpholinyl, and said heterocyclic group being unsubstituted or substituted by from 1 to 2 substituents selected separately from a hydroxy group and a methyl group; and n is 1 or 2. A highly preferred compound of formula (I) of this invention is one in which: B represents a methylene group; R2 represents a methyl group; R3 represents separately a 1,4-dihydroxycyclohexyl, hydroxytetrahi-dropiranium, piperidinyl and morpholinyl group; and n is 1. A most preferred compound of formula (I) of this invention is one in which: R3 represents separately a 1,4-dihydroxycyclohexyl or hydroxytetrahi-dropyranyl group.

General synthesis The compounds of the present invention can be prepared by a variety of known processes for the preparation of compounds of this type, for example, as shown in the following reaction Schemes. Unless otherwise indicated R1, R2, R3, Het and n in the reaction Schemes and the discussion that follows are defined as before. The term "protecting group", as used hereinafter, means a hydroxy or amino protecting group that is selected from the typical hydroxy or amino protecting groups described in "Protective Groups in Organic Synthesis" edited by TW Greene et al (John Wiley &Sons, 1991); All starting materials in the following general syntheses may be commercially available or be obtained by conventional methods known to those skilled in the art. The compound of formula (I) can be prepared in a similar manner or by some method known to any skilled person.

Synthesis of the compound of formula (1) 1 The following reaction schemes illustrate the preparation of the compounds of formula 1.

Scheme 1 E'_apa 1 f Step 1a A compound of formula 1-2 can be prepared by reducing the compound of formula 1-1 with a suitable reducing agent such as, sodium borohydride (NaBH), lithium aluminum hydride (LAH), diborane, borane dimethyl sulphide complex, borane-THF, (preferably hydrogen and a metallic catalyst), usually in excess, in a inert reaction solvent such as diethyl ether, DME, dioxane, tetrahydrofuran (THF) (preferably THF), generally at a temperature from -78 ° C to 60 ° C, preferably from about 0 ° C to 45 ° C for 5 minutes to 24 hours, preferably 60 minutes to 12 hours.

Step 1 b In step 1b, a compound of formula 1-3 can be prepared by reductive amination from the alkanone compound with an amine compound of formula 1-2 in the presence or absence of a reducing agent or a metal agent in a inert solvent. The reaction is usually and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent that is employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable organic aqueous or non-aqueous solvents include: alcohols, such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran, dimethoxyethane or dioxane; acetonitrile; N.N'-dimethylformamide; dimethylsulfoxide; acetic acid; and halogenated hydrocarbon, such as dichloromethane, dichloroethane or chloroform. The reaction can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction with reducing agents at a temperature of -78 ° C to 100 ° C, more preferably of about -20 ° C to 60 ° C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reactants and the solvent employed. However, as long as the reaction is carried out under the preferred conditions indicated above, a period of 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will generally suffice. In the case of a reaction with metallic reagents, it is convenient to carry out the reaction at a temperature of 20 ° C to 100 ° C, preferably of about 20 ° C to 60 ° C for 10 minutes to 48 hours, preferably 30 minutes to 24 hours. Suitable reducing reagents are those typically used in the reduction including, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride. Examples of suitable metal reagents include carbon on palladium, palladium-carbon hydroxide, platinum oxide, platinum-carbon, ruthenium-carbon, rhodium-aluminum oxide, and tris [triphenylphosphine] rhodium chloride. The reduction with metallic reagents can be carried out under a hydrogen atmosphere at a pressure in the range of 1 to 100 atm, preferably 1 to 10 atm. This reduction can be carried out after the formation of the corresponding enamine of the alkanone compound or of the alkanone compound in a reaction-inert solvent such as benzene, toluene, or xylene at a temperature in the range of 20 to 130. ° C for 1 hour to 1 week.

Step 1c Compound 1-4 can be reacted with a compound of formula 1-3 in the presence of an oxidizing agent such as manganese dioxide, pyridinium chloro-chromate, pyridinium dichromate (preferably manganese dioxide), usually in excess, in an inert reaction solvent such as dimethoxyethane, dioxane, acetonitrile, N, N'-dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, tetrahydrofuran (THF), benzene, toluene, or chloroform (preferably benzene or toluene), generally at a temperature of -78 ° C to 120 ° C, preferably from about 0 ° C to 90 ° C for 5 minutes to 24 hours, preferably 60 minutes to 12 hours.

Step 1d Compound 1-3 can be reacted with a compound of formula CH (CO2R4) 2 wherein R4 is methyl or ethyl, in an inert reaction solvent such as dimethoxyethane, dioxane, acetonitrile, N, N'-dimethylformamide, dimethylsulfoxide, dichloromethane, dichloroethane, tetrahydrofuran (THF), benzene, toluene, or chloroform (preferably benzene), generally at a temperature of -78 ° C to 120 ° C, preferably from about 0 ° C to 90 ° C for 5 minutes at 24 hours, preferably 60 minutes to 12 hours.

Step 1e In this Step, an acid compound of formula 1-6 can be prepared by hydrolysis of the ester compound of formula 1-5 in a solvent. The hydrolysis can be carried out according to conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, for example in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example, water, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and 1,4-dioxane; amides such as NN-dimethylformamide (DMF) and hexamethylphosphoryltriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). This reaction can be carried out at a temperature in the range of -20 to 100 ° C, usually 20 ° C to 65 ° C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. The hydrolysis can also be carried out under acidic conditions, for example in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfuric acid; sulphonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p-toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid. Suitable solvents include, for example, water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and 1,4-dioxane; amides such as NN-dimethylformamide (DMF) and hexamethylphosphoryltriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). This reaction can be carried out at a temperature in the range of -20 to 100 ° C, usually 20 ° C to 65 ° C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Alternatively, compound 1-6 can be prepared from the compounds of formula 1-4 using an acid condensation of meldrum under reaction conditions known to a skilled person (Masaji Suzuki et al., Heteropycles, 53, 2471 (2000 )).

Step 1f In this Step, an amide compound of formula (I) can be prepared by the coupling reaction of an amine compound of formula 1-7 with the acid compound of formula 1-6 in the presence or absence of a coupling reagent in an inert solvent. If desired, this reaction can be carried out in the presence or absence of an additive such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole. The reaction is usually and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent that is employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: acetone, nitromethane, DMF, sulfolane, DMSO, NMP, 2-butanone, acetonitrile; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform; and ethers, such as tetrahydrofuran and dioxane. The reaction can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 100 ° C, more preferably from about 0 ° C to 60 ° C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reactants and the solvent employed. However, as long as the reaction is carried out under the preferred conditions cited above, a period of 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will generally suffice. Suitable coupling reagents are those typically used in the synthesis of peptides including, for example, diimides (eg, dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC)), 2-ethoxy-N-ethoxycarbonyl-1, 2- dihydroquinoline, 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 2-chloro-1,3-dimethylimidazolinium chloride, benzotriazoi-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP), azodi-carboxylate-triphenylphosphine of diethyl, diethylcyanophosphate, diethylphosphorylazide, 2-chloro-1-methylpyridinium iodide, N, N'-carbonyldiimidazole, benzotriazol-1-yl-diethyl phosphate, ethyl chlorofor or isobutyl chlorofor. If desired, the reaction can be carried out in the presence of a base such as NN-diisopropylethylamine, N-methylmorpholine and triethylamine. A compound of 1-7 can be prepared from the compounds of formula 2-1 or 2-3 under known reaction conditions for a skilled person as indicated in Scheme 2.

SCHEME 2 .A1 HaM vHßt-8 alqtiilací? H ^ 2-1 2-2 or A1 A * \ aiquil? C? P, p'ß Hel ~ i deprotecclóp H2N '^ Het "B. { f.3) n Stage 2c (3) n Stage 2d \ 1-7 (Rs) n 2-3 2-4 (wherein PG is a protecting group, preferably such as tert-butoxycarbonyl or benzyloxycarbonyl, and Al is an alkanoyl group having from 1 to 4 carbon atoms) In step 2a, and 2c, a compound of formula 2-2 and 2-4 can be prepared by alkylation of a compound of formula 2-1 and 2-3. The reaction can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used.

However, in general, it is convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 0 ° C to 70 ° C. Time - required for the reaction may also vary widely, depending of many factors, notably the reaction temperature and the nature of the reagents and the solvent used. However, as long as the The reaction can be carried out under the preferred conditions mentioned above, a period of 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, will usually suffice. In step 2b, the reduction can be carried out under the same essential conditions as in step 1a. Alternatively, some compounds of formula (I) can be prepared by a method indicated according to scheme 3 as below under conditions known to a skilled person.

SCHEME 3 Alternative route to 1 -5 3-1 3-2 3.3 (in qy§ ñ * s-s methyl ethyl Q) if Rb is a protective group such as Boc: R3 O Sa O R O ' R k * s ^ xSdo, etc ... n 3-4 3-5 a) if B- (R3) n is a piperidine derivative: Rd? protective group (in which Re is hydroxy) if B- (R3) n is an acetic acid derivative: or? giO ° k,? £ ¡1 - ^ ¿Q ft > OR?? W H * -22 ^ co ít'i »v R« »R" * 3-ß 3 * s í «= > (wherein R9 is such as C- alkyl, Rf is C1- alkyl, R9 is C- alkyl, Rh and R 'are C? -4 alkyl or together can form a morpholinyl or piperidinyl.) The compounds of formula (I ), and the intermediates of the aforementioned prepion methods can be isolated and purified according to conventional procedures, such as distillation, recrystallization or chromatographic purification. The optically active compounds of this invention can be prepared by various methods. For example, the optically active compounds of this invention can be obtained by chromatographic sepion, enzymatic resolution or fractional crystallization of the final compounds. Several compounds of this invention possess an asymmetric center. Therefore, the compounds can exist in sepe optically active forms (+) - and (-), as well as in their racemic. The present invention includes all such forms within its scope. The individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic sepion in the prepion of the final product or its intermediate. The substantial invention also includes isotopically labeled compounds, which are identical to those mentioned above in formula (I), but by the fact that one or more atoms are replaced by an atom having an atomic number or a mass number different from that of the atomic number or number of mass found usually in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P , 35S, 18F and 36CI respectively. The compounds of the present invention, their prodrugs, the pharmaceutically acceptable esters of said compounds and the pharmaceutically acceptable salts of said compounds, said esters or said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are in the amplitude of this invention. Certain isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in distribution, drug and / or substrate assays in tissues. The isotopes of tritium, i.e., 3H, and carbon 14, i.e., 14C, are particularly preferred for their ease of presentation and detectability. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, may provide therapeutic benefits that are the result of increased metabolic stability, for example, increased half-life in vivo or lower dosage requirements and hence , which may be preferred in some circumstances. The isotopically-labeled compounds of formula (I) of this invention and their prodrugs can generally be prepared by carrying out the procedure described in the Schemes described above and / or following Examples and Preparations, by subjecting the readily available isotopically-labeled reagent to an isotopically unlabeled reagent. . The present invention includes salt forms of the compounds (I) as obtained. Certain compounds of the present invention may be capable of forming pharmaceutically acceptable non-toxic cations. The non-toxic cations of the pharmaceutically acceptable compounds of formula (I) can be prepared by conventional techniques, for example, by contacting said compound with a stoichiometric amount of an appropriate alkali metal hydroxide or alkoxide or alkaline earth metal (sodium, potassium) , calcium and magnesium) in water or an appropriate organic solvent such as ethanol, sodium propane, mixtures thereof, or the like. The bases which are used to prepare the pharmaceutically acceptable basic addition salts of the acidic compounds of this invention of formula (I) are those which form non-toxic basic addition salts, ie salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benetamine (ie, n-benzyl-2-phenylethylamine), benzathine (ie, NN-dibenzylethylenediamine), choline, diolamine (ie, diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine (i.e., N-methylglucamine), nicotinamide, olamine (ie, ethanolamine), omitin, procaine, proline, pyridoxine, serine, tyrosine, valine, and tromethamine (ie, tris or tris (hydroxymethyl) aminomethane). The basic addition salts can be prepared according to conventional procedures. To the extent that certain compounds of this invention are basic compounds, they are therefore capable of forming a wide variety of different salts with various inorganic and organic acids. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate, adipate, aspartate carnsilate, edisilate (i.e., 1,2-ethanedisulfonate), stolate (ie, lauryl sulfate), gluceptate (ie, glucoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate (i.e. 1-hydroxy-2-naphthoate), isethionate, (i.e., 2-hydroxyethanesulfonate), mucate (i.e., galactarate), 2-nafsylate (i.e., naphthalenesulfonate, stearate, cholate, glucuronate, glutamate, hippurate, lactobionate, lysinate, maleate, mandelato, napadisilato, nicatinato, poligalacturonato, salicilato, sulfosalicilato, tanato, triptofanato, borato, carbonate, oleato, phthalate and pamoato (ie 1, 1'-metilen-bis- (2-hidroxi-3-naftoato ). The acid addition salts can be prepared according to conventional procedures. For a review of suitable salts see Berge et al., J. Pharm. Sci., 66, 1-19, 1977. Also included in the scope of this invention are bioprecursors (also called prodrugs) of the compounds of formula (I). A bioprecursor of a compound of the formula (I) is a chemical derivative thereof which is easily reconverted into the parent compound of the formula (I) in biological systems. In particular, a bioprecursor of a compound of formula (I) is reconverted to the parent compound of formula (I) after the bioprecursor has been administered, and absorbed by a mammalian subject, for example, a human subject. For example, it is possible to make a bioprecursor of the compounds of formula (I) in which both L and W include hydroxy groups by making an ester of the hydroxy group. When only one of L and W includes the hydroxy group, only one monoester is possible. When both L and W include hydroxy, mono- and di-esters (which may be the same or different) may be made. Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when L or W include a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxymethyl derivative (e.g., a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e.g., pivaloyloxymethyl chloride). When the compounds of formula (I) of this invention can form solvates such as hydrates, such solvates are included in the scope of this invention.

METHOD FOR EVALUATING BIOLOGICAL ACTIVITIES The binding affinities of the 5-HT4 receptor of the compounds of this invention are determined according to the following procedures.

Preparation of the membrane Pork heads were supplied from a slaughterhouse. Striatal tissues were dissected, weighed and homogenized in 15 volumes of 50 mM ice-cold HEPES (pH 7.5) in a Polytron homogenizer (30 s at maximum speed). The suspension was centrifuged at 48,000 g and 4 ° C for 15 minutes. The resulting pellet was resuspended in an appropriate volume of 50 mM ice cold HEPES, was aliquoted and stored at -80 ° C until use. Bovine heads were also supplied by a slaughterhouse. Striatal tissues were dissected, weighed and homogenized in 20 volumes of 50 mM ice-cold Tris-HCl (pH 7.4) in a Polytron homogenizer (30 s at maximum speed). The suspension was centrifuged at 20,000 g and 4 ° C for 30 minutes. The resulting pellet was resuspended in 15 volumes of 50 mM ice-cold Tris-HCl, homogenized and centrifuged again in the same manner. The final pellet was resuspended in an appropriate volume of 50 mM Tris-HCl, was aliquoted and stored at -80 ° C until use. Cerebral cortical tissues were removed from male Sprague-Dawley rats (SD) (Japan SLC), weighed and placed in 10 volumes of 50 mM ice-cold Tris-HCl (pH 7.5). This was homogenized in a Polytron homogenizer (30 s at maximum speed) and subsequently centrifuged at 48,000 g and 4 ° C for 15 minutes. The resulting pellet was resuspended in 50 mM ice-cold Tris-HCl, homogenized and centrifuged again in the same manner. The final pellet was resuspended in an appropriate volume of 50 mM Tris-HCl, was aliquoted and stored at -80 ° C until use. The protein concentrations of the homogenates were determined by the Bradford method or the BCA protein method (Pierce) with BSA as standard.

UNION TESTS The affinity of compounds for 5-HT4 receptors of pig or bovine and rat 5-HT3 was evaluated using specific radiolabelled ligands, GIR 113808 (. {1- [2- (Methylsulphonyl) ethyl] -4-piperidinyl}. [methyl-3H3-1 H-indole-3-carboxylate] and BRL 43694 (1-methyl-N- (9- [methyl-3H] -9-azabicyclo [3.3.1] non-3-yl) -1 H -indazole-3-caboxamide). Compounds were incubated with 25-100 pM of [3H] -GR 113808 (Amersham) and 0.6-1 mg protein from pig striatum membranes or bovine suspended in a final volume of 0.8-1 ml of 50 mM Tris-HCl. (pH 7.5). The non-specific binding was determined with 5-HT 10-50 μM. Binding of [3 H] -BRL 43694 (NEN) 0.3 nM was measured using 400 μg of protein from rat cortical membranes suspended in a final volume of 500 μl of 50 mM Tris-HCl (pH 7.5). Non-specific binding was determined with 10 μM 5-HT. Plates were incubated at room temperature on a plate shaker for 30 minutes. The tests were stopped by rapid filtration using a Brandell cell harvester through Wallac-B filters pre-packed in 2% polyethyleneimine at 4 ° C for 60-90 minutes. The filters were washed three times with 1 ml of 50 mM ice-cold HEPES, and were dried in a microwave or at room temperature. They were put in bags and heated with a MeltiLex scintillation counter (Wallac) or soaked in a BetaplateScint (Wallac). The radioactivity of the bound receptor was quantified using the Big-spot counter, Betaplate counter (Wallac) or LS counter (Packard).

Human 5-h junction HEK293 transfected human 5-HT4 (d) cells were prepared and cultured in the laboratory. The harvested cells were suspended in 0.5 mM HEPES (pH 7.4 at 4 ° C) supplemented with protease inhibitor cocktail (Boehringer, 1: 1000 dilution) and homogenized using an ergonomically manual Polytron PT 1200 disruptor set maintained at power maximum for 30 s on ice. The homogenates were centrifuged at 40,000 g x at 4 ° C for 30 minutes. The pellets were then resuspended in 50 mM HEPES (pH 7.4 at 4 ° C) and were centrifuged once more in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM HEPES (pH 7.4 at 25 ° C), were homogenized, divided into aliquots and stored at -80 ° C until use. An aliquot of the membrane fractions was used for the determination of protein concentration using a BCA protein assay kit (PIERCE) and the ARVOsx plate reader (Wallac). For the binding experiments, 25 μl of the test compounds were incubated with 25 μl of [3 H] -GR113808 (Amersham, final 0.2 nM) and 150 μl of membrane homogenate and suspension solutions of beads WGA-SPA (Amersham) (10 μg of protein and 1 mg of SPA beads / well) for 60 minutes at room temperature. The non-specific binding was determined by GR113808 1 μM (Tocris) to the final concentration. The incubation was terminated by centrifugation at 1000 revolutions per minute. The radioactivity of the bound receptor was quantified by counting with the MicroBeta plate counter (Wallac). All the compounds prepared in the working examples as described below were analyzed by this method, and showed Ki values of 1.5 nM to 8.6 nM as regards the inhibition of binding at the 5-HT4 receptor.

FUNCTIONAL ESSAY The presence of 5-HT receptors in the rat esophagus and the ability to demonstrate partial agonism in the preparation of TMM has been reported in the literature (See GS Baxter et al. Naunyn-Schmiedebergs Arch Pharmacol (1991) 343: 439-446; M. Yukiko et al. JPET (1997) 283: 1000-1008; and JJ Reeves et al. Br. J. Pharmacol. (1991) 103: 1067-1072). More specifically, the partial agonist activity can be measured according to the following procedures. Male SD rats (Charles River) weighing 250-350 g were sedated and then sacrificed by cervical dislocation. The esophagus was dissected from immediately proximal to the stomach (including the piece of stomach to mark the distal end) to the level of the trachea and then placed in a freshly prepared Krebs solution.

The outer skeletal muscle layer was removed at one time by removing the underlying smooth muscle layer using forceps (stomach to the tracheal direction). The remaining internal smooth muscle chamber is known as TMM. This was adjusted to 2 cm from the original 'end of the stomach' and the rest was discarded.The TMMs were mounted as 'open' whole chambers in the longitudinal orientation in 5 ml organ baths filled with hot aerated Krebs (32 °) C) The tissues were placed under an initial tension of 750 mg and allowed to equilibrate for 60 minutes Tension was again applied to the tissues twice at 15 minute intervals during the balancing period. 2 ml / min during this time After equilibration, the pump was deactivated The tissues were exposed to 1 μM carbachol and contracted and reached a stable contractile plateau at 15 minutes The tissues were then subjected to 1 μM 5-HT (This was to start the tissues.) The tissues were relaxed in response to 5-HT fairly quickly in 1 minute.As soon as maximum relaxation had occurred and a measurement was taken, the tissues were washed at maximum speed (66 ml / min) for at least 1 minute and until the original bottom line (precarbacol and 5-HT) returned (usually, the baseline fell below the original after the initial equilibration). The flow rate of the pump was reduced to 2 ml / min and the tissues were left 60 minutes.

A cumulative concentration response curve (CEC) of 5-HT was constructed through the range of 0.1 nM to 1 μM, in semi-logarithmic unit increments (curve 1 of 5-HT for data analysis). The contact time between doses was 3 minutes or until the plateau stabilized. The tissues responded faster according to the concentration of 5-HT increased in the bath. At the end of the curve, the tissues were washed (at a maximum speed) as soon as possible to avoid desensitization of the receptors. The speed of the pump was reduced to 2 ml / min and the tissues were left 60 minutes. A second CEC was performed - both for 5-HT (for time control tissues), and for 5-HT4 agonist (standard) or a test compound (curve 2 for data analysis). The contact time varied for other 5-HT4 agonists and test compounds and was adapted according to the individual tissue responses to each particular agent. In tissues exposed to a test compound, a high concentration (1 μM) of a 5-HT4 antagonist (SB 203,186: 2- (1-piperidinyl) ethyl ester of 1 H-indole-3-carboxylic acid, Tocris ) was added to the bath after the last concentration of the test compound. This was to see if any relaxation induced by agonist (if present) could be reversed. SB 203,186 reversed the relaxation induced by 5-HT, restoring the original grade of the tissue of the tone induced by carbachol. The agonist activity of the test compounds was confirmed by preincubating tissues with the standard 100 nM 5HT antagonist such as SB 203,186. SB 203,186 was added to the bath 5 minutes before the addition of carbachol before curve 2. The tissues must be 'paired' for data analysis, i.e., the test compound in the absence of SB 203,186 in a tissue was compared to the test compound in the presence of SB 203,186 in a separate tissue. It was not possible to carry out a curve 3, ie curve 1 of 5-HT, followed by curve 2 of the test compound (-SB 203,186), followed by curve 3 of the test compound (+ SB 203,186).

Increase in agonist-induced cAMP in HEK293 transfected human 5-h n cells HEK293 transfected human 5-HT4 (d) cells were established in the laboratory. Cells were cultured at 37 ° C and 5% CO2 in DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4), 200 g / ml hygromycin B (Gibco), 100 units / ml penicillin and 100 μg / ml of streptomycin. The cells were cultured until confluence of 60-80%. The day before the treatment with FCS dialysis compounds (Gibco) was replaced by normal and the cells were incubated overnight. The compounds were prepared in 96-well plates (12.5 μl / potassium). The cells were cultured with PBS / 1 mM EDTA, centrifuged and washed with PBS. At the beginning of the assay, the cell pellet was resuspended in DMEM supplemented with 20 mM HEPES, 10 VLM pargyline (Sigma) and 1 mM 3-isobutyl-1-methylxanthine (Sigma) at a concentration of 1.6 x 10 5 cells / ml and were left 15 minutes at room temperature. The reaction was initiated by the addition of the cells in plates (12.5 μl / well). After incubation for 15 minutes at room temperature, 1% Triton X-100 was added to stop the reaction (25 μl / well) and the plates were left for 30 minutes at room temperature. The detection of cAMP based on fluorescence resolved in homogeneous time (Schering) was done according to the manufacturer's instructions. The ARVOsx multi-label counter (Wallac) was used to measure HTRF (excitation 320 nm, emission 665 nm / 620 nm, retention time 50 μs, window time 400 μs). The data were analyzed based on the fluorescence intensity ratio of each well at 620 nm and 665 nm followed by the quantification of cAMP using the standard curve of cAMP. The increase in cAMP production obtained by each compound was normalized to the amount of cAMP produced by 1000 nM serotonin (Sigma). All the compounds of the Examples showed agonist activity at the 5HT4 receptor.

Human dofetilide binding HEK293S cells transfected from human HERG were prepared and cultured in the laboratory. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4 ° C) and homogenized using an ergonomically designed Polytron PT 1200 disruptor set at maximum power for 20 s on ice. The homogenates were centrifuged at 48,000 x g at 4 ° C for 20 minutes. The pellets were then resuspended, homogenized, and centrifuged once again in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM Tris-HC1, 10 MM KCl, 1 mM MgCl2 (pH 7.4 at 4 ° C), homogenized, and aliquoted and stored at -80 ° C until use. An aliquot of membrane fractions was used for determination of protein concentration using a BCA protein assay kit (PIERCE) and an ARVOSX plate reader (Wallac). The binding assays were carried out in a total volume of 200 μl in 96-well plates. Twenty μl of test compounds were incubated with 20 μl of [3 H] -dofetilide (Amersham, 5 nM final) and 160 μl of membrane homogenate (25 μg of protein) for 60 minutes at room temperature. Non-specific binding was determined with 10 μM dofetilide at the final concentration. Incubation was terminated by rapid vacuum filtration over a 0.5% Betaplate GF / B filter pre-packed using a Skatron cell harvester with 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl 2, pH 7.4 at 4 ° C. The filters were dried, placed in sample bags and filled with Betaplate Scint. The radioactivity bound to the filter was counted with a Wallac Betaplate counter.

EjTsayojHgRG HEK 293 cells that stably expressed the potassium channel of HERG were used for the electrophysiological study. The methodology for the stable transfection of this channel in HEK cells can be found in other publications (Z. Zhou et al., 1998, Biophysical journal, 74, pp. 230-241). Before the day of experimentation, the cells were grown in culture plates and placed in glass slides in a standard MEM medium with 10% FCS. The cells placed in plates were stored in an incubator at 37 ° C and were maintained in an atmosphere of 95% O2 / 5% CO2. Cells were studied between 15-28 hours after harvest. HERG currents were studied using the technique "standard patch clamp" in the whole cell mode. During the experiment the cells were superfused with an external standard solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. The whole cell records were made using a "patch clamp" amplifier and "patch" pipettes having a resistance of 1-3 MOhm when filled with the internal standard solution of the following composition (mM); KCl, 130; MgATP, 5; MgCl 2, 1, 0; HEPES, 10; EGTA 5, pH 7.2 with KOH.

Only those cells with access resistances below 15 MO and sealing resistances > 1 GO were accepted for the experiments. The compensation of the series resistance was applied up to a maximum of 80%. No loss subtraction was made. However, the acceptable access resistance depended on the size of the recorded currents and the level of compensation of the series resistance that can be safely used. After achieving the configuration of whole and sufficient cells for dialysis of cells with the pipette solution (> 5 min), a standard voltage protocol was applied to the cell to cause membrane currents. The voltage protocol is as follows. The membrane was depolarized from its own potential of -80 mV to + 20mV during 1000 ms. This was followed by a descending voltage ramp (velocity 0.5 mV ms "1) below the potential itself.The voltage protocol was applied to a cell continuously at all moments of the experiment every 4 seconds (0.25 Hz). The maximum current obtained around -40 mV during the ramp was measured.After stable current responses were obtained caused in the external solution, the vehicle (0.5% DMSO in an external standard solution) was applied for 10-20 minutes By means of a peristaltic pump, when there were minimal changes in the amplitude of the current response caused in the vehicle control condition, the test compound at 0.3, 1, 3, 10 μM was applied for a period of 10 minutes. 10 minutes included the time the solution was delivered through the tube from the reservoir of the solution to the recording chamber via the pump.The exposure time of the cells to the solution of the compound was more than 5 minutes after the concentration of drug in the chamber reached the intended concentration well. There was reversibility. Finally, the cells were exposed to high doses of dofetilide (5 μM), a specific blocker of IKr, to evaluate the insensitive endogenous current. All experiments were performed at room temperature (23 ± 1 ° C). The resulting membrane currents were recorded online in a computer, filtered at 500-1 KHz (Bessel-3dB) and sampled at 1-2 KHz using a patch clamp amplifier and specific data analysis software. The maximum current amplitude, which occurred around -40m, was the line measured in the computer. The arithmetic mean of the ten amplitude values was calculated under control conditions and in the presence of the drug. The decrease in percent of IN in each experiment was obtained by the normalized value of current using the following formula: lN = (1- IQ / IC) X 100, where ID is the mean value of current in the presence of the drug e is the average current value under control conditions. Separate experiments were performed for each drug concentration or control by time, and the arithmetic mean in each experiment is defined as the result of the study.

Method of gastric emptying model in rats The effects of compounds on gastric emptying in rats were examined by the modified method of D. A. Droppleman et al. (J. Pharmacol. Methods 4, 227-230 (1980)). The test meal, caloric food without fats, was prepared according to the method of S. Ueki et al. Arzneim.-Forsch. / Drug Res. 49 (11), 618-625 (1999)). IGS-SD rats (Male, 7w, 230-270 g) were purchased from Charles River of Japan (Atsugi). These rats were used in the experiments after a one-week acclimation. In the experiments, the rats were left fasting 15 hours before the experiments, although they had free access to water. Forty-five minutes before the beginning of the experiment, the water was removed from the cage to prevent the rats from taking water. Five minutes before the administration of the test meal, the test compounds, cisapride or the vehicle were medicated via an appropriate route to the rats (n = 8-10) in a volume of 0.1 ml per 100 g of body weight. Cisapride (3 nig / kg) was used as a positive control of the experiment. The rats were given 3 ml of the test meal by priming and returned to the cages. Thirty minutes after the administration of the food, the rats were sacrificed by exposure to CO2. After a median laparotomy, the stomach is linked to the lower esophageal sphincter (LES) and the pylorus. Then the stomach is removed and weighed (A). After the stomach was opened and rinsed with 0.9% saline, the face was dried with the tissue to remove any excess fluid and weighed again (B).

After discarding the rats that had eaten feces or had given artificial losses, the gastric emptying velocity for the individual animals was calculated by the formula: velocity of VG (%) = (A-B) / weight of the test meal.

Gastric motility in conscious dogs Surgical operation in dogs was performed by the modified method of Z. Itoh et al. (Gastroenterol, Jpn., 12, 275-283 (1977)). The effects of test compounds on gastric motility in dogs were examined by the modified method of N. Toshida et al (J. Pharmacol.

Exp / Ther., 257, 781-787 (1991)). An evaluation in a fasted state: A transducer of tension force was placed on the animals chronically in the gastric body, and they were fasted overnight before the experiment. Gastric motility was recorded continuously by a telemetry system for 8 h after the administration of the compound. To quantify the gastrointestinal motility change, the motor index was determined as the area under the contraction curves during each 2 h period divided by the peak height of the interdigestive migrating contraction. An assessment in the postprandial state: The animals were chronically implanted with a force measurement transducer in the gastric body, and they were fasted overnight before the experiment. They were induced postprandial motility by feeding them solid food (100 grams), and the compound was administered 2 h later. Gastric motility was recorded continuously by a telemetry system for 8 h after the administration of the compound. The motor index was determined to quantify the gastrointestinal motility change as the area under the contraction curves during each 1 h period divided by the area under the contraction curves for 1 h before compound administration. The compounds of formula (I) of this invention can be administered via oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses in the range of 0.3 mg to 750 mg per day, preferably 10 mg to 500 mg per day, although variations necessarily occur depending on the weight and condition of the subject being treated. treat, the state of the disease in question and the particular chosen route of administration. However, for example, a dosage level in the range of 0.06 mg to 2 mg per kg of body weight per day is most desirably used for the treatment of inflammation. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the above routes indicated above, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, that is, they can be combined with several inert pharmaceutically acceptable carriers in the form of tablets, capsules, pills, pills, hard candies, powders. , sprays, creams, balsams, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, a sterile aqueous medium and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be suitably flavored and / or flavored. In general, the therapeutically effective compounds of this invention are present in such dosage forms at a concentration level in the range of 5% to 70% by weight, preferably 10% to 50% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose may be employed., sodium citrate, calcium carbonate, dipotassium phosphate and glycine with various disintegrating agents such as starch and preferably grain starch, potato or tapioca, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in reference to this also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sugars or flavoring agents, coloring matters or dyes, and, if desired, emulsifying and / or suspending agents as well, together with such diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations. For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions must be suitably regulated at their pH (preferably pH> 8) if necessary and the liquid diluent must first be isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques known to those skilled in the art. In addition, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this preferably can be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

EXAMPLES The invention is illustrated in the following non-limiting examples in which, unless otherwise indicated: all operations were carried out at room or ambient temperature, i.e., in the range of 18-25 ° C; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 ° C; the reactions were controlled by thin layer chromatography (tic) and the reaction times are given only illustratively; the given melting points (p.f.) are not corrected (the polymorphism can cause different melting points); the structure and purity of all the isolated compounds were checked by at least one of the following techniques: tic (TLC plates pre-coated with Merck silica gel 60 F254 or pre-coated HPTLC plates with Merck NH2 F25 s), spectrometry masses, nuclear magnetic resonance (NMR), infrared absorption (IR) spectra or microanalysis. The returns are provided for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel (230-400 mesh ASTM) or DU3050 Chromatorex® from Fuji Silysia (Amino type, 30-50 μm). The low resolution mass spectral data (El) were obtained in an Integrity mass spectrometer (Waters) or an Automass 120 mass spectrometer (JEOL). The low resolution mass spectral data (ESI) were obtained in a mass spectrometer ZMD2 (Waters) or a mass spectrometer Quattro II (Micromasas). The NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless Indicate otherwise, in relation to tetramethylsilane (TMS) as internal standard in parts per million (ppm); the conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, etc. The IR spectra were measured by a Shimazu infrared spectrometer (IR-470). Optical rotations were measured using a DAS-370 digital polarimeter from JASCO (Spectroscopic Co. of Japan, Ltd.). Chemical symbols have their usual meanings; e.g. (boiling point), m.p. (melting point), L (liter (s)), mi (milliliter (s)), g (gram (s)), mg (milligram (s)), mol (mol), mmol (millimoles), eq. (equivalent (s)).

EXAMPLE 1 5-chloro-N- (1-r (4-hydroxytetrahydro-2h-pyran ^ -yl) methylipiperidine ^ -1.) Meti [) - 1-isopropyl-2-oxo-1,2-dihydroquinoline -3-carboxamide Stage 1. ( { 1- 4-hydroxytetrahydro-2H-pyrn-4-yl) metinpiperidin-4-IV-benzyl methylcarbamate.

A mixture of benzyl (piperidin-4-ylmethyl) carbamate (7.77 g, 31.3 mmol, Bose, D. Subhas et al, Tetrahedron Lett., 1990, 31, 6903) and 1,6-dioxaespiro [2.5] octane (4.29) g, 37.6 mmole, Satyamurthy, Nagichettiar et al., Phosphorous Sulfur, 1984, 19, 113) in methanol (93 mL) was stirred at room temperature for 20 h. Then the mixture was refluxed for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with methanol / dichloromethane (1: 20) to give 5.60 g (49%) of the title compound as a colorless oil. 1 H-NMR (CDCl 3) d: 7.40-7.30 (5H, m), 5.09 (2H, s), 4.85 (1 H, br), 3. 85-3.72 (4H, m), 3.08 (2H, t, J = 6.4 Hz), 2.88-2.83 (2H, m), 2.61 (1H, s), 2.36-2.30 (4H, m), 1.77-1.19 ( 9H, m).

Step 2. 4-ff4- (Aminomethyl) piperidin-1-ylmethyl > tetrahydro-2H-piran A mixture of benzyl (. {- 1 - [(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl.] Methyl) carbamate (5.60 g, 15.5 mmol, step 1) and palladium on activated carbon (10% by weight, 1.20 g) in methanol (250 mL) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as a slightly yellow oil. MS (ESI) m / z: 229 (M + H +). 1 H-NMR (CDCl 3) d: 1.19-1.28 (2H, m), 1.44-1.63 (8H, m), 1.65-1.71 (2H, m), 2.32 (2H, s), 2.35 (2H, t, J = 11.0 Hz), 2.57 (2H, d, J = 5.7 Hz), 2.85-2.90 (2H, m), 3.70-3.81 (4H, m).

Step 3. 5-Chloro-N- (. {1-f (4-hydroxytetrahydro-2H-pyran-4-pmetippiperidin-4-yl> methyl) -1-isopropyl-2-oxo-1, 2- dihydroquinoline-3-carboxamide To a solution of 5-chloro-1-isopropy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (111 mg, 0.418 mmol, step 4 in preparation 1) in dichloromethane (1 mL) was added oxalyl chloride (0.11 mL, 1.26 mmol) and one drop of N, N-dimethylformamide at 0 ° C. The mixture was stirred at room temperature for 0.5 h, The solvent and the excess amount of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (1 mL), 4- was added. { [4- (aminomethyl) piperidin-1-yl] metiI} tetrahydro-2H-pyran-4-ol (191 mg, 0.837 mmol, step 2) at 0 ° C and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL), and the aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layer was dried with sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropanol to give 156 mg (78%) of the title compound as a white solid. MS (ESI) m / z: 476 (M + H +). s p.f .: 227 ° C. IR (KBr) v: 3420, 3271, 2945, 2925, 2860, 2788, 2745, 1672, 1609, 1582, 1545, 1447, 1385, 1344, 1205, 1151, 1101, 1015, 984, 985, 845, 802 cm "1. 1 H-NMR (CDCl 3) d: 9.88 (1 H, br m), 9.34 (1 H, s), 7.53 (2 H, m), 0 7.35 (1 H, m), 3.76 (4 H, m), 337 (2H, t, J = 6.2 Hz), 2.88 (2H, d, J = 11.6 Hz), 2.36 (2H, m), 2.31 (2H, s), 1.75 (2H, d, J = 12.7 Hz), 1.67 (6H, d, J = 7.2 Hz), 1.65-1.30 (7H, m) .The signals due to CH (CH3) 2 and OH were not observed, Anal cale, for C25H3N3O4CI-0.6H2O: C 61.68; H, 7.29; N, 8.63 Found: C, 61.38; H, 7.03; N, 8.59.5 Alternative route to 4- { R4- (aminomethyl) piperidin-1-ipmethyl.} Tetrahydro- 2H -piran-4-ol Stage 1. ( { 1-f (4-hydroxytetrahydro-2H-pyran-4-ipmetillpiperidin-4-ylV 0 tere-butyl methylcarbamate To a stirred solution of tert-butyl (piperidin-4-ylmethyl) carbamate (22.3 g, 104 mmol) in methanol was added 1,6-dioxaespiro [2.5] octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al. Phosphorus Sulfur, 1984, 19, 113) at room temperature. Then, the mixture was heated to 60 ° C for 4 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethylether. The precipitate was collected by filtration and was recrystallized from a mixture of n-hexane and 2-propanol to give 14.2 g (42%) of the title compound as a colorless powder. MS (ESI) m / z: 329 (M + H +). p.f .: 104 ° C. 1 H-NMR (CDCl 3) d: 1.23-1.31 (2H, m), 1.44 (9H, s), 1.51-1.69 (8H, m), 2.27-2.38 (4H, m), 2.83-2.88 (2H, m) , 3.00 (2H, t, J = 6.2 Hz), 3.70- 3.85 (4H, m). 5 Anal. cale, for C? 7H32N2? 4: C, 62.17; H, 9.82; N, 8.53.

Found: C, 62.07; H, 9.92; N, 8.58.

Stage 2. 4-. { í4- (aminometl) pperidin-1-illmethyl) tetrahydro-2H-pyran-4-0I To a solution of tert-butyl (. {- 1 - [(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl.} Methyl) carbamate (50.28 g, 153 mmol, step 1) in methanol, 4 N hydrogen chloride in dioxane (200 mL, 800 mmol) was added at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting amorphous solid was precipitated with diethyl ether / methanol (51). The precipitate was collected and added to 6 N aqueous sodium hydroxide cooled in ice (200 mL) gradually. The mixture was extracted with dichloromethane / methanol (10: 1, 500 mL x 4). The combined organic phases were washed with brine, dried with magnesium sulfate and concentrated in vacuo to give 24.90 g (99%) of the title compound as a brown amorphous solid stick. MS (ESI) m / z: 229 (M + H +). 1 H-NMR (CDCl 3) d: 1.19-1.28 (2H, m), 1.44-1.63 (8H, m), 1.65-1.71 (2H, m), 2.32 (2H, s), 2.35 (2H, t, J = 11.0 Hz), 2.57 (2H, d, J = 5.7 Hz), 2.85-2.90 (2H, m), 3.70-3.81 (4H, m).

EXAMPLE 2 5-Chloro-N- (. {1-f (4-hydroxytetrahydro-2h-pyran-4-ipmethylpiperidin-4-yl> methyl) -1-isopropyl-2-oxo-1,2- ethanedioate dihydroquinoline-3-carboxamide A mixture of 5-chloro-N- (. {1 - [(4-hydroxytetrahydro-2H-pyran-4-yl) -methyl] piperidin-4-yl.} Methyl) -1-isopropyl-2-oxo -1,2-dihydroquinoline-3-carboxamide (27 mg, 0.057 mmol, example 1) and oxalic acid (5.2 mg, 0.057 mmol) was dissolved in methanol and stirred for 1 h. The mixture was concentrated and crystallized from diisopropyl ether to give 6.5 mg (20%) of the title compound as a white solid. MS (ESI) m / z: 476 (M + H +). 1 H-NMR (DMSO-d 6) d: 9.72 (1 H, m), 9.01 (1 H, s), 7.90 (1 H, d, J = 8.8 Hz), 7.70 (1 H, m, J = 7.9, 8.8 Hz), 7.54 (1 H, d, J = 7.7 Hz), 3.70-3.15 (14H, br m), 1.75 (2H, br m), 1.57 (6H, d, J = 7.0 Hz), 1.64-1.45 ( 5H, m).

EXAMPLE 3 N- (1-r (4-hydroxytetrahydro-2h-pyran ^ -ipmetippiperidin-4-ylmethyl) -1- isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide The title compound was prepared according to the procedure of step 3 in Example 1 using 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (step 4 in preparation 2). ) instead of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. MS (ESI) m / z: 456 (M + H +). p.f .: 222 ° C. IR (KBr) v: 3414, 3271, 2926, 2856, 2785, 2742, 1668, 1605, 1587, 1541, 1448, 1380, 1302, 1221, 1153, 1101, 1015, 974, 957, 843, 800, 791 cm -1. 1 H-NMR (CDCl 3) d: 10.04 (1H, br m), 9.13 (1H, s), 7.50 (2H, m), 7. 12 (1H, dd, J = 4.0, 4.0 Hz), 3.76 (4H, m), 3.37 (2H, t, J = 6.3 Hz), 2.88 (2H, d, J = 11.7 Hz), 2.67 (3H, m), 2.36 (2H, t, J = 11.7 Hz), 2.31 (2H, s), 1.76 (2H, m), 1.67 (6H, d, J = 7.0 Hz) , 1.65-1.30 (7H, m). The signals due to CH (CH3) 2 and OH they were not observed. Anal. cale, for C26H37N3O4-0.2H2O: C, 68.01; H, 8.21; N, 9.15. Found: C, 67.86; H, 8.31; N, 8.90.

EXAMPLE 4 N- (1-r (4-hydroxytetrahydro-2h-pyran-4-yl) metinpiperidin-4-ylmethyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-ethanedioate -carboxamide The title compound was prepared according to the procedure of Example 2 using N- (. {1 - [(4-hydroxytetrahydro-2 H -pyran-4-yl) methyl] piperidin-4-yl acid} methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (example 3) instead of 5-chloro-N- (. {1 - [(4-h) Hydroxytetrahydro-2H-pyran-4-yl) methy1] piperidin-4-yl} methyl) -1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide. MS (ESI) m / z: 456 (M + H +). p.f .: 222 ° C. IR (KBr) v: 3858, 3820, 3676, 2361, 2341, 1868, 1844, 1830, 1773, 1717, 1653, 1541, 1508, 14889, 1419, 1364, 1221, 1101 cm "1 H-NMR (DMSO -de) d: 9.85 (1H, br m), 8.89 (1H, s), 7.73 (1H, d, J = 9.0 Hz), 7.61 (1H, dd, J = 7.2, 8.8 Hz), 7.22 (1H, d, J = 7.2 Hz), 3.59 (4H, m), 3.38 (2H, m), 3.29 (2H, t, J = 5.7 Hz), 2.93 (4H, m), 2.61 (3H, s), 1.75 (3H, m), 1. 57 (6H, d, J = 6.8 Hz), 1.65-1.40 (6H, m). The signal due to OH was not observed.

Anal. Cal, for C 26 H 37 N 3 4 4-H 2 O-0.2 C 6 H 14 O (IPE): C, 60.05; H, 7.56; N, 7.19. Found: C, 60.20; H, 7.46; N, 6.99.

EXAMPLE 5 5-Fluoro-N- (. {1-r (4-hydroxytetrahydro-2h-pyran-4-yl) nr? Etippiperidin-4-yl> metip-1-isopropyl-2-oxo-1 hydrochloride , 2-dihydroquinoline-3-carboxamide Stage 1. (2-Amino-6-fluorophene-methanol) The title compound was prepared according to the procedure of step 1 in preparation 1 using 2-amino-6-fluorobenzoic acid, instead of 2-amino-6-chlorobenzoic acid. MS (ESI) m / z: 141 (M + H +). 1 H-NMR (CDCl 3) d: 7.08-7.00 (1 H, m), 6.48-6.34 (2 H, m), 4.78 (2 H, s), 4.35 (2 H, br). The signal due to OH was not observed.

Stage 2. f2-Fluoro-6- (isopropylamino) phenolmethanol The title compound was prepared according to the procedure of step 2 in Preparation 1 using (2-amino-6-fluorophenyl) methanol (step 1) instead of (2-amino-6-chlorophenyl) methanol. (The title compound contained 5-fluoro-2,2-dιmethyl-1,4-dihydro-2H-3,1-benzoxazine as a by-product.) MS (ESI) m / z: 184 (M + H +).

Stage 3. 2-Fluoro-6- (isopropylamino) benzaldehyde The title compound was prepared according to the procedure of step 3 in preparation 1 using [2-fluoro-6- (isopro-phenylamino) phenyl] methanol (step 2) instead of [2-chloro-6- ( isopropylamino) phenyl] methanol. 1 H-NMR (CDCl 3) d: 10.25 (1H, s), 8.69 (1 H, br s), 7.33-7.25 (1 H, m), 6.45 (1 H, d, J = 8.8 Hz), 6.25-6.18 ( 1H, m), 3.79-3.68 (1H, m), 1.27 (6H, d, J = 6.2 Hz) Step 4. 5-Fluoro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl The title compound was prepared according to the procedure of step 1 in the alternative route in preparation 2 using 2-fluoro-6- (isopropylamino) benzaldehyde (step 3) instead of 2- (isopropylamino) -6-methylbenzaldehyde . H-NMR (CDCl 3) d: 8.57 (1H, s), 7.59-7.49 (1H, m), 7.37-7.30 (1 H, m), 6.92 (1 H, t, J = 8.8 Hz), 4.42 (2H, q, J = 7.1 Hz), 1.64 (6H, d, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). The signal due to CH (CH3) 2 was not observed.

Step 5. 5-Fluoro-1-isopropyl-2-oxo-1,2-dichrodoline-3-carboxylic acid The title compound was prepared according to the procedure of step 2 on the alternative route in preparation 2 using ethyl 5-fiuoro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (step 4) ) instead of ethyl 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate. 1 H-NMR (CDCl 3) d: 14.53 (1H, s), 9.19 (1 H, s), 7.75-7.65 (1 H, m), 7.52-7.45 (1H, m), 7.13-7.05 (1 H, m ), 1.71 (6H, d, J = 7.0 Hz). The signal due to CH (CH3) 2 was not observed.

Step 6. 5-Fluoro-N- (. {1-r (4-hydroxytetrahydro-2H-pyran-4-ipmethylpiperidin-4-yl methylV1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hydrochloride.

The title compound was prepared according to the procedure of step 3 in Example 1 using 5-fluoro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (step 5) instead of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. MS (ESI) m / z: 460 (M + H +). p.f .: 275.7 ° C. IR (KBr) v: 3340, 2947, 2551, 1676, 1614, 1556, 1467, 1380, 1161, 1101, 800 cm "1 H-NMR (DMSO-d6) d: 9.83-9.56 (1H, br), 8.81 (1H, s), 7.86-7.61 (2H, m), 7.32-7.11 (1H, m), 5.73 (1H, br s), 5.41-5.23 (5H, m), 3.72-2.89 (9H, m ), 1.91-1.41 (14H, m) The signal due to OH was not observed.

Anal. cale, for C25H35N3O4FCI-O.I H.2O: C, 60.32; H, 7.13; N, 8.44. Found: C, 59.98; H, 7.20; N, 8.30.

EXAMPLE 6 1-isopropyl-5-methyl-2-oxo-N ~ f f 1 - (piper8din- -ylmetiDpiperidin-4-methyl-2-dihydroquinoline-3-carboxamide Stage 1. 4--. { T4 - ((f (1-lsopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-l) carbonyl-amino) methyl) piperidin-1-phenylethyl-1-tert-butylcarboxylate To a solution of 1-isopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide (300 mg, 0.88 mmol, step 4 in the Preparation 3) in N, N-dimethylformamide (30 mL), 4- (iodomethyl) piperidin-1-tert-butylcarboxylate (343 mg, 1.05 mmol, Villalobos Anabella et al., J. Med. Chem., 1994, 37, 2721) and potassium carbonate (610 mg, 4.4 mmol) at room temperature. The mixture was heated at 80 ° C overnight. After cooling to room temperature, water (30 mL) was added and extracted with diethyl ether (50 mL x 2). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried with magnesium sulfate and concentrated in vacuo to give a yellow oil, which was chromatographed on a column of silica gel eluting with sodium oxide. Ammonium / methanol / ethyl dichloromethane 25% (3: 30: 1000) to give 154 mg (32%) of the title compound as a clear, colorless oil. 1 H-NMR (CDCl 3) d: 10.07 (1 H, br s), 9.11 (1 H, s), 7.59-7.44 (2 H, m), 7.19-7.07 (1 H, m), 5.30 (2 H, s), 3.40-3.30 (2H, m), 2.92-2.78 (2H, m), 2.75-2.55 (5H, m), 2.15-2.10 (2H, m), 1.98-1.75 (2H, m), 1.75-1.25 (26H , m).

Step 2. 1-Isopropyl-5-methyl-2-oxo-N-IT1- (piperidin-4-ylmethylpiperidin-4-illmethyl> -1,2-dihydroquinoline-3-carboxamide dihydrochloride 4-. { [4- ( { [(1-lsopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-yl) carbonyl] amino] methyl) piperidin-1-yl] methyl} piperidin-1-tert-butylcarboxylate (150 mg, 0.28 mmol, step 1) was dissolved in 10% methanolic hydrogen chloride (20 mL) and the mixture was stirred for 16 h at room temperature, the mixture was concentrated to give a yellow oil, which was crystallized with diethyl ether and n-hexane. The solid was collected by filtration to give 110 mg (96%) of the title compound as a pale yellow solid. MS (ESI) m / z: 439 (M + H +). p.f .: 240.7 ° C. 1 H-NMR (CDCl 3) d: 10.0-9.83 (1H, br), 8.90 (1 H, s), 7.79-7.70 (1 H, m), 7.67-7.57 (1 H, m), 7.29-7.20 (1H , m), 3.55-1.25 (32H, m). The signal due to CH (CH3) 2 was not observed. Anal. cale, for C 26 H 4 o N 4 O 2 Cl 2-2 H 2 O: C, 57.03; H, 8.10; N, 10.23. Found: C, 56.68; H, 8.25; N, 9.84.

EXAMPLE 7 N - ((1-R (4-hydroxy-piperidin-4-yl) methypiperidin-4-yl} methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolyl ethanedioate na-3-carboxamide Step 1. 4-Hydroxy-4-T4- (. {F (1-isopropyl-5-methyl-2-oxo-1,2-dihydro-quinolin-3-ipcarbonyl-amino) methyl) piperidine 1-ethyl-1-methyl-piperidin-1-tert-butylcarboxylate A solution of 1-isopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide (150 mg, 0.44 mmol, step 4 in preparation 3) and 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid tere-butyl ester (112 mg, 0.53 mmol, Castro Jose L. et al., J. Med. Chem., 1998, 41, 2667) in methanol ( 5 mL) was heated at 80 ° C overnight. After cooling to room temperature, the concentrate gave a yellow oil. The residue was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide / methanol / dichloromethane (2/10/100) to give 111 mg (45%) of the title compound as a white solid. 1 H-NMR (CDCl) d: 10.05 (1 H, br), 9.25 (1 H, s), 7.65-7.41 (2H, m), 7.20-7.10 (1 H, m), 3.94-3.74 (1 H, m), 3.47-3.28 (2H, m), 2.95-2.81 (2H, m), 2.67 (3H, s), 2.47-2.21 (4H, m), 1.86-1.19 (28H, m). The signal due to OH was not observed.

Step 2. N - ((1-r (4-hydroxypiperidin-4-ipmetinpperidin-4-yl> metip-1-yopropyl-5-methyl-2-oxo-1, 2-ethanedioate. -dihydroquinoline-3-carboxamide HO '2, C'COzH 4-Hydroxy-4-. { [4- ( { [(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl) carbonyl] amino} metiI) piperidin-1-yl] methyl} piperidin-1-tert-butylcarboxylate (110 mg, 0.20 mmol) was dissolved in hydrogen chloride in 10% methanol (10 mL) and the mixture was concentrated in vacuo to give a white solid. The solid was suspended in tetrahydrofuran / methanoi (4/1, 80 mL) and potassium carbonate (500 mg, 3.6 mmol) was added. The mixture was stirred for 30 minutes at room temperature, filtered through a pad of Celite, washed with tetrahydrofuran / methanoi (4/1, 30 mL), the filtrate was concentrated to give 52 mg of a yellow stick oil. The resulting oil was dissolved in methanol (5 mL) and oxalic acid (10 mg, 0.11 mmol) was added. The mixture was stirred for 10 minutes and concentrated in vacuo to give a white solid. The solid was suspended in ethyl acetate and was collected by filtration to give 80 mg (74%) of the title compound as a pale yellow solid. MS (ESI) m / z: 455 (M + H +). 1 H-NMR (CDCl 3) d: 9.88 (1 H, br), 8.92 (1 H, s), 7.79-7.72 (1 H, m), 7.68-7.56 (1 H, m), 7.28-7.21 (1 H , m), 2.65 (3H, s), 3.90-1.30 (28H, m). Signals due to NH (piperidine) and OH were not observed. Anal. Cal, for C28H40N4O7-2.5H2O-1 EtOAc: C, 56.71; H, 7.88; N, 8.27, Found: C, 56.77; H, 7.55; N, 8.38.

EXAMPLE 8 N- (. {1-f (4-Hydroxy-1-methyl-piperidin-4-yl) -methylpiperidin-4-yl) methyl) -1-isopropyl-5-methyl-2-oxo- ethanedioate. 1,2-dihydroquinoline-3-carboxamide . { C02H) 2 A mixture of N- (. {1 - [(4-hydroxypiperidin-4-yl) methyl] piperidin-4-yl.} - methyl) -1-isopropyl-5-methyl- 2-oxo-1,2-dihydroquinoline-3-carboxamide (100 mg, 0.22 mmol), formaldehyde (37% by weight solution in water, 1.5 mL) and formic acid (1 mL) was heated to 80 ° C of the overnight. It was then cooled to room temperature, concentrated in vacuo to give a white solid. The resulting solid was added to saturated aqueous sodium bicarbonate (15 mL) and concentrated in vacuo, the residual solid was suspended in tetrahydrofuran / methanoi (4/1, 60 mL) and stirred for 1 h at room temperature. The mixture was filtered through a pad of celite, washed with tetrahydrofuran / methanoi (4/1, 30 mL), concentrated in vacuo to give a white solid. The resulting solid was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide / methanol / dichloromethane (1: 5: 100) to give 53 mg of a clear, colorless oil. The resulting oil was dissolved in methanol (5 mL) and oxalic acid was added (10 mg., 0.11 mmole). After stirring for 10 minutes, it was concentrated in vacuo to give a white solid, which was washed with ethyl acetate, was collected by filtration giving 45 mg (37%) of the title compound as a white powder. MS (ESI) m / z: 469 (M + H +). 1 H-NMR (CDCl 3) d: 9.88 (1 H, br), 8.91 (1 H, s), 7.78-7.72 (1 H, m), 7.68-7.57 (1 H, m), 7.28-7.21 (1 H , m), 2.75 (3H, s), 2.64 (3H, s), 3.90-1.30 (28H, m). The signal due to OH was not observed. Anal. cale, for C28H4oN407-2.5H20-1 EtOAc: C, 56.71; H, 7.88; N, 8.27, Found: C, 56.77; H, 7.55; N, 8.38.

EXAMPLE 9 N- (f 1 -Kcis-1,4-dihydrox 8-cyclohexyl) -methylpiperidin-4-yl-methoxy-1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide ethanedioate Stage 1. (1-oxaespirof2.51oct-6-yloxy) tere-butyl diphenylsilane (eraps) (efe) To a stirred suspension of hydride, sodium (60% in mineral oil, 441 mg, 11.0 mmol) in dimethyl sulfoxide (7 mL) was added trimethylsulfoxonium iodide (2.53 g, 11.5 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 4-. { [tert -butyl (diphenyl) silyl] oxy} cyclohexanone (3.53 g, 10.0 mmol, Okamura, William H. et al, J. Org. Chem., 1993, 58, 600) in dimethyl sulfoxide (35 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was then diluted with water (600 mL), and extracted with diethyl ether (200 mL x 4). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate / n-hexane (1:10), and fire was purified with a TLC plate eluting with ethyl acetate / n-hexane (1: 15) to give 459 mg (13%, trans) and 390 mg (11%, cis) of the title compound as a colorless oil respectively. (trans) 1 H-NMR (CDCl 3) d: 7.70-7.66 (4H, m), 7.46-7.35 (6H, m), .4.03-3.97 (1 H, m), 2.63 (2H, s), 2.07-1.63 (8H, m), 1.08 (9H, s). (cis) 1 H-NMR (CDCl 3) d: 7.70-7.65 (4H, m), 7.46-7.35 (6H, m), 3.97-3.83 (1 H, m), 2.58 (2H, s), 1.83-1.37 ( 8H, m), 1.07 (9H, s).

Step 2. N- ( { 1-r (cis-4-frterc-Butyl (diphenyl) -silypoxy> -1-hydroxycyclohexyl) methylP1peridin-4-yl) metin-1-isopropyl-5-methyl-2 -oxo-1, 2-dihydroquinoline-3-carboxamide A mixture of 1-isopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide (346 mg, 1.01 mmol, step 4 in the Preparation 3) and [(3 s, 6 s) -1-oxa-spiro [2.5] oct-6-yloxy] tere-butyl diphenyl silyl (390 mg, 1.06 mmol, Step 1, cis isomer) in methanol (3 mL) was stirred at room temperature for 16 h, and then the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with methanol / dichloromethane (1: 20) to give 682 mg (95%) of the title compound as a colorless oil. 1 H-NMR (CDCl 3) d: 10.04 (1 H, br), 9.13 (1 H, s), 7.70-7.67 (4 H, m), 7.50-7.32 (8 H, m), 7.12-7.09 (1 H, m) , 3.60 (1 H, br), 3.38-3.34 (2H, m), 2.86-2.82 (2H, m), 2.66 (3H, s), 2.31-2.16 (4H, m), 1.84-0.85 (20H, m ), 1.05 (9H, s). The signal due to OH was not observed.

Step 3. N- ( { 1-f (cis-1,4-DihydroxycyclohexyDmethylpiperidin-4-yl) methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3- carboxamide To a stirred solution of N- (. {1 - [(cis-4. {[[Tert-butyl (diphenyl) silyl] oxy} -1-hydroxy-cyclohexyl) methyl] piperidin-4-yl} methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (682 mg, 0.96 mmol, step 2) in tetrahydrofuran (6 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 2.0 mL, 2.0 mmol) at 0 ° C, and the mixture was stirred at room temperature for 16 h, then refluxed for 6 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide / methanol / dichloromethane (0.2: 1: 10) to give 295 mg (65%) of the title compound as a white solid. 1 H-NMR (CDCl 3) d: 10.04 (1 H, br), 9.12 (1 H, s), 7.50-7.49 (2 H, m), 7.13-7.10 (1 H, m), 3.60-3.52 (1 H, m), 3.41-3.35 (4H, m), 2.91-2.88 (2H, m), 2.66 (3H, s), 2.38-2.28 (4H, m), 1.77-0.98 (18H, m). The signals due to cis-diol (OH x 2) were not observed.

Step 4. N- (. {1 (cis-1,4-dihydroxycyclohexyl) metinpiperidin-4-yl> methy-1-isopropyl-5-methyl-2-oxo-1, 2-ethanedioate. dihydroquinoline-3-carboxamide (CJ-044476-13) A mixture of N- ( { 1 - [(cis-1,4-dihydroxycyclohexyl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-5-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide (295 mg, 0.628 mmol, step 3) and oxalic acid (56.6 mg, 0.628 mmol) was dissolved in methanol and stirred for 1 h. The mixture was concentrated and recrystallized from 2-propanol to give 246 mg (70%) of the title compound as a white solid. MS (ESI) M / z: 470 (M + H +). p.f .: 226 ° C (decomposition). IR (KBr) v: 3377, 3277, 2937, 2868, 1753, 1719, 1663, 1589, 1541, 1464, 1448, 1400, 1381, 1302, 1281, 1223, 1151, 1109, 1053, 1032, 972, 800, 719 cm "1. 1 H-NMR (DMSO-de) d: 9.85 (1 H, br), 8.89 (1 H, s), 7.73 (1 H, d, J = 8.9 Hz), 7.63-7.57 (1 H, m), 7.22 (1 H, d, J = 7.1 Hz), 3.44-3.26 (6H, m), 3.00-2.84 (5H, m), 2.60 (3H, s), 1.78-1.26 (18H, m). The signals due to cis-diol (OH x 2) were not observed.

Anal. cale, for C 27 H 3 N 3 O 4 -C 2 H 2 O 4 -I .OH 2 O: C, 60.30; H, 7.50; N, 7.27, Found: C, 60.67; H, 7.53; N, 7.17.

EXAMPLE 10 N- (. {1-f (trans-1,4-dihydroxycyclohexyl) metinpiperidin-4-ylmethyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-ethanedioate carboxamide Stage 1. N- ( { 1-r (trans-4- {rterc-Butyl (diphenyl) sililloxir-1-hydroxycyclo-hexipmetinpiperidin-4-metip-1-isopropyl-5-methyl-2-oxo- 1,2-dihydroquinolyria-3-carboxamide A mixture of 1-isopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide (156 mg, 0.46 mmol, step 4 in preparation 3) and tert. -Butil [(3r, 6r) -1-oxaespiro [2.5] oct-6-yloxy] diphenylsilane (176 mg, 0.48 mmol, step 1 in Example 9, trans isomer) in methanol (2 mL) was stirred at room temperature for 16 h, and then the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with methanol / dichloromethane (1: 20) to give 313 mg (96%) of the title compound as a colorless oil. H-NMR (CDCl 3) d: 10.05 (1 H, br), 9.14 (1 H, s), 7.67-7.64 (4H, m), 7.51-7.33 (8H, m), 7.14-7.11 (1 H, m ), 3.96 (1 H, br), 3.40-3.35 (2H, m), 2.94-2.90 (2H, m), 2.68 (3H, s), 2.41-2.33 (4H, m), 1.79-1.29 (20H, m), 1.06 (9H, s). The signal due to OH was not observed.

Step 2. N-1 - [(trans-1,4-Dihydroxycyclohexyl) methyl-piperidin-4-yl-methyl) -isopropyl-5-methyl-2-oxo-1,2-d-hydroquinoline-3-carboxamide To a stirred solution of N- (. {1 - [(trans -4- {[[tert-butyl (diphenyl) -silyl] oxy} -1-hydroxycyclohexyl) methyl] piperidin-4-yl}. methi) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (313 mg, 0.44 mmol, step 1) in tetrahydrofuran (3 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.9 mL, 0.9 mmol) at 0 ° C, and the mixture was stirred at room temperature for 16 h, then refluxed for 5 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with a TLC plate eluting with methanol / dichloromethane (1:10) to give 192 mg (92%) of the title compound as a light yellow amorphous solid. 1 H-NMR (CDCl 3) d: 10.02 (1 H, br), 9.08 (1 H, s), 7.47-7.46 (2 H, m), 7.09-7.07 (1 H, m), 3.89 (1 H, br) , 3.35-3.31 (5H, m), 2.90-2.86 (2H, m), 2.63 (3H, s), 2.38-2.29 (4H, m), 1.90-0.81 (17H, m). The signals due to trans-diol (OH x 2) were not observed.

Step 3, N- (1 - [(trans-1,4-dihydroxycyclohexyl) metipiperidin-4-ylmethyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide ethanedioate A mixture N- ( { 1 - [(trans-1,4-dihydroxycyclohexyl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline 3-carboxamide (192 mg, 0.409 mmol, step 2) and oxalic acid (36.8 mg, 0.409 mmol) was dissolved in methanol and stirred for 1 h. The mixture was concentrated and recrystallized from 2-propanol to give 106 mg (46%) of the title compound as a white solid. MS (ESI) m / z: 470 (M + H +). p.f.:212°C (decomposition). IR (KBr) v: 3568, 3377, 2939, 2870, 1751, 1668, 1605, 1589, 1556, 1464, 1448, 1406, 1379, 1310, 1281, 1221, 1196, 1167, 1151, 1099, 1018, 800, 719 cm "1. 1 H-NMR (DMSO-d 6) d: 9.85 (1 H, br), 8.89 (1 H, s), 7.73 (1 H, d, J = 8.8 Hz), 7.63-7.58 (1 H , m), 7.22 (1 H, d, J = 7.2 Hz), 3.67 (1 H, br), 3.45-3.29 (5H, m), 3.04-2.86 (6H, m), 2.61 (3H, s), 1.78-1.29 (17H, m) The signals due to trans-diol (OH x 2) were not observed.

Anal. cale, for C27H39N3? 4-C2H2? 4-0.5H2O: C, 61.25; H, 7.44; N, 7.39. Found: C, 60.90; H, 7.613; N, 7.16.

EXAMPLE 11 1-Isopropyl-5-methyl-N-M - (1-methyl-2-morpholin-4-yl-2-oxoetippip-Tridin-4-immethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hydrochloride Stage 1. 2-f4- ( { R (1-lsopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-i0 carboninamino) methyl) pyridin-1-inpropanoate of tere- butyl A mixture of 1-hydropropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide hydrochloride (467 mg, 0.98 mmol, step 4 in the preparation 3), Tere-butyl 2-bromopropanoate (0.24 mL, 1.47 mmol), and triethylamine (0.41 mL, 2.93 mmol) in tetrahydrofuran (30 mL) was stirred at 70 ° C for 23 h. After cooling to room temperature, the mixture was poured into saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL x 2). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia / methanol / dichloromethane (0.1: 1: 30) to give 299 mg (65%) of the title compound as a yellow amorphous solid. MS (ESI) m / z: 470 (M + H +). 1 H-NMR (DMSO-de) d: 10.02 (1 H, br), 9.13 (1 H, s), 7.53-7.47 (2 H, m), 7.12 (1 H, t, J = 3.6 Hz), 3.38 ( 2H, t, J = 6.3 Hz), 3.18 (1 H, q, J = 7.1 Hz), 3. 03-2.90 (2H, m), 2.67 (3H, s), 2.44-2.20 (2H, m), 1.81 (2H, br d, J = 12.5 Hz), 1. 68 (6H, d, J = 7.1 Hz), 1.46 (9H, s), 1.50-1.25 (3H, m), 1.25 (3H, d, J = 7.1 Hz), The signal due to CH (CH3) 2 was not observed.

Stage 2. 2- [4- (. {R (1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-ylcarbonyl-amino) methyl) piperidin-1-inpropanoic acid hydrochloride A solution of 2- [4- ( { [(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl) carbonyl] amino} methyl) piperidine 1-yl] tere-butyl propanoate (299 mg, 0.64 mmol, step 1) in trifluoroacetic acid / dichloromethane (11.20 mL) was stirred at room temperature for 16 h. Then, the solvent was removed in vacuo. To the residue was added 10% hydrogen chloride in methanol, and was evaporated in vacuo. This was repeated three times to give 295 mg (quant.) Of the title compound as an amorphous yellow solid. MS (ESI) m / z: 414 (M + H +), 412 (M-H ").

H-NMR (DMSO-de) d: 9.86 (1 H, br), 8.89 (1 H, s), 7.73 (1 H, d, J = 8.7 Hz), 9.61 (1 H, t, J = 7.4 Hz) , 7.22 (1H, d, J = 7.1 Hz), 3.80-3.25 (7H, m), 2.61 (3H, s), 1.95-1.52 (5H, m), 1.57 (6H, d, J = 6.8 Hz), 1.47 (3H, d, J = 7.1 Hz). The signals due to CH (CH3) and C02H were not observed.

Step 3. 1-Isopropyl-5-methyl-N- (p- (1-methyl-2-morpholin-4-yl-2-oxoethyl) piperidin-4-ylmethyl) -2-oxo-1, 2- hydrochloride dihydroquinoline-3-carboxamide To a mixture of 2- [4- (. {[[(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-ii) carbonyl] amino} methyl) piperidine- hydrochloride. 1-ylpropanoic acid (243 mg, 0.54 mmol, step 2), morpholine (52 mg, 0.60 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in dichloromethane (15 mL) was added HBTU (226 mg, 0.60 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 1 h and at room temperature for 3 h. Then, the resulting mixture was poured into saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia / methanol / dichloromethane (0.1: 1: 30) to give 265 mg of the title compound as the salt in free form. This was treated with 10% hydrogen chloride in methanol (5 mL), and the solvent was removed in vacuo to give 194 mg (69%) of the title compound as an amorphous yellow solid. MS (ESI) m / z: 483 (M + H +). s IR (KBr) v: 3375, 3254, 2930, 2868, 1680, 1655, 1616, 1541, 1464, 1448, 1381, 1238, 1217, 1115, 1034, 953, 800 cm "1 H-NMR (DMSO-de) d: 9.87 (1 H, br), 9.59 (1 H, br), 8.91 (1 H , s), 7. 75 (1 H, d, J = 8.3 Hz), 7.63 (1 H, t, J = 6.6 Hz), 7.23 (1 H, d, J = 6.4 Hz), 4.57 (1 H, q, J = 6.3 Hz) , 3.90-2.75 (14H, m), 2.63 (3H, s), 2.00-1.45 (5H, m), 1.59 (6H, d, or J = 6.3 Hz), 1.07 (3H, d, J = 9.6 Hz) . The signal due to CH (CH3) 2 was not observed. Anal. cale, for C27H39CIN4O4-l .OMeCN-3.OH2O: C, 56.71; H, 7.88; N, 11.40. Found: C, 56.56; H, 7.54; N, 11.45.

EXAMPLE 12 1-Isopropyl-5-methyl-N- (1-f1- (morpholin-4-yl) carbonyl) pentinpiperidin-4-yl hydrochloride > methyl) -2-oxo-1,2-dihydroq-inoline-3-carboxamide Step 1. 2- [4 - ((r (1-lsopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl) carbonyl-amino) methyl) piperidin-1-tert-butyl thiohexanoate The title compound was prepared according to the procedure of step 1 in example 11 using tere-butyl 2-bromohexanoate (PL Stotter and KA Hill, Tetrahedron Letters, 1972, 40, 4067) instead of 2-bromopropanoate. tere-butyl. MS (ESI) m / z: 512 (M + H +). 1 H-NMR (CDCl 3) d: 10.02 (1 H, br), 9.13 (1 H, s), 7.52-7.47 (2 H, m), 7.12 (1 H, t, J = 4.1 Hz), 4.35 (1 H, t, J = 7.1 Hz), 3.37 (2H, t, J = 6.1 Hz), 2.67 (3H, s), 3.08-2.20 (4H, m), 1.67 (6H, d, J = 7.1 Hz), 1.46 ( 9H, s), 1.85-1.20 (11 H, m), 0.89 (3H, t, J = 6.6 Hz). The signal due to CH (CH3) 2 was not observed.

Stage 2. 2- [4- ( { I (1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-ipcarbonyl-aminolmethyl) piperidin-1-yl-hexane-5-hydroxychloride The title compound was prepared according to the procedure of step 2 in example 11 using 2- [4- ( { [(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin -3-yl) carbonyl] amino.}. Methyl) piperidin-1-yl-hexanoate tere-butyl (step 1) instead of 2- [4- ( { [(1-isopropyl-5-methyl-2- Oxo-1, 2-dihydroquinolyl-3-yl) carbonyl] amino} tert-butyl methyl) piperidin-1-yl] propanoate. MS (ESI) m / z: 414 (M + H +), 412 (MH "). 1 H-NMR (DMSO-de) d: 9.85 (1 H, br), 8.89 (1 H, s), 7.73 (1H , d, J = 8.6 Hz), 7.61 (1 H, t, J = 7.2 Hz), 7.22 (1 H, d, J = 7.2 Hz), 4.24 (1 H, t, J = 7.2 Hz), 3.30 (2 H, br) , 2.61 (3H, s), 2.70-2.05 (4H, m), 1.57 (6H, d, J = 7.0 Hz), 1. 90-1.20 (11H, m), 0.86 (3H, t, J = 6.6 Hz). The signals due to CH (CH3) 2 and CO2H were not observed.

Step 3. 1-Isopropyl-5-methyl-N- (. {1-yl- (morpholin-4-ylcarbonyl) phenylpiperidin-4-yl) methyl) -2-oxo-1,2-dihydroquinoline-3 hydrochloride -carboxamide The title compound was prepared according to the procedure of step 3 in example 11 using 2- [4- (. {[[(1-isopropyl-5-methyl-2-oxo-1, 2- hydrochloride] dihydroquinolin-3-yl) carbonyl] amino.} methyl) -piperidin-1-yl] hexanoic acid (step 2) instead of 2- [4- ( { [(1-isopropyl-5-methyl) hydrochloride] -2-oxo-1, 2-dihydroquinolyl-3-yl) carbonyl] amino} methyl) piperidin-1-ylpropanoic acid. MS (ESI) m / z: 525 (M + H +). IR (KBr) v: 2963, 2930, 2866, 1672, 1543, 1448, 1381, 1306, 1261, 1221, 1113, 1069, 1034, 953, 802 cm "1 H-NMR (DMSO-de) d: 9.85 (1H, br), 9.60-9.50 (1 H, br), 8.89 (1 H, s), 7.73 (1 H, d, J = 8.8 Hz), 7.61 (1 H, t, J = 7.3 Hz), 7.22 (1H, d, J = 7.2 Hz), 4.55-4.45 (1 H, m), 3.75-2.65 (14H, m), 2.61 (3H, s), 1.57 (6H, d, J = 6.8 Hz), 1.95-1.10 (11 H, m), 0.87 (3H, t, J = 7.0 Hz) Anal cale, for C30H45CIN4O4-O.5MeCN-2.2H2O: C, 59.93; H, 8.26; N, 10.14. C, 59.75; H, 8.41; N, 10.14.

PREPARATION 1 N-f (1-Butylpiperidin-4-yl) metin-5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hydrochloride Stage 1. (2-Amino-6-chlorophenyl) methanol To a suspension of lithium aluminum hydride (1.1 g, 29.1 mmol) in tetrahydrofuran (150 mL) was added 2-amino-6-chlorobenzoic acid (5 g, 29.1 mmol) at 0 ° C. The mixture was stirred at room temperature for 16 h. Then, the reaction mixture was quenched with sodium sulphate decahydrate (3 g) and brine (10 ml) and filtered through a pad of Celite. The organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethylolhexane acetate (1: 2) to give 2.4 g (52%) of the title compound as a colorless oil. 1 H-NMR (CDCl 3) d: 7.01 (1 H, dd, J = 7.9, 8.1 Hz), 6.76 (1 H, d, J = 7.9 Hz), 6.58 (1H, d, J = 8.1 Hz), 4.88 (2H, s). The signals due to NH2 and OH were not observed.

Stage 2. r2-Chloro-6- (isopropylamino) phenemethanol To a mixture of (2-amino-6-chlorophenyl) methanol (2.3 g, 14.6 mmol, step 1), acetic acid (14 mL), sodium acetate hydrate (4.8 g, 58.5 mmol), acetone (7 mL) , ethanol (4.8 mL), and water (14 mL) was added a solution of sodium borohydride (1.66 g, 43.9 mmol) in a 2 N aqueous sodium hydroxide solution (4.8 mL) at 0 ° C for a period of 4 h. The mixture was basified with potassium carbonate (3 g) and water (150 mL) was added. The aqueous layer was extracted with n-hexane. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 2.74 g of the mixture of the title compound and 5-chloro-2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine ( eleven). The mixture was used in the next reaction without further purification. 1 H-NMR (CDCl 3) d: 7.01 (1 H, dd, J = 8.1, 7.9 Hz), 6.67 (1 H, d, J = 7.9 Hz), 6.53 (1 H, d, J = 8.1 Hz), 4.81 (2 H) , s), 3.64 (1 H, m), 1.24 (6H, d, J = 6.2 Hz). The signals due to NH and OH were not observed.

Stage 3. 2-Chloro-6- (isopropylamino) benzaldehyde A mixture of [2-chloro-6- (isopropylamino) phenyl] methanol, 5-chloro-2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine (2.7 g, ratio; 11, step 2) ) and manganese dioxide (3.9 g, 33.8 mmol) in toluene (50 mL) was stirred at reflux temperature for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethylolhexane acetate (1: 30) to give 1.2 g (45% (2-amino-6-chlorophenyl) methanol) of the title compound as a yellow solid. MS (ESI) m / z: 198 (M + H +). 1 H-NMR (CDCl 3) d 10.44 (1 H, s), 9.03 (1 H, br s), 7.22 (1 H, dd, J = 7.7, 8.8 Hz), 6.62 (1 H, d, J = 8.8 Hz ), 6.57 (1 H, d, J = 7.7 Hz), 3.74 (1 H, m), 1.26 (6H, d, J = 6.2 Hz).

Step 4. 5-Chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid To a solution of 2-chloro-6- (isopropylamino) benzaIdehyde (1.1 g, . 57 mmoles, step 3) in methanol (10 mL) was added ethylene diamine (0.186 mL, 2.78 mmol) and acetic acid (0.319 mL, 5.57 mmol). Meldrum acid (1.6 g, 11.1 mmol) was added to the mixture at 0 ° C. Then, the mixture was stirred at room temperature for 16 h. The formed precipitate was filtered and washed with methanol. The filtrate was evaporated and crystallized from methanol to give 200 mg (14%) of the title compound as a white solid. MS (ESI) m / z: 266 (M + H +). 1 H-NMR (DMSO-d 6) d: 8.96 (1 H, s), 8.02 (1 H, d, J = 8.8 Hz), 7.83 (1 H, dd, J = 8.1, 8.6 Hz), 7.64 (1 H, d, J = 7.9 Hz), 1.61 (6H, d, J = 6.8 Hz). The signals due to C02H and CH (CH3) 2 were not observed.

Step 5. N-R (1-Butylpiperidin-4-yl) methan-5-chloro-1-ylpropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hydrochloride To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.376 mmol, step 4) in dichloromethane (1 mL) was added oxalyl chloride (0.10 mL). , 1.13 mmol) and one drop of N, N-dimethylformamide at 0 ° C. The mixture was stirred at room temperature for 1.5 h. The solvent and the excess amount of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (1 mL) and added at 0 ° C [(1-butylpiperidin-4-yl) methyl] amine (128 mg, 0.753 mmol) in dichloromethane (1 mL) and the mixture was stirred at room temperature. environment for 1 h. Then, the mixture was quenched with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layer was dried with sodium sulfate and concentrated in vacuo to give a colorless oil. The resulting oil was dissolved in 10% methanolic hydrogen chloride (5 mL) and was stirred for 16 h. The formed precipitate was filtered and washed with methanol to give 100 mg (59%) of the title compound as a white solid. MS (ESI) m / z: 418 (M + H +). p.f .: 248 ° C.

IR (KBr) n: 2964, 2935, 2873, 2515, 1678, 1618, 1551, 1445, 1375, 1278, 1207, 1136, 1003 cm'1. 1 H-NMR (DMSO-de) d: 9.74 (1H, t, J = 5.9 Hz), 9.03 (1H, s), 7.92 (1H, d, J = 9.1 Hz), 7.74 (1H, dd, J = 7.9 , 8.7 Hz), 7.55 (1H, d, J = 7.6 Hz), 3.50-3.15 (6H, br m), 3.00-2.80 (2H, m), 1.90-1.50 (7H, m), 1.60 (6H, d , J = 6.9 Hz), 1.31 (2H, m), 0.91 (3H, t, J = 7.3 Hz). The signal due to CH (CH3) 2 was not observed. Anal. cale, for C 23 H 33 N 302 Cl 2: C, 60.79; H, 7.32; N, 9.25. Found: C, 61.08; H, 7.68; N, 9.06.

PREPARATION 2 N-f (1-Butylpiperidin-4-yl) methan-1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hydrochloride Stage 1. (2-Amino-6-methylphenyl) methanol The title compound was prepared according to the procedure of step 1 in preparation 1 using 2-amino-6-methiibenzoic acid instead of 2-amino-6-chlorobenzoic acid. 1 H-NMR (CDCl 3) d: 7.01 (1 H, dd, J = 7.7 Hz), 6.60 (1 H, d, J = 7.7 Hz), 6.58 (1 H, d, J = 7.7 Hz), 4.75 (2H, s), 2.35 (3H, s). The signals due to NH2 and OH were not observed.

Stage 2. r2- (lsopropylamino) -6-methylphenolmethanol The title compound was prepared according to the procedure of step 2 in preparation 1 using (2-amino-6-methylphenyl) methanol (step 1) instead of (2-amino-6-chlorophenyl) methanol. 1 H-NMR (CDCl 3) d: 7.09 (1 H, dd, J = 8.11, 7.9 Hz), 6.58 (1 H, d, J = 8.1 Hz), 6.52 (1 H, d, J = 7.5 Hz), 4.72 ( 2H, s), 3.64 (1 H, m), 2.35 (3H, s), 1.23 (6H, d, J = 6.2 Hz). The signals due to NH and OH were not observed, Stage 3. 2- (lsopropylamino) -6-methylbenzaldehyde The title compound was prepared according to the procedure of step 3 in preparation 1 using [2- (isopropylamino) -6-methylphenylmetatanol (step 2) instead of [2-chloro-6- (isopropylamino) phenyl] methanol . MS (ESI) m / z: 178 (M + H +). 1 H-NMR (CDCl 3) d: 10.30 (1 H, s), 9.00 (1 H, br s), 7.23 (1 H, dd, J = 8.6, 7.3 Hz), 6.59 (1 H, d, J = 8.8 Hz), 6.35 (1 H, d, J = 7.2 Hz), 3.74 (1 H, m), 2.55 (3 H, s), 1.27 (6 H, d, J = 6.2 Hz).

Step 4. 1-Isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid The title compound was prepared according to the procedure of step 4 in preparation 1 using 2- (isopropylamino) -6-methylbenzaldehyde (step 3) instead of 2-chloro-6- (isopropylamino) benzaldehyde. MS (ESI) m / z: 246 (M + H +), 244 (MH "). 1 H-NMR (CDCl 3) d: 14.92 (1 H, s), 9.14 (1 H, s), 7.66-7.55 (2H , m), 7.25-7.18 (1 H, m), 2.69 (3H, s), 1.70 (6H, d, J = 6.6 Hz) The signal due to CO2H was not observed.

Step 5. N-R (1-butylpiperidin-4-yl) metip-1-isopropyl-5-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxamide hydrochloride The title compound was prepared according to the procedure of step 5 in preparation 1 using 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (step 4) instead of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. MS (ESI) m / z: 398 (M + H +). p.f .: 233 ° C. IR (KBr) v: 3242, 2931, 2876, 2642, 2534, 1684, 1616, 1553, 1466, 1379, 1310, 1217, 1119, 951, 799, 785 cm "1 H-NMR (DMSO-d6) d : 9.85 (1 H, br m), 8.89 (1 H, s), 7.73 (1 H, d, J = 8.81 Hz), 7.61 (1H, dd, J = 7.3, 8.8 Hz), 7.22 (1H, d, J = 7.2 Hz), 3.47 (2H, br m), 3.28 (2H, m), 2.95 (2H , m), 2.82 (2H, m), 2.61 (3H, s), 1.81 (3H, m), 1.67-1.45 (4H, m), 1.57 (6H, d, J = 7.0 Hz), 1.28 (2H, m), 0.88 (3H, t, J = 7.3 Hz). The signal due to CH (CH3) 2 was not observed. Anal. Cal, for C 24 H 36 N 3? 2 Cl 2 H 2? -0.2 C 6 H 10 O (diisopropyl ether): - C, 64.06; H, 8.70; N, 8.89. Found: C, 64.45; H, 8.54; N, 9.07.

Alternative route to 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (in Step 4) Stage 1. 1-lsopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl A mixture of 2- (isopropylamino) -6-methylbenzaldehyde (22.4 g, 127 mmol, step 2 in preparation 2), diethyl malonate (22.3 g, 139 mmol), piperidine (1.29 g, 15.2 mmol), and benzoic acid (572 mg, 4.7 mmol) in benzene (500 mL) was refluxed with stirring for 4 days. After cooling to room temperature, the solvent was removed N vacuous. The residue was chromatographed on a column of silica gel eluting with ethylolhexane acetate (1: 15-1: 2) to give 19.6 g (57%) of the title compound as a yellow solid. MS (ESI) m / z: 274 (M + H +). 1 H-NMR (CDCl 3) d: 8.57 (1H, s), 7.52-7.41 (2H, m), 7.08-7.03 (1 H, m), 4.43 (2H, q, J = 7.1 Hz), 2.61 (3H, s), 1.64 (6H, d, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). The signal due to CH (CH3) 2 was not observed.

Step 2. 1-Isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid A mixture of ethyl 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (15.0 g, 54.9 mmol), 2 N aqueous sodium hydroxide (41 mL, 82 mmol), and ethanol (150 mL) was stirred at room temperature for 2 h. Then, 2 N aqueous hydrochloride (41 mL, 82 mmol) was added, and the white precipitate was collected by filtration. This solid was washed with water to give 12.6 g (93%) of the title compound as a yellow stick solid. MS (ESI) m / z: 246 (M + H +), 244 (MH "). 1 H-NMR (CDCl 3) d: 14.92 (1H, s), 9.14 (1H, s), 7.66-7.55 (2H, m ), 7.25-7.18 (1H, m), 2.69 (3H, s), 1.70 (6H, d, J = 6.6 Hz) The signal due to CH (CH3) 2 was not observed.

PREPARATION 3 N-f-f 1 -f 1 -f4-hydroxytetrahydro-2h-pyran-4-ipetinpiperidin-4-yl-methyl-1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide Stage 1. 4-Ethylhydro-2H-pyran To a suspension of (ethylene triphenylphosphonium bromide (1.22 g, 3.30 mmol) in diethyl ether (25 mL) was added dropwise a solution of n-butyllithium in hexane (1.56 M, 2.1 mL, 3.3 mmole) at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. Then, a solution of tetrahydro-4H-pyran-4-one (300 mg, 2.99 mmol) in diethyl ether (5 mL) was added dropwise at 0 ° C, and the resulting mixture was stirred at room temperature for 4.5 h . Then, the mixture was poured into water (50 mL), and the aqueous layer was extracted with diethyl ether (100 mi x 2). The combined organic layers were dried with sodium sulfate, and concentrated in vacuo. The residue was suspended in hexane, and the insoluble matter was removed by filtration. The filtrate was concentrated in vacuo to give about 500 mg of the title compound as a colorless oil. This was used for the next stage without purification. 1 H-NMR (CDCl 3) d: 5.30-5.20 (1H, m), 3.69-3.63 (4H, m), 2.27 (2H, t, J = 5.7 Hz), 2.20 (2H, br t, J = 5.9 Hz) , 1.59 (3H, d, J = 6.8 Hz).

Stage 2. 2-Methyl-1, 6-dioxaespirof2.51octane A mixture of 4-ethylidenehydro-2H-pyran (approximately 500 mg, step 1) and 3-chloroperoxybenzoic acid (1.11 g, 4.49 mmol) in dichloromethane (50 mL) was stirred at 0 ° C at room temperature for 1 h. Then, the saturated aqueous sodium hydrogen carbonate solution (50 mL) and a solution of saturated aqueous sodium thiosulfate (50 mL) was added, and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo to give 337 mg of the bulk title compound as a yellow oil. This was used for the next stage without further purification. 1 H-NMR (CDCl 3) d: 3.88-3.75 (4H, m), 2.92 (1 H, q, J = 5.6 Hz), 1. 95-1.80 (2H, m), 1.65-1.40 (2H, m), 1.30 (3H, d, J = 5.4 Hz). Rf: 0.6 (ethyl acetate / hexane = 1: 1).

Step 3. 4 - ((r (1-lsopropyl-5-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) -carbonipamin-methyl) piperidin-1-tert-butylcarboxylate To a solution of 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (8.00 g, 32.6 mmol, step 4 in preparation 2) in dichloromethane (200 mL) was added dropwise. Oxalyl chloride drop (8.5 mL, 98 mmol) at 0 ° C. Then, N, N-dimethylformamide (3 drops) was added to the mixture carefully. The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 3 h. Then, the mixture was evaporated in vacuo to give the acid chloride in bulk as a yellow solid. Then, to a mixture of tere-butyl 4- (aminomethyl) piperidine-1-carboxylate (9.08 g, 42.4 mmol) and diisopropylethylamine (11.4 mL, 65.2 mmol) in dichloromethane (200 mL) was added dropwise a solution of Bulk acid chloride in dichloromethane (50 mL) at 0 ° C, and the mixture was stirred at room temperature for 3 h. The resulting mixture was poured into water (300 mL), and the aqueous layer was extracted with dichloromethane (200 mL x 3). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel with ethyl acetate / hexane (1/5) and then methanol / dichloromethane (1/40-1 / 10) to give 15.0 g (quant.) Of the title compound as a solid yellow stick.

MS (ESI) m / z: 442 (M + H +). 1 H-NMR (CDCl 3) d: 10.07 (1 H, br), 9.13 (1H, s), 7.53-7.47 (2H, m), 7.13 (1H, t, J = 3.6 Hz), 4.20-4.06 (2H, m), 3.39 (2H, t, J = 6.3 Hz), 2.78-2.66 (2H, m), 2.68 (3H, s), 1.67 (6H, d, J = 7.1 Hz), 1.45 (9H, s), 1.85-1.18 (5H, m). The signal due to CH (CH3) 2 was not observed.

Step 4. 1-lsopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide A solution of 4- ( { [(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl) carbonyl] amino.} Methyl) piperidin-1-tert-butylcarboxylate (15.0 g, 32.6 mmol, step 3) in 10% hydrogen chloride in methanol was stirred at room temperature for 12 h. Then, the solvent was removed in vacuo to give the title compound as a hydrochloride salt. This salt was poured into the saturated aqueous sodium hydrogen carbonate solution (500 mL), and the aqueous layer was extracted with dichloromethane (500 mL x 5). The combined organic layers were dried with magnesium sulfate and sodium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl silica gel eluting with methanol / dichloromethane (1:10) to give 10.3 g (92%) of the title compound as an amorphous yellow stick solid.

MS (ESI) m / z: 342 (M + H +). H-NMR (CDCl 3) d: 10.04 (1 H, br), 9.13 (1 H, s), 7.55-7.42 (2H, m), 7.12 (1H, t, J = 4.1 Hz), 3.38 (2H, t , J = 6.3 Hz), 3.10 (2H, br d, J = 11.9 Hz), 2.68 (3H, s), 2.67-2.55 (2H, m), 1.85-1.60 (3H, m), 1.67 (6H, d , J = 7.1 Hz), 1.35-1.15 (2H, m). The signals due to CH (CH3) 2 and NH (piperidine) were not observed.

Step 5. N- (. {1-p- (4-hydroxytetrahydro-2H-pyran-4-ypetinpiperidin-4-yl> methyl) -1-isopropyl-5-methyl-2- hydrochloride. oxo-1,2-dihydroquinoline-3-carboxamide A solution of 1-isopropyl-5-methyl-2-oxo-N- (piperidin-4-ylmethyl) -1,2-dihydroquinoline-3-carboxamide (200 mg, 0.59 mmol, step 4) and 2-methyl- 1,6-dioxaespiro [2.5] octane (bulk, 2.99 mmol, step 2) in methanol was stirred in a sealed tube at 130 ° C for 30 h. After cooling to room temperature, water (100 mL) was added, and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia / methanoi / dichloromethane (0.1: 1: 15) to give 180 mg of the bulk product. This was chromatographed on a column of aminopropyl silica gel eluting with ethylolhexane acetate (1: 1.5) to give 51 mg of the title compound as a salt in free form. This was treated with 10% hydrogen chloride in methanol, and the solvent was removed in vacuo to give 35 mg (12%) of the title compound as an amorphous white solid. MS (ESI) m / z: 470 (M + M +). IR (KBr) v: 3225, 2957, 2866, 2702, 1678, 1616, 1587, 1541, 1464, 1385, 1310, 1217, 1157, 1101, 968, 950, 799 cm "1. 1 H-NMR (DMSO-de ) d: 9.85 (1 H, m), 8.89 (1 H, s), 7.76 (1 H, d, J = 8.9 Hz), 7.62 (1 H, t, J = 7.3 Hz), 7.22 (1 H, d, J = 7.3 Hz), 5.47 (1H, m), 3.80-3.15 (11H, m), 2.61 (3H, s), 2.00-1.25 (9H, m), 1.57 (6H, d, J = 6.8 Hz), 1.23 (3H, d, J = 6.9 Hz) The signal due to OH was not observed, cale anal, for C27H40CIN3O4-O.2iPr2O-O.7H2O: C, 62.82; H, 8.26; N, 7.79. Found: C , 62.72; H, 7.95; N, 7.50.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (I): wherein: Het represents a heterocyclic group having a nitrogen atom, to which B is directly attached, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected separately from of the group consisting of substituents s1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, an n-propyl group or a cyclopentyl group; R 2 represents a methyl group, a fluorine atom or a chlorine atom; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents selected separately from the group consisting of substituents a2, or (iii) a heterocyclic group having 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents selected separately from the group consisting of β substituents, said substituents s1 are selected separately from a hydroxy group and an amino group; said a2 substituents are selected separately from a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof.

2. The compound or its pharmaceutically acceptable salt of claim 1, further characterized in that Het represents a heterocyclic group selected from: said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected separately from the group consisting of substituents 1.

3. - The compound or its pharmaceutically acceptable salt of claim 1, further characterized in that Het represents a group of the formula: and this group being unsubstituted or substituted by a substituent selected from the group consisting of substituents s1; A represents an alkylene group having from 1 to 3 carbon atoms; and R1 represents an isopropyl group or a cyclopentyl group.

4. The compound or its pharmaceutically acceptable salt of claim 1, further characterized in that Het represents a group of the formula: A represents an alkylene group having 1 to 2 carbon atoms; B represents an alkylene group having from 1 to 5 carbon atoms; R3 represents separately: an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 5 to 7 carbon atoms, and said cycloalkyl group selected separately by 1 to 3 substituents being substituted from the group consisting of substituents a2, or (iii) a heterocyclic group having from 5 to 7 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected separately from the group consisting of substituents β, said substituents a 2 are selected separately from a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2, or 3.

5. The compound or its pharmaceutically acceptable salt of claim 1, further characterized in that: A represents a methylene group; B represents an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group; R3 represents separately: (i) an oxo group or a hydroxy group; (ii) a cycloalkyl group having from 5 to 6 carbon atoms, and said cycloalkyl group being substituted by 1 to 2 substituents selected separately from the group consisting of substituents a2, or (iii) a heterocyclic group having 5 to 6 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents selected separately from the group consisting of β substituents, said substituents a2 are selected separately from a hydroxy group or an amino group; and said β2 substituents are selected from a hydroxy group, an amino group and an alkyl group having from 1 to 4 carbon atom group; and n is 1 or 2.

6. The compound or its pharmaceutically acceptable salt of claim 1, further characterized in that: B represents an alkylene group having from 1 to 3 carbon atoms; R3 represents separately: (i) an oxo group or a hydroxy group; (ii) a cyclohexyl group substituted by 1 to 2 hydroxy groups, (iii) a heterocyclic group selected from a hydroxytetrahi-dropiranyl, piperidinyl and morpholinyl, and said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents selected separately from a hydroxy group and a methyl group; and n is 1 or 2.

7. The compound or its pharmaceutically acceptable salt of claim 6, further characterized in that: B represents a methylene group; R2 represents a methyl group; R3 represents separately a 1,4-dihydroxycyclohexyl, hydroxytetrahi-dropyranyl, piperidinyl and morpholinyl group; and n is 1.

8. The compound or its pharmaceutically acceptable salt of claim 7, further characterized in that R3 represents separately a 1,4-dihydroxycyclohexyl or hydroxytetrahydropyranyl group.

9. The compound of claim 1, further characterized in that it is: N- (. {1 - [(cis-1,4-dihydroxycyclohexyl) methyl] piperidin-4-yl.} Methyl ethanedioate) -1- iso-propyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; N- (. {1 - [(trans-1,4-dihydroxycyclohexyl) methyljpiperidin-4-yl.] methyl) -1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-ethanedioate -carboxamide, or its pharmaceutically acceptable salt.

10. A pharmaceutical composition for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (Sil), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes, apnea syndrome, postoperative bowel motility , which comprises a therapeutically effective amount of a compound of formula (I): wherein: Het represents a heterocyclic group having a nitrogen atom, to which B is directly attached, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected separately from of the group consisting of substituents al; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, an n-propyl group or a cyclopentyl group; R 2 represents a methyl group, a fluorine atom or a chlorine atom; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents selected separately from the group consisting of substituents a2, or (iii) a heterocyclic group having 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents selected separately from the group consisting of β substituents, said substituents s1 are selected separately from a hydroxy group and an amino group; said a2 substituents are selected separately from a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxy group and an alkoxy group having from 1 to 4 carbon atoms; and said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof.

11. The use of a compound of formula (I): wherein: Het represents a heterocyclic group having a nitrogen atom, to which B is directly attached, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4-substituents selected separately from from the group consisting of substituents s1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, an n-propyl group or a cyclopentyl group; R 2 represents a methyl group, a fluorine atom or a chlorine atom; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents selected separately from the group consisting of substituents a2, or (iii) a heterocyclic group having 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents selected separately from the group consisting of β substituents, said substituents a are selected separately from a hydroxy group and an amino group; said a2 substituents are selected separately from a hydroxy group, an amino group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; said β substituents are selected from a hydroxy group, an alkyl group substituted by hydroxy having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkyl group substituted by amino having from 1 to 4 carbon atoms and a carbamoyl group; and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of disease conditions mediated by 5-HT4 receptor activity and / or 5-HT3 activity, in a mammalian subject.

12. The use claimed in claim 11, wherein said condition is selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (Sil) , constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorders, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and syndrome of apnea, and postoperative bowel motility. SUMMARY OF THE INVENTION This invention provides a compound of the formula (I): wherein: Het represents a heterocyclic group having a nitrogen atom, to which B is directly attached, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected separately from of the group consisting of substituents s1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, an n-propyl group or a cyclopentyl group; R 2 represents a methyl group, a fluorine atom or a chlorine atom; R3 represents separately: (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents, or (iii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents; and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof; these compounds have 5-HT4 receptor agonist activity, and are then useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammals, especially humans. PFIZER P06 / 672F