SK3632002A3 - Piperidine quinolyl propyl derivatives, preparation method and compositions containing same - Google Patents

Abstract

1-Substituted 4-(3-(6-alkoxy-4-quinolinyl)-propyl)-piperidine derivatives (I) are new. Quinolinylpropyl-piperidine derivatives of formula (I), in the form of diastereomers or their mixtures, and their salts are new. [Image] R 1H, halo or OH; R' 1H; or may also be halo if R 1= halo; R 0H; or R 0+ R 1bond, in which case R' 1= H; R 2COOH, CH 2COOH, CH 2CH 2COOH or CH 2OH; R 3(i) 1-6C alkyl substituted by 1-3 groups selected from OH, halo, oxo, COOH, alkoxycarbonyl, alkoxy, alkylthio, Ph', SPh' or Ph'-alkylthio, cycloalkyl, cycloalkylthio, Het and -S-Het; (ii) propargyl substituted by Ph', cycloalkyl or Het; (iii) cinnamyl or (iv) 4-phenylbuten-3-yl; provided that if R 3CH 2OH, then R 3= (i) 1-6C alkyl substituted by SPh', cycloalkylthio or -S-Het; or (ii) propargyl substituted by Ph', cycloalkyl or Het; R 41-6C alkyl, (2-6C) alkenyl-CH 2O- or (2-6C) alkynyl-CH 2O-; Ph' : phenyl (optionally substituted by 1-3 of halo, OH, alkyl, alkoxy, CF 3, OCF 3, COOH, alkoxycarbonyl, CN or NH 2); Het : 5- or 6-membered aromatic heterocycle containing 1-4 of N, O and S as heteroatom(s) (optionally substituted by 1-3 of halo, OH, alkyl, alkoxy, CF 3, OCF 3, oxo, COOH, alkoxycarbonyl, CN or NH 2); unless specified otherwise alkyl moieties have 1-3C and cycloalkyl moieties 3-7C. An independent claim is included for the preparation for (I). ACTIVITY : Antibacterial. (I) are effective in vitro against methicillin-resistant Staphylococcus aureusAS5155 at 0.03-4 Microg/ml, Streptococcus pneumoniaeIP53146 at 0.12-8 Microg/ml, Enterococcus faeciumat 0.5-64 Microg/ml and Moxarella catharrhalisIPA152 at 0.25-32 Microg/ml; and in vivo against Staphylococcus aureusIP8203 in mice at 10-150 mg/kg s.c. (CD 50) or (in some cases) 20-150 mg/kg p.o. (No specific results for individual compounds are given). MECHANISM OF ACTION : None given.

Description

Quinolylpropylpiperidine derivatives, their preparation and pharmaceutical compositions containing them

Technical field

The present invention relates to quinolylpropylpiperidine derivatives of formula I

which are active as antimicrobials. The invention further relates to their preparation and compositions containing them.

BACKGROUND OF THE INVENTION

Patent application WO 93/37635 discloses antimicrobial quinolylpropylpiperidine derivatives of the general formula

wherein R ¹ is especially alkoxy of 1 to 6 carbon atoms, R ² is hydrogen, R ³ is in the 2 or 3 position and represents an alkyl group of 1 to 6 carbon atoms which may optionally be substituted with 1 to 3 substituents selected from the group consisting of thiol, halogen, alkylthio, trifluoromethyl, alkyloxycarbonyl, alkylcarbonyl, Alk e2 nyloxykarbonylová, alkenylcarbonyl, hydroxyl optionally substituted by alkyl, etc., R ⁴ is -CH 2 R ⁵ wherein R ⁵ is a group selected from the group consisting of alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaroyl, and the like, n is 0 to 2, m is 1 or 2 and A and B are on in particular oxygen, sulfur, sulfinyl, sulfonyl or CR ⁶ R ⁷ , wherein R ⁵ and R ⁷ represent hydrogen, thiol, alkylthio, halogen, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amino and so on.

European patent application EP 30044 describes quinoline derivatives used as cardiovascular agents, which correspond to the general formula

wherein R ¹ is especially alkoxy, AB is -CH ₂ -CH ₂ -, -CH (OH) -CH ₂ -, -CH ₂ -CH (OH) -, -CH ₂ CO-, or -CO-CH 2 -, R ¹ is H, OH or alkoxy, ^R2 is ethyl or vinyl, R ³ is in particular an alkyl, hydroxyalkyl, cycloalkyl, hydroxy, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, optionally substituted diphenylalkyl, optionally substituted phenylalkenyl, optionally substituted benzoyl or benzoylalkyl, or optionally substituted heteroaryl or heteroarylalkyl and Z is hydrogen or alkyl or forms a cycloalkyl group with R ³ .

SUMMARY OF THE INVENTION

It has now been found, and it is the essence of the present invention, that the products of formula (I) wherein

R ¹ is a hydrogen atom or a halogen atom or a hydroxyl group,

R ¹ is a hydrogen atom or can be a halogen atom when R ¹ is also a halogen atom, and

R c is hydrogen or

R ¹ and R 0 together form a bond, and

R ¹ is a hydrogen atom,

R ² is carboxyl, carboxymethyl, or

2-carboxyethyl, and

R ³ represents an alkyl group (1 to 6 carbon atoms) substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, oxo, carboxyl, alkoxycarbonyl, alkyloxy or alkylthio or phenyl, phenylthio or phenylalkylthio which may carry 1 to 4 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido (C 1 -C 4) or amino], or a cycloalkyl group or a cycloalkylthio group, wherein the cyclic moiety contains 3 to 7 members, or a 5- to 6-membered aromatic heterocyclyl or heterocyclylthio group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted by a halogen atom , hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano or amino], or R ³ represents a phenyl-substituted propargyl group which may itself carry 1 to 4 substituents [selected from, which represents a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, an alkoxycarbonyl group, a cyano group or an amino group] or substituted by a 3 to 7 membered cycloalkyl group; A 6-membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone by [halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano, cyano amino] or R ³ is cinamyl or 4-phenylbuten-3-yl, or

R ² is a hydroxymethyl group, an alkoxycarbonyl group, a alkyloxykarbonylmetylovú or 2- (alkyloxycarbonyl) ethyl radical, wherein the alkyl portion contains 1 to 6 carbon atoms, and

R ³ represents an alkyl group (having 1 to 6 carbon atoms) substituted by a phenylthio group which itself may carry 1 to 3 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkoxycarbonyl, cyano or amino] or substituted by cycloalkylthio, wherein the cyclic moiety contains from 3 to 7 members, or substituted by a 5- to β-membered aromatic heterocyclyl group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted by [atom] halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano or amino] or R ³ represents a propargyl group which itself may carry 1 to 4 substituents y [selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkoxycarbonyl, cyano or amino] or substituted with 3 to 7 membered cycloalkyl or substituted 5- to 6- a membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone by [halogen atom, hydroxyl group, alkyl group, alkyloxy group, trifluoromethyl group, trifluoromethoxy group, oxo group, carboxyl group, alkoxycarbonyl group or cyano group] , and

R ⁴ is alkyl (with 1 to 6 carbon atoms), alkenyl-CH 2 radical or an alkynyl-CH 2 ^- / wherein the alkenyl or alkynyl moiety contains 2 to 6 carbon atoms wherein it is to be understood that the alkyl radicals and portions are straight chain or branched chain, in their diastereoisomeric forms or in their mixtures, and also as salts, are potent antibacterial agents.

It is to be understood that the alkyl groups and moieties are straight or branched chain groups containing (unless specifically indicated) 1-4 carbon atoms and alternatively, when R ¹ or R ¹ represents a halogen atom or when R ³ carries a halogen atom then the halogen atom is selected from fluorine, chlorine, bromine or iodine, preferably chlorine.

In the above formula, when R ³ carries an aromatic heterocyclyl substituent, the substituent is selected from, but not limited to, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl. It is also to be understood that in the definition of R ^{3, a} substituted alkyl group only carries one cyclic group simultaneously.

According to the present invention, the compounds of the formula I can be obtained by condensation of the R ³ chain with a quinolylpropylpiperidine derivative of the formula II

wherein R ⁴ is as defined above, R ¹ and R ¹ are hydrogen or together form an oxo group and R ² is a protected carboxyl, carboxymethyl or 2-carboxyethyl or alkyloxycarbonyl, alkyloxycarbonylmethyl or 2- (alkyloxycarbonyl) ethyl group, to obtain a quinolylpropylpiperidine derivative of the Formula III

wherein R ¹ , R ¹ , R ² and R ⁴ are as previously defined, and then the acid protecting group is removed,

And then, if appropriate, reduction of the oxo group represented by R ¹ or R ¹ to an alcohol, wherein R ¹ is a hydroxyl group, and then optionally halogenation, if desired, to give a quinolylpropyl piperidine derivative wherein R ¹ is a halogen atom, and optionally dehydrohalogenating the corresponding halogenated derivative to give a quinolylpropylpiperidine derivative wherein R ¹ and Ŕ ° together form a bond, or further dihalogenating the product of formula III wherein R ¹ and R ¹ together form an oxo group to give a quinolylpropylpiperidine derivative wherein R ¹ and R ¹ are halogen atoms and / or, if desired, followed by reaction of the acid protected in the form of the R ² group at the 3-position of the piperidine group to a hydroxymethyl group, or optionally followed by conversion to a carboxymethyl or 2-carboxyethyl group according to conventional methods, optionally removing the acid protecting group and optionally converting from product to sol.

The condensation of the R ³ chain with the piperidine group is preferably carried out by treatment with a derivative of the general formula IV

R ^{3 -} X (IV) wherein R ³ is as defined above and X represents a halogen atom, a methylsulfonyl group, a trifluoromethylsulfonyl group or a p-toluenesulfonyl group, the reaction being carried out in an anhydrous medium, preferably an inert medium (e.g. nitrogen or argon) in an organic solvent such as an amide (such as dimethylformamide), a ketone (such as acetone), a nitrile (such as acetonitrile) in the presence of a base such as a nitrogenous organic base (such as triethylamine) or an inorganic base (such as an alkali metal carbonate such as potassium carbonate); at a temperature between 20 ° C and the boiling point of the solvent. Preferably, the reaction is carried out with a derivative wherein X is a bromine or iodine atom.

When R ³ is a propargyl group substituted with a phenyl, cycloalkyl or heterocyclyl group, it is often preferred to condense the propargyl halide and then substitute the chain with a phenyl, cycloalkyl or heterocyclyl group.

In this alternative, the addition of the propargyl chain carried out using propargyl bromide under conditions as above for R ^3, with or without an alkali metal iodide such as potassium iodide or sodium iodide. If the substitution is to be carried out by a phenyl or heterocyclyl group, then the reaction is carried out by treatment with a halogenated

a derivative derived from a cyclic group participating in a substitution reaction in the presence of triethylamine in an anhydrous medium, in a solvent such as an amide (e.g. dimethylformamide) or a nitrile (e.g. acetonitrile) and in the presence of a palladium salt such as tetrakis (triphenylphosphine) palladium; copper (I) iodide, at a temperature between 20 ° C and the boiling point of the solvent.

If the substitution is to be carried out by a cycloalkyl group, the reaction is carried out by treating an propargyl derivative obtained as described above in an anhydrous medium in a solvent such as ether (for example tetrahydrofuran) by treating an organic lithium compound such as n-butyllithium or tert-butyllithium. ), at a temperature between -78 and 0 ° C, and then treatment with cycloalkanone followed by deoxygenation of the intermediate alcohol according to conventional methods.

It will be appreciated that when the alkyl groups represented by R ³ carry carboxyl groups or amino groups, then these groups are first protected and subsequently released after the reaction. These operations are carried out according to conventional conditions which do not adversely affect the rest of the molecule, in particular according to the methods described by TW Greene and PGM Wuts, Protective Groups in Organic Synthesis (2nd edition), and Wiley-1989 Science Publication. (1991) or Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

The protected carboxyl group represented by R ² may be selected from readily hydrolyzable esters. Examples which may be mentioned are methyl, benzyl or tert-butyl esters or. alternatively phenylpropyl or propargyl esters. Optionally, the protection of the carboxyl group is carried out simultaneously with the reaction. In this case, the product of formula (II) carries a R ² group which is a carboxyl group.

The reduction of the oxo group to the hydroxyl group is carried out by conventional methods which do not adversely affect the rest of the molecule, in particular by the action of a reducing agent such as an alkali metal hydride such as sodium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride or lithium aluminum hydride; the reaction is preferably carried out under an inert atmosphere in an organic solvent such as an alcohol (e.g. methanol, ethanol or isopropanol) or an ether (e.g. tetrahydrofuran) or a chlorinated solvent (e.g. dichloromethane) at a temperature between 20 ° C and the boiling point of the solvent.

The halogenation in which a quinolylpropylpiperidine derivative in which R ¹ is a halogen atom is to be obtained from a derivative in which R ¹ is a hydroxyl group can be carried out in the presence of an aminosulfur trifluoride (e.g. diethylaminosulfur trifluoride, bis (2-methoxyethyl) aminosulfurofluoride) ) or alternatively in the presence of sulfur hexafluoride using reagents such as tetraalkylammonium, trialkylbenzylammonium or trialkylphenylammonium halide, or using an alkali metal halide, optionally with the addition of a crown ether. Fluorination can also be accomplished by treatment with a fluorinating agent such as morpholine sulfurtrifluoride, sulfur fluoride (J. Org. Chem., 40, 3808 (1975), diethylaminosulfurtrifluoride (Tetrahedron, 44, 2875 (1988)) or bis (2-methoxyethyl) aminosulfurtrifluoride ( Deoxofluor®).

Alternatively, the fluorination reaction can be carried out with a fluorinating agent such as hexafluoropropyldiethylamine (JP 2 039 546) or N- (2-chloro-1,1,2-trifluoroethyl) diethylamine. When a tetraalkylammonium halide is used, it may be selected from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium (e.g., tetra-n-butylammonium), tetrapentylammonium, tetracyclohexylammonium ammonium triethylammonium ammonium triethylammonium trimethyl ammonium triethylammonium trimethyl ammonium triethylammonium trimethyl ammonium triethylammonium trimethyl ammonium triethylammonium triethylammonium triethylammonium triethylammonium triethylammonium triethylammonium trimethyl). . The reaction is carried out in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane or chloroform) or an ether (e.g. tetrahydrofuran or dioxane) at a temperature between -78 and 40 ° C (preferably at a temperature between 0 and 30 ° C). is to carry out the reaction in an inert medium (especially argon or nitrogen).

The reaction may also be carried out by treating a halogenating agent such as thionyl chloride or phosphorus trichloride in an organic solvent such as a chlorinated solvent (e.g. dichloromethane or chloroform) at a temperature between 0 ° C and the boiling point of the solvent.

The dihalogenation of the product of formula III, wherein R ¹ and R ¹ together form an oxo group, in order to obtain a quinolylpropylpiperidine derivative in which R ¹ and R ¹ are halogen atoms, may be carried out using conditions analogous to the above halogenation conditions.

The dehydrohalogenation of a halogenated derivative obtained from a derivative in which R ¹ is a hydroxyl group can be carried out, in particular, by treatment of diazabicyclo [5.4.0] undec-7-ene in an aromatic organic solvent (e.g. toluene) at a temperature between 20 ° C and the boiling point of the solvent. .

The reduction of the acid protected in the form of the R ² group at the 3-position of the piperidine group to the hydroxymethyl group is carried out by conventional methods which do not adversely affect the rest of the molecule. In particular, the reduction is effected by treatment with hydride (e.g. lithium aluminum hydride or diisobutylaluminium hydride) in a solvent such as ether (e.g. tetrahydrofuran). ), at a temperature between 20 and 60 ° C.

Conversion of the hydroxymethyl group at the 3-position of the piperidine group to the carboxymethyl group is accomplished by conventional means which do not adversely affect the rest of the molecule, in particular by a halogenating agent such as thionyl chloride or phosphorus trichloride or phosphorus tribromide and then alkali metal cyanide (such as for example, potassium cyanide or sodium cyanide to give the corresponding cyanomethyl derivative, followed by hydrolysis of the nitrile Halogenation may be carried out in a chlorinated solvent (such as dichloromethane or chloroform) at a temperature between 0 ° C and the boiling point of the solvent. may be carried out in a solvent such as dimethylsulfoxide, an amide (e.g. dimethylformamide), a ketone (e.g. acetone), an ether (e.g. tetrahydrofuran) or an alcohol (e.g. methanol or ethanol) at a temperature between 20 ° C and the boiling point of the solvent. The hydrolysis of the nitrile can be carried out according to known methods which do not adversely affect the rest of the molecule, in particular by treating with hydrochloric acid in methanol at a temperature between 20 and 70 ° C, followed by saponification of the ester obtained (e.g. sodium hydroxide in dioxane / water). or directly by treatment with aqueous sulfuric acid at a temperature between 50 and 80 ° C.

The conversion of the hydroxymethyl group at the 3-position of the piperidine group to the 2-carboxyethyl group is carried out, for example, from a halogenated derivative prepared as described above by condensation with sodium salt of diethyl malonate and subsequent acid hydrolysis of the product obtained in aqueous medium.

If desired, the removal of the acid protecting group in order to obtain a quinolylpropylpiperidine derivative, wherein R ² is a carboxylate, is accomplished by conventional means, in particular by acid hydrolysis or saponification of the R ² ester. In particular, sodium hydroxide is reacted in an aqueous or organic solvent, for example an alcohol such as methanol or an ether such as dioxane at a temperature between 20 ° C and the boiling point of the solvent. The hydrolysis can also be carried out in a hydrochloric acid environment at a temperature of i

between 20 and 100 ° C.

The quinolylpropylpiperidine derivative of the formula II or the corresponding acid, wherein R ² represents a carboxyl group, can be prepared by an analogous method as described in the examples below or in an analogous manner to that described in patent application EP 30044 or in international patent application WO 99/37635 . Intermediates of quinolylpropylpiperidine derivatives wherein R ⁴ is alkenyl-CH ₂ O- or alkynyl-CH ₂ O- can be prepared analogously to intermediates where R ⁴ is alkoxy by treatment with the corresponding halogenated or quinoline derivative having a hydroxyl group at the 6-position.

The protected 2-carboxyethyl derivatives of formula (II) may be obtained by an analogous method to that described in International Patent Application WO 99/37635 followed by hydrolysis of the nitrile and esterification of the acid thus obtained, or may be prepared by analogous methods as described in the Examples below.

It will be appreciated that the derivatives of formula I, II or III, or the starting intermediates for their preparation, may exist in cis or trans form with respect to the substituents at the 3 and 4 positions of piperidine. The trans configuration derivatives can be obtained from the cis configuration derivatives by an analogous method as described in international patent application WO 99/37635.

If desired, the quinolylpropylpiperidine derivatives of formula I can be purified by physical methods such as crystallization or chromatography.

It is further to be understood that when R ¹ is a hydrogen atom and R is a hydroxyl group or a halogen atom, then there may be diastereoisomeric forms, and that these diastereoisomeric forms and mixtures thereof are also within the scope of the present invention. In particular, these mixtures can be separated by silica gel chromatography or high performance liquid chromatography (HPLC).

The quinolylpropyl piperidine derivatives of formula (I) may be converted to their acid addition salts by known methods. It is to be understood that these salts are also within the scope of the present invention.

Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids (chlorides, bromides, sulfates, nitrates or phosphates) or with organic acids (succinates, fumarates, tartarates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, benzenesulfonates, benzenesulfonates, benzenesulfonates, benzenesulfonates, benzenesulfonates , p-toluenesulfonates, isethionates, naphthalenesulfonates or camphorsulfonates) or with substituted derivatives of these compounds.

Some quinolylpropylpiperidine derivatives of the formula I which contain a carboxyl group can be converted into metal salts or nitrogen-base addition salts by methods known in the art. These salts are also within the scope of the present invention. These salts can be obtained by treating a compound of the present invention in a suitable solvent such as an alcohol, ether or water, or by reaction with an organic acid salt, by treating a compound of the present invention with a metal base (e.g. an alkali or alkaline earth metal base), ammonia or amine. The salt, if necessary, forms a precipitate, which may be separated by filtration, sedimentation or lyophilization. Examples of pharmaceutically acceptable salts include alkali metal salts (sodium, potassium or lithium) or alkaline earth metals (magnesium or calcium), ammonium salts or salts with nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine; diisopropylamine, N, N-dimethyiethanolamine, benzylamine, dicyclohexylamine, N-benzyl-β-phenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine or leucine. !

The quinolylpropylpiperidine derivatives of the invention are particularly preferred as antibacterial agents.

The quinolylpropylpiperidine derivatives of the invention exhibit in vitro activity against gram-positive bacteria and are active at a concentration of 0.017 to 4 pg / ml for Staphylococcus aureus AS5155, and most are active at concentrations between 0.06 and 8 pg / ml for Streptococcus pngumoniae IP53146, and at concentrations between 0.12 and 64 pg / ml for Enterococcus faecium ATCC19434 or H983401, and in vitro activity against gram-negative microorganisms, where they are active at concentrations between 0.12 and 64 pg / ml. 32 pg / ml for Moraxella catharrhalis IPA152; in vivo, they are active in experimental infections with Staphylococcus aureus IP8203 in mice at doses between 10 and 150 mg / kg subcutaneously (CD ₅₀ ) and for some of them at doses between 20 and 150 mg / kg orally.

The products of the present invention are particularly advantageous because of their low toxicity. None of the products exhibited toxicity at a dose of 100 mg / kg subcutaneously. mice (2 administrations).

Of the compounds of the present invention, quinolylpropylpiperidine derivatives of formula I are particularly preferred

R ¹ is an atom pina, H or a halogen atom or a hydroxyl group R ¹ ' is an atom H, and R is an atom H, or

R ¹ and R 0 together form a bond, and

R ¹ is a hydrogen atom,

R ² is carboxyl or carboxymethyl radical, and

R ³ represents an alkyl group (1 to 6 carbon atoms) substituted with 1 to 3 substituents selected from the group consisting of halogen, oxo, alkyloxy or alkylthio or phenyl or phenylthio which may bear 1 to 4 halogen atoms, or cycloalkyl or a cycloalkylthio group wherein the cyclic moiety contains from 3 to 7 members, or a 5- to 6-membered aromatic heterocyclyl or heterocyclylthio group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted by halogen, or R ³ is propargyl a phenyl substituted group which may itself carry 1 to 3 halogen atoms or a propargyl group substituted with a 5 to 6 membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or R ³ represents a cinamyl group; or

R ² represents a hydroxymethyl, alkyloxycarbonyl or alkyloxykarbonylmetylovú group (wherein the alkyl portion contains 1 to 6 carbon atoms), and

R ³ represents an alkyl group (containing 1 to 6 carbon atoms) substituted by a 5- to 6-membered aromatic heterocyclylthio group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or R ³ represents a propargyl group substituted with a 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; and

R ⁴ represents an alkyl group (containing 1 to 6 carbon atoms), wherein the alkyl groups and moieties are straight or branched chain, as well as diastereomeric forms and mixtures thereof, as well as salts thereof, of which the following are particularly preferred:

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-thienylthio) ethyl] piperidine-3-acetic acid;

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-thienylthio) ethyl] piperidine-3-acetic acid;

(3R, 4R) -4- [3-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-thienylsulfanyl) ethyl] piperidin-3-acetic acid;

(3R, 4B) -1- [2- (3-Fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] piperidine-3-acetic acid;

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3,

5-Trifluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid.

Particularly preferred are the compounds cited in the examples; The quinolylpropylpiperidine derivatives listed below are also preferred compounds:

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-phenylbutyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6 -Methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [4- (3-fluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-Fluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4- Fluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) propyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,3-difluorophenyl) butyl] piperidine-3-carboxylic acid piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,6-difluorophenyl) butyl] piperidine-difluorophenyl) propyl] piperidine- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [4- (3-Chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) (propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (2,3-Dichloro (phenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenyl) propyl] piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,6-dichloro-18-phenyl) butyl] piperidine-3-carboxylic acid-3-carboxylic acid 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-methylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinoline-4-) yl) propyl] -1- [5- (2-methylphenyl) pentyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (3-Methylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) propyl] piperidine-3-carboxylic acid (3-carboxylic acid) R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-methylphenyl)] butyl] piperidine-3-carboxylic acid {3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-Methoxyphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4 -methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenyl) propyl] piperidine-3- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-trifluoromethylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4-carboxylic acid -4 - [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-trifluoromethyl phenyl) propyl] piperidine-3-carboxylic acid (3 R, 41?) - 4- [3- (6-methoxy-quinolin-4-yl) propyl] ^-1,?

- [4- (3-Trifluoromethylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenyl) (propyl) piperidine-3-carboxylic acid {3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-trifluoromethylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-) yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-Fluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidine-3-carboxylic acid] piperidine-3-carboxylic acid acid.

R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenylthio) propyl] piperidine-3-carboxylic acid ( 32 R, 41 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,6-difluorophenylthio) ethyl] piperidin-3 (31 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenylthio) propyl] piperidine-3-carboxylic acid-31-carboxylic acid R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenyl20-thio) ethyl] piperidine-3-carboxylic acid (3R, 4R) R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine-3-carboxylic acid. .

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-Dichloro-phenylthio) -ethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2, 4-methoxy-4-yl) -propyl] - 3-Dichlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,6-dichlorophenylthio) ethyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenylthio) propyl] piperidine-3-carboxylic acid piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3-carboxylic acid) R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [3- (4-methylphenyl-21-thio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (2-Trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4F) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- ( 2-Trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) p Ropyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-Trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3F, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine -3-Carboxylic acid {3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine-3-carboxylic acid [3R] 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4B) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-Methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Met oxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidine-3-carboxylic acid (3K, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutyl) ethyl] piperidine-3-carboxylic acid (3 R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclopentylmethyl] piperidine-3-carboxylic acid

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [cyclohexylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (Cyclohexyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropylthio) ethyl] piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4-carboxylic acid - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) -yl) propyl] -1- [3- (cyclobutylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidine-3-carboxylic acid and

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclohexylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [3-Methylthiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-ethylthioethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-ethylthiopropyl] piperidine-3-carboxylic acid (3R, 4E) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (n-propylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [3- (n-Propylthio) propyl] piperidine-3-carboxylic acid (3E, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (n-butylthio) (ethyl) piperidine-3-carboxylic acid (3R, 4E) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (n-butylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (thien-2-yl) butyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) thiopropyl] piperidine-3-carboxylic acid d-3-carboxylic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) propyl] piperidine-3-carboxylic acid (32 R); 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (5-chlorothien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (5-chlorothien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) -thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorothien-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (3-chloro rtien-224

(yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4P) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) propyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl) butyl] piperidine-3-carboxylic acid piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (5-methylthien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) thiopropyl] piperidine-3-carboxylic acid

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R, 4R) (R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6 (Methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [4- (thien-3-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2] - (thien-3-yl) thioethyl] piperidine-3-carboxylic acid, (3R, 4P) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien- 3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4P) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) propyl]] piperidine-3-carboxylic acid and (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (fur-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (fur-2-yl) thio [25] ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3 propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [3-Pyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-yl] piperidine-3-carboxylic acid (3P, 4R) ) 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [3 l

(3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3-yl] -propyl] -piperidine-3-carboxylic acid propyl] -piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-2-yl) thioethyl] piperidine-3-carboxylic acid (3F, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-propyl) -propyl] -1- [3- (2-yl) -thiopropyl] piperidine-3-carboxylic acid yl) propyl] piperidine-3-carboxylic acid (3P, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-3-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [3-yl) propyl] piperidine-3-carboxylic acid (fur-2-yl) thio (fur-3-yl) for (fur-3-yl) bu (fur -3-yl) thio (fur-3-yl) thio (1-methylpyrrole (1-methylpyrrole) (1-methylpyrrole (1-methylpyrrole) (1-methylpyrrole) -thiazol-2 (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1,3-thiazol-2)

(yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-2-yl)] Thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) propyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R, 4R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylimidazol-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidine-3-carboxylic acid {3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [3- (3-methylpyrazol-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylpyrazol-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 2- (3-Methylpyrazol-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3- methylpyrazol-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) propyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) 27 butyl] piperidine-3-carboxylic acid] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] (propyl) -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (Pyridin-3-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridine-3-) yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-3-yl) thioethyl] piperidin-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) carboxylic acid } -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [5- (pyridin-4-yl) pentyl] piperidine-3-carboxylic acid [3R, 4R] -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 3- (Pyridin-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidine-228)

(yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-2-yl) butyl] piperidine- 3-Carboxylic acid {3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6 (Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [2- (pyrimidin-4-yl) thioethyl] piperidine-3-carboxylic acid (3Β, 4β) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (Pyrimidin-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5) (yl) propyl] piperidine-3-carboxylic acid (3F, 4F) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 4- (Pyrimidin-5-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-5-) yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5-yl) thiopropyl] piperidine- (3R, 4F) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyazin-2-yl) propyl] piperidine-3-carboxylic acid 3-carboxylic acid {3 R 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrazin-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine-3-carboxylic acid {3R, 4R} -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-) yl) propyl] -1- [3- (pyridazin-3-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [4- (pyridazin-3-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 2- (pyridazin-3-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine-3-) yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) propyl] piperidine (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridazin-4-yl) -butyl] -piperidine-3-carboxylic acid -3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3E, 4R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3E, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinoline) In-4-yl-propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid · (3R, 4R) -4- [3- (β-Methoxyquinoline-4)] -yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4E) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-Methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4E) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 3- (4-Methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2- (Trifluoromethyl) phenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3- (trifluoromethyl). phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4- (trifluoromethyl) (phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) prop (2R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] -2-ynyl] piperidine-3-carboxylic acid piperidine-3-carboxylic acid [3R, 4R} -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,4-difluorophenyl) prop-2-ynyl] piperidine-3- carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid carboxylic acid [3R, 4R] -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (3,4-dichlorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid { 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenyl) prop-2-ynyl] piperidine-3-carbo (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid xylic acid (3R, 4R) -4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [3- (2,4,6-trichlorophenyl) prop-2-ynyl] piperidine-3- acid (3 R, 4 R) -4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [3- (3,5-dichlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2-ynyl] piperidine-3- acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3- carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3- carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-5-fluorophenyl) prop-2-ynyl] piperidine-3- carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-2-fluorophenyl) prop-2-carboxylic acid Inyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop-2] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) -propinyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) -2-ynyl] piperidine-3-carboxylic acid (Prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) (phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chloro- 2-Methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (3,5-bis) (Trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3) (5R-Dimethyl-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- (3- (2,4- D their chloro-6-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5 (3-R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3-R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (3-methyl-thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid -3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1- methylpyrrol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3B, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrole) -3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1,3- thiazol-2-yl) prop-2-ynyl] piperidine-3-carboxylate (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-4-yl) prop-2-ynyl] piperidin-3 xylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-5-yl) prop-2-ynyl] piperidine-carboxylic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-imidazol-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid 3-Carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) prop-2-ynyl] piperidin-3 -carboxylic acid {3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) prop-2-ynyl] piperidine- 3-Carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine-3- (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazol-4-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid carboxylic acid [ 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R) 4R} -4- [3- (6-Methoxyc Hinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] (propyl) -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] 1- [3- (Pyrimidin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (Pyrimidin-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3] - (Pyrimidin-5-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- ( Pyrazin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid {3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine) -3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine-4-) yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-phenylbuten-3-yl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-phenylbutyl] piperidine-3-carboxylic acid [3R, 4R] -4- [3- {R (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-fluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4H) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-fluorophenyl) butyl] piperidine-3-carboxylic acid (3H, 4R) -4 - [3- (R, S) -hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,3-difluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6-difluorophenyl) butyl] piperidine-3-carboxylic acid (3 R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4P) 4- [3- (R _f S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (2-chlorophenyl) butyl] piperidine-3-carboxylic acid (3 R, 4 R ) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidine-3-carboxylic acid (3 R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorophenyl) butyl] piperidine-3-carboxylic acid ( 3 R, 4 R) -4- [3- (R, S) -Hydro xy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( R, S} -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,3-dichlorophenyl) butyl] piperidine-3-carboxylic acid (3 R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2,6-dichloro-phenyl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6-dichlorophenyl) butyl] piperidine-3-carboxylic acid (3 R, 4 R} -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (2-methyl-phenyl) -butyl] -piperidine-3- acid (3R, 4R) -4- [3- (R, S) -H carboxylic acid hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [5- (2-methylphenyl) pentyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) propyl] piperidine-3-carboxylic acid (3 R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-methyl-phenyl) -butyl] -piperidine-3-carboxylic acid (3R, 42%) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) propyl] piperidine-3-carboxylic acid (32 R, R); 4 R - 4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidine- 3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidine (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) -3-carboxylic acid (propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (2-Trifluoromethylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-trifluoromethylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) (propyl) -1- [3- (3-trifluoromethylphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4-) yl) propyl] -1- [4- (3-trifluoromethylphenyl) butyl] piperidine-3-carboxylic acid

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenyl) propyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-trifluoromethyl-phenyl) -butyl] -piperidine-3-carboxylic acid (3R; 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-phenyl-thioethyl] -piperidine-3-carboxylic acid-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2,3-difluoro-phenylthio) -ethyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenylthio) propyl] carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2,6-) -] - piperidine-3-carboxylic acid Difluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -137

- [3- (2,6-Difluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (2-chlorophenylthio) ethyl] piperidine-3-carboxylic acid {3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) (propyl) -1- [3- (2-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4F) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline)] n-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-dichlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- [R] , S) -hydroxy-3- (6-methyl oxyquinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,6-dichlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidine-3-carboxylic acid (3H, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenylthio) -propyl] -piperidine-3-carboxylic acid (3R, 4R) 4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-y1) propyl] -138

- [2- (4-Methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (N-methoxyquinolin-4-yl) propyl] - 1- [3- (4-Methylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4K) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [2- (2-Trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2-methoxy-phenylthio) -ethyl] -piperidine-3- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methoxy-phenylthio) -propyl] -piperidine-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methoxy-phenylthio) -ethyl] -piperidine-3-carboxylic acid -3-Carboxylic acid (3R, 4R) -4- [3- (H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] (3R, 4E) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (4-methoxy-phenylthio) -ethyl] -piperidine-3-carboxylic acid piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4 -methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidine-3- carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclopentylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclohexylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropylthio) ethyl] piperidine-3-carboxylic acid.

(3R _of 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclobutylthiopropyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclohexylthio) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-methylthiopropyl] piperidine-3-carboxylic acid (3 R, 4R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-ethylthioethyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-ethylthiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (n-propylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (n-propylthio) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (n-butylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (n-butylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-2-yl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (thien-2-yl) -butyl] -piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl)] Thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothiene) (2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4] - (5-chlorothien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (P, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (5-chlorothien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4) -yl) propyl] -1- [3- (5-chlorothien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorothien-2-) yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-Chloro-thien-2-yl) -thioethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - 1- [3- (3-Chloro-thien-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- [R, S] -Hydroxy-3- (6-methoxy-quinoline-4- yl) propyl] -1- [3- (5-methylthien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (5-methylthien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- {R (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3F, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-thien-2-yl) -propyl] -piperidine-3-carboxylic acid ( 3R, 4Ŕ) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-thien-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) propyl] piperidine-3-carboxylic acid (3i) R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (thien-3-yl) -butyl] -piperidine- (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-3- yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (thien-3-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (fur-2-yl) propyl] pi (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (4- (fur- 2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6) -methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-3-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (fur-3-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-3-yl) -thiopropyl] -piperidine-3-carboxylic acid (3i) ?, 4?? -4- [3 - (R, S) -Hydroxy-3- (1,6-methoxyquinolin-4-yl) propyl] -1-

- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [4- (1-methylpyrrol-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - [ R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-2-yl) -propyl] -piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (1-methyl-pyrrol-3-yl) -butyl] -piperidin-3 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (2- (1-methyl-pyrrol-3-yl) -carboxylic acid) (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrole) thioethyl] piperidine-3-carboxylic acid 3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1,3-thiazol-2-yl) -elina] propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1,3) (thiazol-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1,3-Thiazol-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (1-methylimidazol-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-methylimidazole (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [azol-4-yl] -propyl] -piperidine-3-carboxylic acid 4- (3-Methylimidazol-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidine-3-carboxylic acid [3R, 4R] -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S)] -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylpyrazol-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylpyrazol-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) thiopropyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazol-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) propyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-2-yl) -thiopropyl] -piperidine carboxylic acid -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -145

- [3- (pyridin-3-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-3-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6 R) -methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-3-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( 2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (2S, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridin-4-yl) -butyl] -piperidine-3-carboxylic acid (32) R, 42 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [5- (pyridin-4-yl) pentyl] piperidine-3 (32 R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) -carboxylic acid Thioethyl] piperidine-3-carboxylic acid (32 R, 42 R) -4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidine-3-carboxylic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) thiopropyl] piperidine -3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2) (yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 4- (pyrimidin-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -146

- [4- (pyrimidin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (pyrimidin-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] piperidine-3-carboxylic acid

I {3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -propyl] -piperidine -3-Carboxylic acid {3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-5-) yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidine) (5-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (pyrimidin-5-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (pyrazin-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [4- (pyrazin-2-yl) butyl] piperidine-3-carboxylic acid (3K, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4) -yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-3-yl) -propyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridazin-3-yl) butyl] 3-carboxylic acid piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazine-3-) yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine) -3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4K) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -147

- [3- (pyridazin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [4- (pyridazin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (H, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-chloro-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2- (trifluoromethyl) phenyl) prop-2- Inyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3 - (trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (4- (trifluoromethyl) phenyl) prop-2-ynyl] (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-piperidin-3-carboxylic acid)] -methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3F, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (3-methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,4-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid ( 3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,4-dichlorophenyl) prop-2 (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-vinyl] piperidine-3-carboxylic acid - (2,3-dichlórfény1) prop-2-iny1] piperidine-3-carboxylate (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichlorophenyl) xylic acid (Prop-2-ynyl) piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (2,4, β-Trichlorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,5-dichlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3F) , 4F) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-chloro-4-fluorophenyl) prop-2-iny1 piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro- 4-Fluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3K, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (3-Chloro-5-fluorophenyl) prop-2-ynyl] -piperidine-3-carbox (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-chloro-2-fluorophenyl) -propyl] -propyl acid -2-ynyl] -piperidine-3-carboxylic acid (3R, 4K) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-Fluoro-4-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3F, 4E) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5- chloro-2-methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] 1- [3- (3,5-bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxamide (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -150-ylic acid

- [3- (3,5-Dimethyl-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinoline-4) -yl) propyl] -1- [3- (2,4-dichloro-6-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) prop-2 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3- methylthien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (Thien-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid and (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) prop- 2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1 (3-Thiazol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy 3- (6-methoxy-quinolin-4-yl) -propyl] -151

- [3- (1,3-thiazol-5-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3F, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-imidazol-4-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) prop-2- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazole-2-ynyl) -piperidine-3-carboxylic acid] (yl) prop-2-ynyl] piperidine-3-carboxylic acid (3K, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid [3R, 4R] -4- [3- ( R S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (E, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-4-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2- Inyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl-1- [3- (pyrimidin-4) (yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (pyrimidin-5-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3S, 4S) -4- [3- (F, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (pyrazin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-phenyl-propen-2-yl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4-phenyl-buten-3-yl] -piperidine-3-carboxylic acid piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-phenylbutyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-fluoro-phenyl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (2-fluoro-phenyl) -butyl] -piperidine-carboxylic acid 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) propyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-fluorophenyl) butyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (β-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) propyl] piperidine-3-carboxylic acid ] piperidine-3-carboxylate (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-fluoro-phenyl) -butyl] -piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) propyl] piperidine carboxylic acid -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,3-difluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6) (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) -propyl] -1- [4 - (-difluorophenyl) propyl] piperidine-3-carboxylic acid 2, β-Difluorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-Chloro-phenyl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (2-chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-chloro-phenyl) -butyl] -piperidine-carboxylic acid 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-chlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2,3-)] piperidine-3-carboxylic acid dichlorophenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (4- (2,3-dichlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-Dichloro-phenyl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl -1- [4- (2,6-dichlorophenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidine 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-methylphenyl) butyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [5- (2-methylphenyl) pentyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenyl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methyl-phenyl)] - piperidine-3-carboxylic acid butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) (propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4- methylphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2 -methoxyphenyl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- ( 2-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3 R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -propyl] -piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-methoxy-phenyl) -butyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-trifluoromethyl-phenyl) -propyl] -piperidine-carboxylic acid 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-trifluoromethylphenyl) butyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenyl) propyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1-piperidine-3-carboxylic acid - [4- (3-trifluoromethylphenyl) butyl] piperidine-3 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-trifluoromethyl-phenyl) -propyl] -piperidine-carboxylic acid 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-trifluoromethylphenyl) butyl] piperidine (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthioethyl] piperidine-3-carboxylic acid 3-Carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine-3 (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) -carboxylic acid propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- ( 3-Fluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-Fluorophenylthio) ethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinone) (4-Chloro-4-yl) -propyl] -1- [2- (4-fluoro-phenylthio) -ethyl] -piperidine-3-carboxylic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3] - (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidine-3-carboxylic acid (32 R, 42 R) -4- [3- (2 R, S)] - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenylthio) propyl] piperidine-3-carboxylic acid (32R, 42R) -4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,6-difluorophenylthio) ethyl] piperidine-3-carboxylic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenylthio) propyl] piperidine -3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) (Ethyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (2-Chloro-phenylthio) -propyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl)] propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6) -methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-dichlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2 R, 3 R); S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,6-dichlorophenylthio) ethyl] piperidine-3-carboxylic acid (32) ?, 42?) -4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenylthio) propyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (2S, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2-methyl-phenylthio) -ethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) acid (propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3) (methyl) phenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (3-methylphenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinoline)] In-4-yl) propyl] -1- [2- (4-methylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro] -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (2R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -157

- [2- (3-Trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (3-Trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl -1- [2- (4-Trifluoromethylphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4-) yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4 - [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (4-methoxy-phenylthio) -ethyl] -piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1. - [3- (4-Methoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutyl) ethyl] piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [cyclopentylmethyl] -piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentyl) ethyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclohexylmethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclohexyl) -ethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopropylthio) -ethyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclopropyl-thio) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclobutylthio) -ethyl] -piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclobutylthiopropyl) piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid t

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclohexylthio) -propyl] -piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-methylthiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1

- [2-ethylthioethyl] piperidine-3-carboxylic acid (3R, 4E) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (n- propylthio) ethyl] piperidine-3-carboxylic acid (3E, 4E) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1I

- [3- (n-propylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (n-butylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (β-methoxyquinolin-4-yl) propyl -1- [3- (n-butylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (thien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [4- (thien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3 - (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (5-chlorothien-2-yl) butyl] piperidine-3-carboxylic acid (3E, 4R) -4 - [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (5-chloro-thienyl-2-yl l) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (E, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1-

- [3- (5-Chloro-thien-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (E, S) -Fluoro-3- (6-methoxy-quinoline-4- yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4E) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorothien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-methyl-thien-2-yl) -propyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl) butyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (5-methyl-thien-2) -piperidine-3-carboxylic acid] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-meto) -thioethyl] piperidine-3-carboxylic acid xyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthien-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-3-yl) -propyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (thien-3-yl) butyl] 3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (thien-3-yl)] - piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy) -thioethyl] piperidine-3-carboxylic acid quinolin-4-yl) propyl] -1- [3- (thien-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3 - ( 2R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidine-3-carboxylic acid (32R, 42R) - 4- [3- (2H, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (32) R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] piperidine- (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-3- yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2] - (fur-3-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -F Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- ( 2- (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-carboxylic acid (32 R, 42 R); ) -4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrrol-2-yl) butyl] piperidin-3 (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrole-) -carboxylic acid 2-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (1-Methyl-pyrrol-2-yl) -thiopropyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-carboxylic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro] -3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrrol-3-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxych (4R, 4R) -indolin-4-yl) propyl] -1- [2- (1-methylpyrrol-3-yl) thioethyl] piperidine-3-carboxylic acid ) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -162

- [3- (1,3-thiazol-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4P) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [4- (1,3-thiazol-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S)] -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1,3-thiazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4 - [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) acid] (propyl) piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-Methylimidazol-2-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3 - ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) thi] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (propyl) piperidine-3-carboxylic acid 3-Methylimidazol-4-yl) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylimidazol-4-yl) butyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6) -methoxyquinolin-4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) ) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -propyl] -piperidine-3-carboxylic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-tinolin-4-yl) -propyl] -1- [4- (3-methyl-pyrazol-4-yl) -butyl] -piperidine-3 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methyl-pyrazol-4-yl) -carboxylic acid thioethyl] piperidine-3-carboxylate (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -yl] -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazole) -thiopropyl] -piperidine-3-carboxylic acid -2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] (propyl) -1- [3- (oxazol-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (pyridin-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -4- [3- (pyridin-3-yl) -propyl] -piperidin-3-one (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridin-3-yl) -carboxylic acid] butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridine- 3-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (pyridin-3-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -164

- [3- (pyridin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [4- (pyridin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)] -y1) propyl] -1- [5- (pyridin-4-yl) perityl] piperidine-3-carboxylic acid

(3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyridin-4-yl) -thioethyl] -carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-4-yl) -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidine-) -thiopropyl] -piperidine-3-carboxylic acid 2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (Pyrimidin-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyrimidin-4-yl) -butyl] -piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyrimidin-4-yl) -thioethyl] carboxylic acid piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-) yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidine) -5-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -165

- [4- (pyrimidin-5-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-5-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4-) yl) propyl] -1- [3- (pyrimidin-5-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (pyrazin-2-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrazin-2-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R) S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) propyl] piperidine-3-carboxylic acid

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridazin-3-yl) butyl] piperidine- 3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-3-yl)] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine-3) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1-yl) -thiopropyl] -piperidine-3-carboxylic acid. I. ¹

- [3- (pyridazin-4-yl) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridazin-4-yl) butyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-methoxy-quinolin-4-yl) -propyl] -166

- [3-phenylprop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) (propyl) -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- [ R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) - 4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methyl-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidine -3-carboxylic acid {3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxych) Inolin-4-yl) propyl] -1- [3- (4-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- [R, S] -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2- (trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3- (trifluoromethyl) -phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid ( 3R, 4P) -4- [3- (£, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4- (trifluoromethyl) phenyl) prop-2-ynyl (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methoxy-phenyl)] -piperidine-3-carboxylic acid (Prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (3-methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -167

- [3- (4-Methoxy-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) (propyl) -1- [3- (3,4-difluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3,4-dichloro-phenyl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2,3-dichlorophenyl) prop-2-ynyl] -piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-chlorophenyl) (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-prop-2-ynyl] -piperidine-3-carboxylic acid - (2,4,6-Trichlorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4) -yl) propyl] -1- [3- (3,5-dichlorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2 ynyl] -piperidine-3-carboxylic. (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-4-fluorophenyl) prop- 2-Inyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- ( 2-Chloro-4-fluorophenyl) prop-2-ynyl-piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) ) -propyl] -168

- [3- (3-chloro-5-fluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid i

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop- 2-Inyl] -piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [ 3- (4-Chloro-3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3 - (β-methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-ynyl) piperidine-3-carboxylic acid] (5-Chloro-2-methoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) n-4-yl) propyl] -1- [3- (3,5-bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) pr polyl] -1- [3- (3,5-dimethylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3 - (β-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichloro-6-methylphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3 R, 4 R) - 4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- Chlorothien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (E, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-3-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (l-methylpyrrole-2-yl) pr op-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-Methylpyrrol-3-yl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (1,3-thiazol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1,3-thiazol-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) } -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1,3-thiazol-5-yl) -prop-2- Inyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazole) -2-yl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (β-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) prop-2-ynyl] -piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R) S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid

(3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazole-5-) yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (pyridin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-4-yl) -prop-2-ynyl] -piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -prop-2-ynyl] piperidine -3-Carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl)] prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3-phenylpropen-2-yl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [4-phenylbuten-3-yl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [4-Phenylbutyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) propyl] piperidin-3 -acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-fluorophenol yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-fluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-fluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] 1- [3- (2,3-difluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,3-Difluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6) -difluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,6-difluorophenyl) butyl] piperidine- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) propyl] piperidine-3-acetic acid (3-acetic acid) ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6 -Methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4- chlorophenyl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-methoxy-quinolin-4-yl) _{and the} propyl] -1- [3- (2,3-dichlorophenyl) propyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,3-dichlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,6-dichlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 4- (2-methylphenyl yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [5- (2-methylphenyl) pentyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Me ') Toxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [4- (4-Methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) (propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline) 4-yl (l) propyl] -1- [3- (4-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4] - (4-Methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenyl) propyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-trifluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) 4 E) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-trifluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) (propyl) -1- [3- (4-trifluoromethylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-Trifluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidine-3-acetic acid .

(3R, 4R) -4- [3- (6'-Methoxychirolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-Fluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- ( 3-Fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [3- (2,3-difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [2- (2,6-Difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2 (β-Difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) ethyl] piperidine -3-Acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidine-3-acetic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (4-Chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3-dichlorophenylthio)] ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-dichloro) Phenylthio) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,6-dichlorophenylthio) ethyl] piperidine -3-Acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-dichlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [3- (3-methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 2- (4-Methylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenylthio)] propyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (6-Methoxyquinoline) In-4-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] 1- [3- (2-Trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-Trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (32 R, 42 R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine-3-acetic acid

Ίξ>

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-) yi) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenylthio) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidine -3-Acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutyl) ethyl] piperidin-3-oc (32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclopentylmethyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3] - (6-methoxy-quinolin-4-yl) propyl] -1- [2- (cyclopentyl) ethyl] piperidine-3-acetic acid _t I, (32 ?, 42?) -4- [3- (6-methoxy-quinolin-4 (yl) propyl] -1- [cyclohexylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexyl)] ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropylthio) ethyl] piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] ] -1- [3- (cyclobutylthio propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (Cyclohexylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclohexylthio) propyl] piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-methylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-ethylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-ethylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (n-propylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (n-propylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (n-butylthio) ethyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (n-butylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (thien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (thien-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- ( Thien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) thio] propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) propyl] piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (5-chlorothien-2-yl) butyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (5-chlorothien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chloro-thien-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorothien-2-yl) pr] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorothien-2-yl) butyl] piperidin-3-yl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorothien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4Rj-4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6 -Methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline-4-) yl) propyl] -1- [2- (5-methylthien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (5-Methyl-thien-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-Methylthien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthien) -2-yl) butyl] piperidine-3-acetic acid and (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidine-3-acetic acid {3 R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (shadow-3-yl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (thien-3-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 3- (furr-2-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (fur-2- yl) butyl] piperidine-3-acetic acid (3R, 4S) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidine -3-acetic acid ^1- (3R, 4S) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-2- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] -1H-propyl] piperidine-3-acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (fur-3-yl) butyl] piperidine-3- (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (fur-3-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrrol-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrol-2-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline-4-) yl) propy 1] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [4- (1-methylpyrrol-3-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 2- (1-Methylpyrrol-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- ( 1-methylpyrrol-3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2) (yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (thiazol-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (thiazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R, 4R) (R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) propyl] piperidine-3-acetic acid (32) R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- (4- (3-methylimidazol-4-yl) butyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3] - (3-Methylimidazol-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazole) -4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylpyrazol-4-yl)] butyl] piperidine-3-acetic acid (3R, 4R -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (2- (3-methylpyrazol-4-yl) thioethyl) piperidine-3-acetic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) butyl] pipericin-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl)] Thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidine-3-acetic acid {3R, 4i? ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3] - (pyridin-3-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-3) (yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) propyl] piperidine-3-acetic acid (3R, 4R, 4R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [5- (pyridin-4-yl) pentyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R, 4R) 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (pyrimidin-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidine- 4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-4-yl) thioethyl] piperidine -3-Acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] pip (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -propyl] -piperidine-3-acetic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-5-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-5-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (pyrimidin-5-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- ( Pyrazin-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine-3-acetic acid] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (6-methoxyquinoline In-4-yl-propyl] -1- [4- (pyridazin-3-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [3- (pyridazin-3-yl) -thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- ( pyridazin-4-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridazine) -4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-4-yl)] thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine-3 -acetic acid (32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-acetic acid -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R, 4R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) - 4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] ) propyl] -1- [3- (2-Methyl-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- ( 3-Methyl-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methyl) phenyl] (Prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-4-yl) -propyl] -acetic acid; phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-phenyl) prop-2- Inyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-phenyl) prop-2-ynyl] piperidine-3- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) ) -4 -, [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- (3- (2-chlorophenyl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] ] -1- (3- (3 phenyl) prop-2-ynyl) piperidine-3-acetic acid methylphenyl) (trifluoro (trifluoro (trifluoromethoxymethoxymethoxy4-difluoro4-difluoro4-dichloro-3-dichloro-4-dichloro4,6-tri5-dichloro) (3R, 4 R) -4- [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-5-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-2-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-acetic acid ( 3 R, 4 R) -4- [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine acetic acid -3-Acetic acid (3R, 4R) -4- [3- (6-Methoxyquino) lin-4-yl) propyl] -1- [3- (5-chloro-2-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (3,5-bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6 -Methoxyquinolin-4-yl) propyl] -1- (3- (3,5-dimethylphenyl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- (3- (2,4-dichloro-6-methylphenyl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinoline-4-) yl) propyl] -1- [3- (5-chlorothien-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- (3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3-chlorothien-2-yl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (5-methylthien-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (3-methylthien-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (shadow-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6 -Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [3- (thiazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) -4- yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] 1- [3- (1-Methylimidazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-Methyl-pyrazol-4-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline-4)] -yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-one) - yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-acetic acid {3R, 4R} -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [3- (pyrimidin-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [3- (pyrimidin-5-yl) prop-2-ynyl] piperidin-3-o (3 R, 4 R) -4- [3- (β-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylpropen-2-yl] piperidine-3-acetic acid (32 R, 42 R) -4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-phenylbuten-3-yl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylpropyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-phenylbutyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) propyl] piperidine-3-acetic acid (32 R, 42 R); -4- [ 3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidine-3-acetic acid (32) R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- [R, S] -Hyloxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (3-fluorophenyl) butyl] piperidine -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (4-fluorophenyl) propyl] piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (4-fluoro-phenyl) -butyl] -piperidine-3-acetic acid -acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2,3-difluorophenyl) propyl] piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (2,3-difluoro-phenyl) -butyl] -piperidine-3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2,6-difluorophenyl) propyl] (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy) -piperidine-3-acetic acid quinolin-4-yl) propyl] - [4- (2,6-difluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] - [3- (2-chlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] - [4- (2-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] - [3- (3-chlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] - [4- (3-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4)] -yl) propyl] - [3- (4-chlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] - [4- (4-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] (propyl) - [3- (2,3-dichlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4-) yl) propyl] -1

- [4- (2,3-Dichloro-phenyl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hyloxy-3- (6-methoxy-quinolin-4-yl) propyl] - [3- (2,6-dichlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] - [4- (2,6-dichlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4)] -yl) propyl] - [3- (2-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] - [4- (2-methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] - [5- (2-methylphenyl) pentyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] - [3- (3-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl 4- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (3-methyl-phenyl) -butyl] -piperidine-3-acetic acid] - [3- (4-Methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (4-methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (2-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (3-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (3-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (4-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R) , S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (2-trifluoromethyl (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (trifluoromethyl-phenyl) -propyl] -piperidine-3-acetic acid 3-Trifluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-Trifluoromethylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4 - (4-Trifluoromethylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl]] - 1- [2-Phenylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] -phenylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- ( 2-Fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidin (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-fluoro-phenylthio) -ethyl] -pyridine-3-acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio)] propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) (Ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (3-difluorophenylthio) -ethyl] -piperidine-3-acetic acid (2,3-Difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2 - (2,6-Difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [ 3- (2,6-difluorophenylthio) propyl] piperidine-3-acetic acid (3 R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (2-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (3-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (3-chloro-phenylthio) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (4-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (1,6-methoxyquinolin-4-yl) propyl] - [3- (4-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (2,3-dichloro-phenylthio) -ethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2,3-dichlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -Hydroxy-3- (6-methoxyc Hinolin-4-yl) propyl] - [2- (2, β-dichlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] - [3- (2, β-dichlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] - [2- (2-methylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] - [3- (2-methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-methylphenylthio) ethyl] piperidine-3-acetic acid (3E, 4E) -4- [3- (E, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) ) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (E, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (E, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4P) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (4-methoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [cyclopropylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6) -methoxyquinolin-4-yl) propyl] - [2- (cyclopropyl) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] - [cyclobutylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [ 2- (cyclobutyl) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [cyclopentylmethyl] piperidine -3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (cyclopentyl) -ethyl] -piperidine-3-acetic acid ( 3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [cyclohexylmethyl] -piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (cyclohexyl) -ethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (cyclopropylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (cyclopropylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (cyclobutylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] - [3- (cyclobutylthiopropyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] - [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) -propyl] - [3- (cyklopentylti o) Propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2 (cyclohexylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (cyclohexylthio) propyl] piperidine-3 - (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2-methyl-thioethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3-methylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2-ethyl-thioethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3-ethyl-thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] - [2- (n-propylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] - [3- (n-propylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 methoxyquinolin-4-yl) -propyl] - [2- (n-butylthio (Ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (n-butylthio) (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (thien-2-yl) propyl] piperidine-3-acetic acid (propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (thien-2- yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (thien-2) (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (β-methoxyquinolin-4-yl) -propyl] - [3- (thienyl- thioethyl) -thioethyl] piperidine-3-acetic acid 2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-Chloro-thien-2-yl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (f, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (5-Chloro-thien-2-yl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) (propyl) - [2- (5-chloro-thien-2-yl) -thioethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3] - (6-Methoxyquinolin-4-yl) propyl] - [3- (5-chlorothien-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (3-chlorothien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, (S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (3-chloro-thien-2-yl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (3-chlorothien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (3-chloro-thien-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (5-methyl-thien-2-yl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (5-methylthien-2-yl) butyl] piperidine-3 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (5-methylthien-2-yl) thioethyl] -acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) n-4-yl) propyl] - [3- (5-methylthien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] - [3- (3-methylthien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] - [4- (3-methylthien-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (3-methylthien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (3-methylthien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (shadow-3-yl) -propyl] -piperidine-3-acetic acid (3R, 4R) - 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (shadow-3-yl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (shadow-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (thien-3-y1) thiopropyl] piperidin-3-ol (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (fur-2-yl) -propyl] -piperidine-3-acetic acid -acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (fur-2-yl) butyl] piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (fur-2-yl) -thioethyl] -piperidine-3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (fur-2-yl) -thiopropyl] (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (fur-3-yl) -propyl] -piperidine-3-acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (fur-3-yl)] butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (fur-3-yl) (thioethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (fur-3- yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (1-methylpyrrole) 2-yl) -propyl] (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (1-methyl-pyrrol-2-yl) -piperidine-3-acetic acid] (butyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1- methylpyrrol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (1-Methyl-pyrrol-2-yl) -thiopropyl] -piperidine-3-acetic acid (3F, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- [R, S] -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrrol-3-yl) butyl] piperidine-3-acetic acid ¹ (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrol-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-3-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) 4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl ·) propyl] -1- [3- (thiazol-2-yl) propyl] pipe ridino-3-acetic acid (3R, 4R) -4- [3- (7R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (thiazol-2) (yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- ( thiazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (Thiazol-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (7R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl 1- [3- (1-Methylimidazol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - { R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) thiopropyl] piperidine-3-acetic acid (37 R, 47 R) -4- [3- (7R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-meth) (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-Methylimidazol-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - ( 6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 3R, 3R, 4R)] S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methyl-pyrazol-4-yl) -butyl] -piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylpyrazol-4-yl) thioethyl ] piperidin-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3 methylpyrazol-4-yl) thiopropyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) propyl] selina piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (oxazole) -2-yl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (oxazol-2-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S)] -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (4- (pyridin-2-yl) butyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3-acetic acid (32R, 42R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine (3 R, 4 R) -4- [3- (2 R, 5 S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridine-) amino-3-acetic acid] 3-yl) propyl] piperidine-3-acetic acid

100 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyridin-3-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (pyridin-3) (3R, 4R) -4-, [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (1-yl) -thioethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridin-3-yl) -thiopropyl] -piperidine-3-acetic acid (pyridin-4-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyridin-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) (propyl) - [5- (pyridin-4-yl) pentyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] - [2- (pyridin-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] - [3- (pyridin-4-yl) thiopr (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) -propyl] - [3- (2-methyl-piperidin-3-acetic acid)] pyrimidin-2-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyrimidin-2-yl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] - [2- (pyrimidin-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-4-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R) R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyrimidin-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1

[2- (pyrimidin-4-yl) thioethyl] piperidine-3-acetic acid

101 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyrimidin-4-yl) -thiopropyl] -piperidine-3- acetic acid

I (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyrimidin-5-yl) -propyl] -piperidin-3- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyrimidin-5-yl) butyl] piperidine- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (pyrimidin-5-yl) -thioethyl] -piperidine-3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyrimidin-5-yl) -thiopropyl] (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyrazin-2-yl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (pyrazin-2-yl)] - piperidine-3-acetic acid butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [2- (pyrazin-2-yl) (Thioethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrazine-2-) yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinone) (4-Chloro-4-yl) -propyl] - [3- (pyridazin-3-yl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] - [4- (pyridazin-3-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] - [2- (pyridazin-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] - [3- (pyridazin-3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] - [3- (pyridazin-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-methoxy-quinolin-4-yl) propyl] -1

- [4- (pyridazin-4-yl) butyl] piperidine-3-acetic acid

102 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1

- [2- (pyridazin-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl ] -1

- [3- (pyridazin-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl ] -1

- [3-phenylprop-2-ynyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl]] - 1

- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) ) propyl] -1

- [3- (3-Fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) ) propyl] -1

- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxy-quinolin-4-yl) propyl] -1

- [3- (3-Chloro-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) ) propyl] -1

- [3- (4-Chloro-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) ) propyl] -1

- [3- (2-Methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxy-quinolin-4-yl) propyl] -1

- [3- (4-Methyl-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) ) propyl] -1

- [3- (2- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1

- [3- (3- (Trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) 4-yl) propyl] -1

103

- [3- (4- (Trifluoromethyl) phenyl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- (3- (2-methoxyphenyl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3,4-difluorophenyl) prop-2-ynyl) -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,4-difluorophenyl) prop-2-ynyl) - piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3,4-dichlorophenyl) (Prop-2-ynyl) -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- ( 3- (2,3-Dichloro-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-meth) oxyquinolin-4-yl) propyl] -1- (3- (2,4-dichlorophenyl) prop-2-ynyl) -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4,6-trichlorophenyl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) - 4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- (3- (3,5-dichlorophenyl) prop-2-ynyl) piperidine-3- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-chloro-3-fluorophenyl) -propoxy] -acetic acid -2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3 - (3-Chloro-4-fluorophenyl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (2-chloro-4-fluorophenyl) prop-2-ynyl] -piperidine-3-acetic acid

104 (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- chloro-5-fluorophenyl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline) n-4-yl) propyl] -1- [3- (4-chloro-2-fluorophenyl) prop-2-ynyl] -piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-fluoro-4-methyl-phenyl) -prop-2-ynyl] -piperidine- 3-Acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- ( 4-Chloro-3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop (2 R, 4 R) -4- [3- (2 R, 5 S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-ynyl] piperidine-3-acetic acid 3- (5-chloro (R-2-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [3- (3,5-bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3] - (2R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3,5-dimethyl-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichloro-6-methylphenyl) (Prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (Thien-2-yl) prop-2-ynyl] piperidine-3-acetic acid

105 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -prop] (2R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -2-ynyl] -piperidine-3-acetic acid - 1- [3- (3-Chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-thien-2-yl) -prop-2-ynyl] -piperidin-3 -acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) (Prop-2-ynyl) piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, 5 S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (1-Methyl-pyrrol-2-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) - 4- [3- (2R, S) -Hydroxy-3- (6-methoxy) quinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 4R, 4R)] S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidine-3 -acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazole-2) -yl) prop-2-ynyl] -piperidine-3-acetic acid, 4- (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (3-methylimidazol-4-yl) prop-2-ynyl] -piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) 1-Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -prop-2-ynyl] -piperidine-3-acetic acid (32? 4 R - 4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid

106 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (oxazol-4-yl) -prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (oxazol-5-yl) prop (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridine- 2-ynyl) -piperidine-3-acetic acid] 2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [ 3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyridin-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy- 3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-5-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3 (R, S 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrazin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3] - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridazin-3-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridazin-4-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [3-phenyl-propen-2-yl] -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] - [4-phenyl-buten-3-yl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-phenyl-propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4-phenyl-butyl] -piperidine-3-acetic acid

107 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2-fluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (2-fluoro-phenyl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (3-fluoro-phenyl) -propyl] -piperidine-3-acetic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (3-fluorophenyl) butyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- (4-fluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (4-fluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (2,3-difluorophenyl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (2,3-difluorophenyl) butyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3] - (2,6-Difluorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [ 4- (2,6-Difluorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- (2-Chloro-phenyl) -propyl] -piperidine-3-acetic acid i

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [4- (2-chloro-phenyl) -butyl] -piperidine-3-acetic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (3-chloro-phenyl) -propyl] -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (3-chlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] piperidine-3-acetic acid

108 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-chloro-phenyl) -butyl] -piperidine-3- (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (2,3-dichlorophenyl) propyl] acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (2,3-dichloro-phenyl) -piperidine-3-acetic acid (butyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2, 2, 3, 4R) 6-Dichlorophenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6-Dichlorophenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-Methyl-phenyl) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1 - [4- (2-Methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [5- (2-Methyl-phenyl) -pentyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline) -4-yl) propyl] -1- [3- (3-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6 -methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-methylphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidine-3-acetic acid

109 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -propyl] -piperidin-3-acetic acid -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-methoxyphenyl) butyl] piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-trifluoromethyl-phenyl) -propyl] -piperidine-3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-trifluoromethylphenyl) butyl] ] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenyl)] propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-trifluoromethylphenyl) (butyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4- trifluoromethylphenyl) propyl] piperidine-3-acetic acid (3R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-trifluoromethyl-phenyl) -butyl] -piperidine-3-acetic acid (3) R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R / S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-fluoro-phenylthio) -propyl] -piperidine-3-acetic acid (3R, 4R) - 4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine-3-acetic acid

110 (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [2- (4-fluorophenylthio) ethyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-fluoro-phenylthio) -propyl] -piperidine-3-acetic acid -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,3-difluorophenylthio) piperidine-3-acetic acid) (propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (2 6-Difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-Difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-Chloro-phenylthio) -ethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1 - [3- (2-Chloro-phenylthio) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -F Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (3-chlorophenylthio) ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine-3-acetic acid (3'R, 4R) -4- [3 - ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-dichlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (2,3-dichloro-phenylthio) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- (2- (2,6-dichlorophenylthio) ethyl] piperidine-3-acetic acid

111 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2,6-dichlorophenylthio) -propyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2-methyl-phenylthio) -ethyl] -piperidine-3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methyl-phenylthio) -ethyl] -piperidine-3-acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenylthio)] propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-methylphenylthio) (Ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4- methylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-trifluoromethyl-phenylthio) -ethyl] -piperidine-3-acetic acid methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6 -methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -4- [2- (4-trifluoromethylphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine-3-acetic acid

112 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methoxy-phenylthio) -ethyl] -piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methoxy-phenylthio) -propyl] -piperidine-3-acetic acid -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenylthio) -propyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [cyclopropylmethyl] -piperidine-3-acetic acid -3-acetic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclobutyl) -ethyl] -piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -I- [cy Clopentylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentyl) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [cyclohexylmethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclohexyl) -ethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopropylthio) -ethyl] -piperidine-3-acetic acid ( 3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidine-3-acetic acid

113 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclobutyl-thiopropyl] -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid (3R, 4 R) -4- [3- {R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidine-3-acetic acid ¹ (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclohexylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-methyl-thiopropyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R) (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-ethylthioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3-ethylthiopropyl] pipe ridino-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (n-propylthio) ethyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (n-propylthio)] piperidin-3-acetic acid propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (n-butylthio) (Ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (n- butylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiene) (2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4] - (Shadow-2-yl) butyl] piperidine-3-acetic acid

114 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (thien-2-yl) -thioethyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-2-yl) -thiopropyl] -acetic acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5- Chlorothien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [ 4- (5-Chloro-thien-2-yl) -butyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl -1- [2- (5-chloro-thien-2-yl) -thioethyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline-) 4-yl) propyl] -1- [3- (5-chlorothien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R _of S)] -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-chlorothien-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4 - [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -thiopropyl] -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) propyl] piperidine-3 -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl)] butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (5-methylthien) -2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (5-methylthien-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1

[3- (3-Methyl-thien-2-yl) -propyl] -piperidine-3-acetic acid

115 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthien-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien- 2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (3-methylthien-2-yl) thiopropyl] piperidine-3-acetic acid {3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinoline-4)] (yl) propyl] -1- [3- (thien-3-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [4- (thien-3-yl) butyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro] -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (shadow-3-yl) thiopropyl] piperidine-3-acetic acid (32 R, R); 42-) 4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) propyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-2- yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (fur-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline) n-4-yl) propyl] -1- [3- (fur-2-yl) thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3 - ( 2- (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-3-yl) butyl] piperidine-3-acetic acid (32 R, 42 R); R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (fur-3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (fur-3-yl) -thiopropyl] piperidine-3-acetic acid

116 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-propyl) piperidine-3-acetic acid] (methyl-pyrrol-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (1-Methylpyrrol-2-yl) thioethyl] piperidine-3-acetic acid ¹ (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (1-methylpyrrol-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrrol-3-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (1-methyl-pyrrol-3-yl) -thioethyl] -piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (l-methylpyrrole-3-yl) thiopropyl] piperidine-3-acetic acid acidly to (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thiazol-2-yl) -propyl] -piperidine- 3-Acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (thiazol-2-yl)] butyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thiazole- 2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (Thiazol-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (1-Methylimidazol-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6) -methoxyquinolin-4-yl) propyl] -1- [2- (1-methylimidazol-2-yl) thioethyl] piperidine-3-acetic acid

117 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-imidazol-2-yl) -thiopropyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-imidazole-4) -piperidine-3-acetic acid] (yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- ( 3-Methylimidazol-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (3-Methylimidazol-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] (propyl) -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methylpyrazol-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylpyrazol-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) thiopropyl] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazol-2-yl) -piperidine-3-acetic acid (propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (oxazole- 2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) -thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (pyridin-2-yl) propyl) piperidine-3-acetic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidine-3-acetic acid

118 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [2- (pyridin-2-yl) -thioethyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridin-2-yl) -thiopropyl] -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] - [3- (pyridin-3-yl)] - piperidine-3-acetic acid (propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyridine-3- yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl]] - [2- (pyridine- 3-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyridine) -3-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- ( pyridin-4-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [4- (pyridin-4-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquino) lin-4-yl) propyl] - [5- (pyridin-4-yl) pentyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6 -methoxyquinolin-4-yl) propyl] - [2- (pyridin-4-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] - [3- (pyridin-4-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3] - (6-Methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] - [4- (pyrimidin-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] - [2- (pyrimidin-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - [3- (pyrimidin-2-yl) thiopropyl] piperidine-3-acetic acid

119 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) propyl] ] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-4-yl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-4-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S)] - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-5-yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-5-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) R - 4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) n-4-yl) propyl] -1- [3- (pyrimidin-5-yl) thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) propyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrazin-2-yl) butyl] piperidine-3-acetic acid (3R, 4R) R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 '- [3- (pyrazin-2-yl)] Thiopropyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- ( pyridazin-3-yl) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [4- (pyridazin-3-yl) butyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4) -yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidin-3-acet onic acid

120 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-3-yl) -thiopropyl] -piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-4-yl) -propyl] -acetic acid piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyridazine-4-) yl) butyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazine) -4-yl) thioethyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (pyridazin-4-yl) thiopropyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3-phenylprop-2-ynyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6) -me Toxinquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidin-3-acetic acid (3R, 4R) -4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-chloro-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenyl) -prop-2-ynyl] acid piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) prop -2-ynyl] piperidine-3-acetic acid

121 (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2- (trifluoromethyl) phenyl)] prop-2-ynyl] -piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (3- (Trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6? -methoxyquinolin-4-yl) propyl] -1- [3- (4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-acid] -inyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (β-methoxyquinolin-4-yl) propyl] -1- [3- ( 3,4-Difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4 [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,4-dichlorophenyl) prop- 2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- (3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [3] - (2,3-Dichloro-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- (3- (2,4-dichlorophenyl) prop-2-ynyl) piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,4,6-trichlorophenyl) prop-2-ynyl) piperidine-3-acetic acid (32 R, 42 R) - 4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3,5-dichlorophenyl) prop-2-ynyl) piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4 chloro-3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid

122 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-4-fluorophenyl) -acetic acid prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-Chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-5-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-2-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-fluoro-4-methyl-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R) 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) prop- 2-Inyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid n-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-2-methoxy-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [3- (3,5-bis (trifluoromethyl) phenyl) prop-2- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1123-piperidin-3-acetic acid

- [3- (3,5-Dimethyl-phenyl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4S) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (2,4-dichloro-6-methylphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4S) -4- [3- (7H-4-yl) -propyl] -piperidine-3-acetic acid (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1I

- [3- (Thien-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (7R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (5-chlorothien-2-yl) prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (75 (S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -prop-2-ynyl] -piperidine-3-acetic acid (37? 42-) - 4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-methyl-thien-2-yl) -prop-2- Inyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (7R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-Methyl-thien-2-yl) -prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (thien-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) 1-Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-2-yl) -prop-2-ynyl] -piperidine-3-acetic acid (32 R, 42) R - 4- [3- (2 R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-3-yl) -prop-2-ynyl] ] -piperidin idin-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazole- 2-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (Thiazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 7R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) prop-2-ynyl] -piperidine-3-acetic acid ( 32 R, 47 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) prop 2-ynyl] -piperidine-3-acetic acid

124 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -acetic acid] prop-2-ynyl] -piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [ 3- (2R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazol-5-yl) -prop-2-ynyl] -piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl)] prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- (3- (pyridin-4-yl) prop-2-ynyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (2 ?, S) Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidin-3-acetic acid (32 R, 42 R); ) -4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidine- 5-yl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (pyrazin-2-yl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] piperidine-3-acetic acid ( 32 R, 42 R) -4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylpropen-2-yl] piperidine -3-acetic acid

125 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4-phenyl-buten-3-yl] -piperidin-3- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3-phenyl-propyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-phenylbutyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [3- (2-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [3- (4-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (4-fluorophenyl) butyl] piperidine- 3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2,3-difluorophenyl) propyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- (4- (2,3-difluorophenyl)) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-

(Difluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (4- (2 (6-Difluorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-Chloro-phenyl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- (3- (6-Methoxy-quinolin-4-yl) -propyl) -1- (4- (2-Chloro-phenyl) -butyl] -piperidin-3-yl} -propan-1-enoic acid

126 (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidin-3-yl} propan-1- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (3-chloro-phenyl) -butyl] -piperidin-3-yl} -propan-1-acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-chloro-phenyl) -propyl] -piperidin-3-yl] -propan-1-acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (4-chloro-phenyl) -butyl] -piperidin-3-yl} -propane- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2,3-dichloro-phenyl) -propyl] -piperidin-3-yl} -acetic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,3-dichlorophenyl) butyl] piperidine-3- yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2,6-dichlorophenyl) propyl] piperidine- 3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2,6-dichlorophenyl) butyl] (3R, 4R) -3- {4- [3- (6-Methyl) -piperidin-3-yl} -propan-1-ynoic acid oxyquinolin-4-yl) propyl] -1- (3- (2-methylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6- Methoxyquinolin-4-yl) propyl] -1- (4- (2-methylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- (5- (2-methylphenyl) pentyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- (3- (3-methylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- (4- (3-methylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- (3- (4-methylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6- Methoxyquinolin-4-yl) propyl] -1- [4- (4-methylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid

127 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methoxy-phenyl) -propyl] -piperidin-3-yl} -propan-1-one (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R / 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methoxy-phenyl) -propyl] -piperidin-3-yl] -propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methoxy-phenyl) -butyl] -piperidin-3-yl} -propan-1- (3R, 4R) -3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -propyl] -piperidin-3-yl} -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (4-methoxy-phenyl) -butyl] -piperidin-3-yl} -propane- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2-trifluoromethyl-phenyl) -propyl] -piperidin-3-yl} -propanoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (2-trifluoromethyl-phenyl) -butyl] -piperidin-3-yl} -acetic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinoline-4) -propan-1-enoic acid) -yl) propyl] -1- [3- (3-trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- -yl) propyl] -1- [4- (3-trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [3- (4-trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [4- (4-trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-) yl) propyl] -1- [3-phenylthiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [2- (2-Fluorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid

128 (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidin-3-yl} propan-1- (3R, 4R) -3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (3-fluoro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-acid (3R, 4R) -3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-fluoro-phenylthio) -propyl] -piperidin-3-yl} -propane- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (4-fluoro-phenylthio) -ethyl] -piperidin-3-yl) -propanoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-fluoro-phenylthio) -propyl] -piperidin-3-yl} -acetic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidine-3- yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenylthio) propyl] piperidine- 3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,6-difluorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R) 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid

129 (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (2- (2,3-dichlorophenylthio) ethyl] piperidin-3-yl) propan-1 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2,3-dichloro-phenylthio) -propyl] -piperidin-3-yl} -propanoic acid (1R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,6-dichlorophenylthio) ethyl] piperidine- 3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2,6-dichlorophenylthio)) propyl] piperidin-3-yl (propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio)] ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio)] (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [2- (3-methylphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenylthio)] propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4)] -yl) propyl] -1- (2- (4-methylphenylthio) ethyl] piperidin-3-yl) propan-1-ynoic acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4)) -yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4)) -yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (6-methoxyquinolin-4)) -yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- (2- (3-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid

130 (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidin-3-yl} propan-1- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (2-methoxy-phenylthio) -ethyl] -piperidin-3-yl} -propan-1- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methoxy-phenylthio) -propyl] -piperidin-3-yl} -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methoxy-phenylthio) -ethyl] -piperidin-3-yl} -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methoxy-phenylthio) -propyl] -piperidin-3-yl] -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (4-methoxy-phenylthio) -ethyl] -piperidin-3-yl} -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenylthio) -propyl] -piperidin-3-yl} -propan-1- acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) 3- {4- [3- (6-methoxy-quinolin-4-y1) p Ropyl] -1- [2- (cyclopropyl) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclobutylmethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- ( (cyclobutyl) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl)] propyl] -1- [cyclopentylmethyl] piperidine- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopentyl) -ethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [cyclohexylmethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclohexyl) -ethyl] -piperidin-3-yl} -propan-1-enoic acid

131 (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropylthio) ethyl] piperidin-3-yl} propan-1-one (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidin-3-yl} propane acid (1 R, 4 R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclobutyl-thiopropyl] -piperidine-3- (1 R, 4 R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidin-3-yl} propan-1-enoic acid -yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio)] propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) (Ethyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclohexyl) -propyl] -1- xylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [2-methylthioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [3-Methylthiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-ethylthioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- [4- [3- (6-Methoxyquinolin-4-yl) propyl] [3-ethylthiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl)] - 1 '; yl) propyl] -1- [2- (n-propylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (6-Me) (4-oxoquinolin-4-yl) propyl] -1- [3- (n-propylthio) propyl] piperidin-3-yl) propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (n-butylthio) ethyl] piperidin-3-yl} propan-1-enoic acid

132 (3R, 4R) -3 - (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (n-butylthio) propyl] piperidin-3-yl} propane-1- (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [3- (thien-2-yl) propyl] piperidin-3-yl] propane acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (thien-2-yl) butyl] piperidin-3-yl] -1-acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (shadow-2-yl) thioethyl] piperidin-3} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (thien-2-yl) -thiopropyl] -piperidine-yl} -propan-1-ynoic acid 3-y1} -propan-1-oic acid (3 R _Z 4 R) -3- (4- [3- (6-methoxy-quinolin-4-yl) propyl] -l- [3- (5-chloro-thienyl-2-yl (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (5-chlorothiene) propyl] piperidin-3-yl} propan-1-enoic acid (2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (5-Chloro-thien-2-yl) -thioethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -thiopropyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-methoxy-quinoline-4-) yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6) (3R, 4R) -3- (4-Methoxy-quinolin-4-yl) -propyl] -1- [4- (3-chloro-thien-2-yl) -butyl] -piperidin-3-yl} -propan-1-enoic acid 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (3-chlorothien-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) ) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (5-methylthien-2-yl) propyl) piperidin-3-yl (propan-1-enoic acid) (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (5-methylthien-2-yl) butyl] piperidin-3-yl} propane- 1-Acetic acid

133 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (5-methyl-thien-2-yl) -thioethyl] -piperidin-3-yl} -propane (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (5-methyl-thien-2-yl) -thiopropyl] -piperidin-3-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-thien-2-yl) -propyl] -yl} -propan-1-yl (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methyl-thieno-)] - piperidin-3-yl} -propan-1-enoic acid 2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-Methylthien-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1 - [3- (3-Methyl-thien-2-yl) -thiopropyl] -piperidin-3-yl] -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl)] propyl] -1- [3- (thien-3-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline-4- yl) propyl] -1- [4- (thien-3-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline- 4-yl) propyl] -1 - [2- (Thien-3-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (fur-2-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-one) yl) propyl] -1- [4- (fur-2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6) (Methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] piperidin-3-yl} propan-1-enoic acid

134 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (fur-3-yl) -butyl] -piperidin-3-yl-propan-1-one (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (fur-3-yl) -thioethyl] -piperidin-3-yl} -propan-1 acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-3-yl) -thiopropyl] -piperidin-3-yl} -propan-1-acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-2-yl) -propyl] -piperidin-3-yl-acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (1-methylpyrol-2-yl) butyl] piperidine] propan-1-ynoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrol-2-yl) (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrole) -thioethyl] -piperidin-3-yl} -propan-1-ynoic acid (2-yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-Methyl-pyrrol-2-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1 - [4- (1-m (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [ethyl-pyrrol-3-yl] -butyl] -piperidin-3-yl} -propan-1-enoic acid 2- (1-Methylpyrrol-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-Methyl-pyrrol-3-yl) -thiopropyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4- y1) propyl] -1- [3- (thiazol-2-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinoline- 4-yl) propyl] -1- [4- (thiazol-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (thiazol-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid

135 [3R, 4R} -3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-imidazol-2-yl) -propyl] -piperidin-3-yl} (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (1-methyl-imidazol-2-yl) -butyl] -piperidin-1-enoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (1-methyl imidazole-2- y1) Thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1- methyl imidazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-Methyl-imidazol-4-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl)] propyl] -1- [4- (3-methylimidazol-4-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4 - [3- (β-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidin-3-yl} prop n-1-Acetic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methyl pyrazol-4-yl) propyl] piperidine (3 R, 4 R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [4- (3-methyl-pyrazole-) -3-yl} -propan-1-enoic acid 4-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- ( 3-Methyl-pyrazol-4-yl) -thioethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1 - [3- (3-Methyl-pyrazol-4-yl) -thiopropyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4)] -yl) propyl] -1- [3- (oxazol-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid

136 (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidin-3-yl} propane- (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-2-yl) -propyl] -piperidin-3-yl-1-acid (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [4- (pyridin-2-yl) butyl] piperidin-3) propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [2- (pyridin-2-yl) -thioethyl] -piperidine] -yl} -propan-1-enoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-3-yl)] - piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridin-3) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [2- (pyridine) butyl] piperidin-3-yl} propan-1-enoic acid -3-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (PYR (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3-pyridin-3-yl] -propyl] -piperidin-3-yl} -propan-1-ynoic acid - (pyridin-4-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (Pyridin-4-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [5- (Pyridin-4-yl) pentyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyridin-4-yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4)] yl) propyl] -1- [3- (pyrimidin

-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid

137 (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-2-yl) butyl] piperidin-3-yl (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine} propan-1-enoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2)] (yl) -thiopropyl-piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-4-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinoline-4-) yl) propyl] -1- [2- (pyrimidin-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3] - (6-Methoxyquinolin-4-yl) propyl -1- [3- (pyrimidin-5-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4)] (yl) propyl] -1- [4- (pyrimidin-5-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (6 (Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-5-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5-yl) -thiopropyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) - 3- (4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrazin-2-yl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3 R, 3 R, 3 R) 42-) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyrazin-2-yl) butyl] piperidin-3-yl} propan-1- (3R, 4R) -3- (4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- [2- (pyrazin-2-yl) thioethyl] piperidine-3-) yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl)] Thiopropyl] piperidin-3-yl} propan-1-enoic acid

138 (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) propyl] piperidin-3-yl} propane (1R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridazin-3-yl) butyl] piperidin-3-one acid (R) - (R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] -yl} propan-1-enoic acid piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazine-3) (yl) -thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [4- (pyridazin-4-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (6-methoxyquinoline) 4-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6'-Methoxyquinolin-4-yl) propyl] - 1- [3-Phenylprop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] 1- [3- (2-Fluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- (3- (6-methoxy-quinoline) 4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- (4 - [3]) - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2-chloro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid (3 R, 3 S, 2 S); 42-) 3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1- (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine-3-ynoic acid yl} propan-1-enoic acid

139 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methyl-phenyl) -prop-2-ynyl] -piperidin-3-yl (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenyl) -prop-2-ynyl] -piperidine} propan-1-enoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenyl) prop- 2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2 - (Trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1- [3- (3- (Trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) - 3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid to (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidin-3-yl} propane (1R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,4-difluorophenyl) prop-2-ynyl] piperidine-1-acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop -2-ynyl-piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3 (4-Dichlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (5-Methoxyquinolin-4-yl) propyl] - 1- [3- (2,3-Dichloro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinoline- 4-yl) propyl] -1- [3- (2,4-

-dichlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid

140 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (2,4,6-trichloro-phenyl) -prop-2-ynyl] -piperidin-3 (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,5-dichlorophenyl) prop] -yl} propan-1-enoic acid -2-ynyl-piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -chloro-3-fluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid -1- [3- (3-chloro-4-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (β) -Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chloro-5-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (4-chloro-2-fluoro-phenyl) -prop-2-ynyl] -piperidin-3- yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop- 2-in yl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro- 3- (Trifluoromethyl) phenyl) prop-2-ynyl-piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-Chloro-4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R) , 4 R) -3- {4- [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (5-chloro-2-methoxyphenyl) prop-2-ynyl] piperidine-3-yl} (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl]] - 1- (3- (3,5-bis (trifluoromethyl) -phenyl) -phenyl) -propan-1-enoic acid (2-ynyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] - (5-dimethyl-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid 1- [3- (2,4-Dichloro-6-methyl-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3 R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidin-3-yl} propane (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -prop-2-ynyl] -acetic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2)] - piperidin-3-yl} -propan-1-ynoic acid -yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 3- (5-Methyl-thien-2-yl) -prop-2-ynyl-piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinoline-4- yl) propyl] -1- [3- (3-methylthien-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (1-methylpyrrole-2-yl) prop-2-ynyl] piperidine-3-yl} propan-1-oic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-3-yl) -prop-2-ynyl] -piperidin-3 acid (3R, 4R) -3- {4- [3- (6-M-1-yl) -propan-1-enoic acid] ethoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) 3- (4- [3- (6-methoxy-quinolin-4-yl) propyl] -l- [3- (thiazol-5-yl) prop-2-ynyl] piperidine-3-yl} propan-1-oic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-imidazol-2-yl) -prop-2-ynyl] -piperidin-3 acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-imidazol-4-yl) -prop-1-yl] -propan-1-yl} -prop -2-ynyl] piperidin-3-yl} propan-1-enoic acid

142 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -prop-2-ynyl] -piperidin-3 (3R, 4R) -3- {4- [3- (β-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (oxazol-4-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [yl] -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid 3- (oxazol-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidin-3-yl] propan-1-one acid (3R, 4 R) -3- {4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) prop-2-ynyl] piperidin-3-yl] propan-1 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -prop-2-ynyl] -piperidin-3-acid (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrazin-2-yl) -prop-2-yl] -propan-1-yl} -propan-2-yl (3R, 4R) -3- (4- [3- (6-Methoxyquinolin-4-yl) -propyl] -1- [3- (pyridazine-3-yl) -piperidin-3-yl} -propan-1-ynoic acid) (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [yl] -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid 3- (pyridazin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylpropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) ) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl]

-1- [4-phenylbutyl] piperidin-3-yl} propan-1-enoic acid

143 (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2R, 4R) -3- {4- [3- (2R, 5S) -Hydroxy-3- (6-methyl) -propyl] piperidin-3-yl) propan-1-enoic acid (4-Oxoquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-fluorophenyl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3 R) (Fluorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4)] - -yl) propyl] -1- [3- (4-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, 2 R, R 3 -alkyl)] S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) propyl] piperidine-3- yl} propan-1-ol (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,3-Difluorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6? -methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [ 3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6-difluorophenyl) butyl] piperidin-3-yl (32 R, 42 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3]} propan-1-enoic acid - (2-Chloro-phenyl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6- Methoxyquinolin-4-yl) propyl] -1- [4- (2-chlorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) propyl] piperidin-3-yl} propane (1 R, 4 R) -3- (4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1-acid

-1- [4- (3-chlorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R) S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-chlorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) 3- (4- (3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,3-dichlorophenyl) propyl] piperidin-3-yl (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (4- (2) -propan-1-enoic acid) (3-Dichloro-phenyl) -butyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinoline-4- yl) propyl] -1- (3- (2,6-dichlorophenyl) propyl] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S)) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6-dichlorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidin-3-yl} propan-1 -about (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [4- (2-methylphenyl) butyl] acid) (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (piperidin-3-yl) -propan-1-enoic acid [5- (2-Methyl-phenyl) -pentyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinoline)) -4-yl) propyl] -1- [3- (3-methylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-methylphenyl) propyl] piperidin-3-y1) propan-1 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4-methyl-phenyl) -butyl] -acetic acid piperidin-3-yl (propan-1-enoic acid)

145 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -piperidin-3-yl} -propyl -1- [4- (2-methoxyphenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) ) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -propyl] -piperidin-3-yl} (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (4- methoxyphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (2-Trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-o (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (2-trifluoromethyl-phenyl) -butyl] -acetic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1-piperidin-3-yl} -propyl] -1 - [3- (3-Trifluoromethyl-phenyl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid.

(3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-trifluoromethyl-phenyl) -propyl] -piperidine- (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4-yl} -propan-1-ynoic acid - (4-Trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4)] yl) propyl] 146

-1- [2-Phenylthioethyl] piperidin-3-yl) propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidin-3-yl} propan-1 (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3- Fluorophenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- ( 4-Fluorophenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- ( 2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid '.

(3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,6-difluorophenylthio) (Ethyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] (propyl) -1- [3- (2,6-difluorophenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (2R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2-chloro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid

147 (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (2-chlorophenylthio) propyl] (3R, 4R) -3- (4- [3- [R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (piperidin-3-yl) -propan-1-enoic acid (2- (3-Chloro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidin-3-yl} -propan-l (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2,3-dichloro-phenylthio) -acetic acid (Ethyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,3-dichlorophenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3) - (6-metoxychinolín- 4-yl) propyl] -1- (2- (2,6-dichlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R) (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,6-dichlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidin-3 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-] -yl} -propan-1-enoic acid (2-Methylphenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4-) yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid

148 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenylthio) -propyl] -piperidine -3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 2- (4-Methylphenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propanedioic acid (3R, 4R) -3- ( 4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-y1) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidin-3-y1} -propan-1-oic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-trifluoromethyl-phenylthio) -ethyl] -piperidine -3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (3-Trifluoromethyl-phenylthio) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hyd Roxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propanedioic acid (3R, 4R) -3- {4 - [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (4-trifluoromethyl-phenylthio) -propyl] -piperidin-3-yl) -propan-1-acid (3 R, 4 R) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-y1) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-yl} -propan-1-ynoic acid - (2-Methoxyphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid

149 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methoxy-phenylthio) -ethyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- ( 3- (3-Methoxy-phenylthio) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinoline- 4-yl) propyl] -1- (2- (4-methoxyphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (β-methoxyquinolin-4-yl) propyl] -1- (3- (4-methoxyphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- { 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [cyclopropylmethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) - 3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopropyl) -ethyl] -piperidin-3-yl} -propan-1- (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [cyclobutylmethyl] -piperidin-3-yl} -propanoic acid (1R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclo butyl) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) 1- (Cyclopentylmethyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4-)) yl) propyl] -1- (2- (cyclopentyl) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [cyclohexylmethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S)) -Hydroxy-3- (β-methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexyl) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopropylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] 150

-1- [3- (cyclopropylthio) propyl] piperidin-3-yl) propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (cyclobutylthio) ethyl] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- {4- [3- (R), (S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclobutylthiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- { 4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclopentylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid ( 3R, 4P) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidin-3-yl (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclohexylthio) -propan-1-enoic acid} (Ethyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cyclohexylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2-methylthioethyl] piperidin-3-yl} propan-1-enoic acid {3R, 4R) -3- (4- [3- (F, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-methyl-thiopropyl] -piperidin-3-yl} - { (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2-ethyl-thioethyl] -piperidine-1-propanoic acid -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S} -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3-ethylthiopropyl, piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [2- (n-propylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, R)] S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (n-propylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-y1) propyl] -1- [2- (n-butylthio) ethyl] piperidin-3-yl} propan-1 (3 R, 4 R) -3- [4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (n- butylthio) propyl] piperidin-3-yl} propan-1-enoic acid

151 (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-2- yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [4- (thien-2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy] -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- (4- [3- (2H, S) -Hydroxy-3- (β-methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) thiopropyl] piperidine-3- yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- ( 3- (5-Chloro-thien-2-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (2R, S) -Hydroxy- 3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (5-chlorothien-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (5-chloro-thien-2-yl) -thioethyl] -piperidine-3 yl} -propan-l-s (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothiene-) - 2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid

II _(· '''' and (32?, 42?) - 3- {4- [3- (2, S) -hydroxy-3 - (6-methoxy-quinolin-4-yl) propyl] -1- [ 4- (3-Chloro-thien-2-yl) -butyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorothien-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-chloro-thien-2-yl) -thiopropyl] -piperidin-3 -yl} propan-1-enoic acid

152 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-methyl-thien-2-yl)] (3 R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl) -propyl] -piperidin-3-yl} -propyl -1- [4- (5-methylthien-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (5-methylthien-2-yl) thioethyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) - 3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-methyl-thien-2-yl) -thiopropyl] -piperidine-3- yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- ( 3-Methyl-thien-2-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinoline) -4-yl) propyl] -1- [4- (3-methylthien-2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxyquinoline holin-4-y1) propyl] -1- [3- (3-methylthien-2-yl) thiopropyl] piperidin-3-yl} -propan-l-oic acid, ^'first

(3 R, 4 R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-y1) propyl] -1- [3- (thien-3-yl) propyl] (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (piperidin-3-yl) -propan-1-ynoic acid [4- (Shadow-3-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6) -methoxyquinolin-4-yl) propyl] -1- [2- (shadow-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-3-yl) -thiopropyl] -piperidin-3-yl} -propan-1-enoic acid

153 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-2-yl) -propyl] (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [4- (fur-2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3 - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-2-yl) -thiopropyl] -piperidin-3-yl} -propan-1-enoic acid ( 3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-3-yl) -propyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 4- (fur-3-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (fur-3-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- ( R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (fur-3-yl) -thiopropyl] -piperidine-3- (1R) 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- ( 1-Methyl-pyrrol-2-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinoline) -4-yl) propyl] -1- [4- (1-methylpyrrol-2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (1-methyl-pyrrol-2-yl) -thioethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-pyrrol-2-yl)] Thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl]

-1- [3- (1-methylpyrrol-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid

154 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (1-methyl-pyrrol-3-yl) (butyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (1-methylpyrrol-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) -propyl] -piperidin-3-yl} -propan (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (thiazol-2) -acetic acid] (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) butyl) piperidin-3-yl] propan-1-ynoic acid propyl] -1- [2- (thiazol-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy) -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- { 4- [3- (R, S) -hydroxy-3- (6-metoxychinolín- 4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (1-methylimidazol-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (l-methylimidazol-2-yl) thioethyl (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1-piperidin-3-yl} -propyl] -1 - [3- (1-Methylimidazol-2-yl) thiopropyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) propyl] piperidin-3-yl} propan-1-one

155 (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylimidazole) -4-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [2- (3-methylimidazol-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [ 3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidin-3-yl } Propan-1-enoic acid (3R, 4R) -3- (4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl)} -1- [3- (3-methylpyrazol-4-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, S) 1-Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methyl-pyrazol-4-yl) -butyl] -piperidin-3-yl} -propan-1-enoic acid 42-) 3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylpyrazole- 4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- (4- [3- (2 R, S) -Hydroxy-3- (6-methyl) -propan-1-ynoic acid) oxyquinolin-4-yl 1) propyl] -1- [3- (3-methylpyrazol-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- ( 2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid ( 32 R, 42 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (oxazole) -2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid ( 32 R, 42 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] 156

-1- [3- (pyridin-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3-yl} propan-1-oic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (pyridin-2-yl) -thiopropyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - (3- (pyridin-3-yl) propyl) piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [4- (pyridin-3-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine -3-yl} propan-1-enoic acid (3R, 4R ) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) propyl] piperidine-3 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (yl) -propan-1-enoic acid] (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) butyl) piperidin-3-yl) propan-1-ynoic acid -yl) propyl] -1- [5- (pyridin-4-yl) pentyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (pyridin-4-yl) -thiopropyl] -piperidin-3-yl} (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidine-) -propan-1-enoic acid 2-yl) propyl] piperidin-3-yl} propan-1-enoic acid

157 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyrimidin-2-yl) butyl] (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [2- (pyrimidin-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3 - (R, S) -Hydroxy-3- (β-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidin-3-yl} propan-1-enoic acid ( 3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-4-yl) butyl] piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [ 2- (pyrimidin-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- ( R, S) -hydroxy-3- (6-methoxy xyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-5-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyrimidin-5-yl) -thioethyl] -piperidine-3 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-] -yl} -propan-1-enoic acid (pyrimidin-5-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (pyrazin-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid

158 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyrazin-2-yl)] butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- (2- (pyrazin-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) - 3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-3-yl) -propyl] -piperidin-3-yl (3R, 4R) -3- (4- (3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1-propyl) -1-propan-1-enoic acid - [4- (pyridazin-3-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2H, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (pyridazin-3-yl) -thiopropyl) -piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl)] - (propyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl)) propyl] -1- [4- (pyridazin-4-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, 3 R, R 3); S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (32? (R) -3- {4- [3- (2S, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazine-4-) yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidin-3-yl} propan-1-enoic acid

159 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-fluoro-phenyl) -prop-2] (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -inyl] piperidin-3-yl} propan-1-enoic acid -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidin-3-yl (propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (4-fluorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-chloro-phenyl) -prop-2-ynyl] -piperidin-3-yl (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-propyl) -propanoic acid] (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -chlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid -4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- (4- (3- (R, S) -hydroxy-3- (6-m ethoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-methylphenyl) prop-2-ynyl] piperidine-3-yl} -propan-l-oic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (β-methoxyquinolin-4-yl) propyl] -1- (3- (2- (trifluoromethyl) phenyl)) prop-2-ynyl] piperidin-3-yl (propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] ) propyl] -1- (3- (3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-yl} -propan

160

(3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4- (1-propyl) -acetic acid) Trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl (propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methoxy-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -prop-2- Inyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- (3- (3,4-Difluorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,4-difluorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R ) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (3,4-dichlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,3-dichlorophenyl) prop-2- (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -propyl] -piperidin-3-yl} -propan-1-ynoic acid 1- (3- (2,4-Dichloro-phenyl) -prop-2-ynyl) -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,4,6-trichlorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid (3R) , 4 R) -3- (4- (3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] 161

-1- [3- (3,5-Dichloro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S)) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-chloro-4-fluoro-phenyl) -prop (2-ynyl) piperidin-3-ylpropan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] 1- (3 ^- (2-chloro-4-fluorophenyl) prop-2-ynyl] piperidine-3-yl} propan-1-oic acid (3 R, 4 R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (3-chloro-5-fluorophenyl) prop-2-ynyl] piperidine-3-yl} propan-1-oic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (4-chloro-2-fluorophenyl) (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -prop-2-ynyl) -propan-1-ynoic acid) yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop-2-ynyl] piperidin-3-yl] propan-1-ynoic acid (3R, 4R) -3- (4- (3- ( R, S) -hydroxy-3- (6-methoxycinnamate quinolin-4-yl) propyl] -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-chloro-4- (trifluoromethyl) phenyl) prop-2 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -inyl] -piperidin-3-yl} -propan-1-ynoic acid -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- (3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (5-chloro-2-methoxyphenyl) prop-2-ynyl] piperidine-3-yl} propane 1-Acetic acid

162 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (3,5-bis (trifluoromethyl)) (phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3,5-dimethylphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3 - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2,4-dichloro-6-methyl-phenyl) -prop-2-ynyl] -piperidin-3-yl (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien) -propan-1-ynoic acid (2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- (3- (5-chlorothien-2-yl) prop-2-ynyl) piperidin-3-yl) propanoic acid (3R, 4R) -3- { 4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl} propyl] -1- [3- (3-chloro-thienyl-2-yl) prop-2-ynyl] piperidine-3 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-] -yl} -propan-1-enoic acid (5-Methyl-thien-2-yl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4 R) -3- (4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) prop-2 (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -inyl] -piperidin-3-yl} -propan-1-ynoic acid -1- [3- (Shadow-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S)] -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (l-methylpyrrole-3-yl) -prop 2-iny1] piperidin-3-yl} propan-1-oic acid

163 (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thiazol-2-yl) -acid) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4-)) yl) propyl] -1- [3- (thiazol-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- ( R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-one (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (1-methyl-imidazol-2-yl) -acetic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid y1) propyl] -1- [3- (3-methylimidazol-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3] - (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-pyrazol-4-yl) -prop-2-ynyl] -piperidin-3-yl} -propane (3R, 4R) -3- (4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazole-2) -acetic acid] -yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) - 3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl) -1-propyl) -1-pyridin-3-yl [3- (oxazol-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Hydroxy- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) - 3- (4- (3- _{(S S} S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl]

164

-1- [3- (pyridin-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid ( 3R, 4R) -3- (4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (pyrimidin-2-yl) prop- 2-Inyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (pyrimidin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R) 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrazin-2-yl) -prop-2- Inyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] p (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (piperidin-3-yl) -propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (β-methoxyquinolin-4-yl)] - [3-phenyl-propyl] -piperidin-3-yl} -propan-1-ynoic acid propyl] -1- [4-phenylbutyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (2-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] 165-1- [3- (3-fluoro-phenyl) -propyl] -piperidin-3-yl} -propan-1 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-fluorophenyl) -acetic acid] (butyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-one)] (yl) propyl] -1- [3- (4-fluorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- ( 2- (S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-fluorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid (32) R, 42 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3- Difluorophenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [4- (2,3-difluorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenyl) propyl] piperidin-3-yl} propan-1-one (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2,6- Difluorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline) - 4-yl) propyl] -1- [3- (2-chlorophenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2-chlorophenyl) propyl] piperidin-3-yl} propan-1-enoic acid , S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-chlorophenyl) butyl] piperidin-3-yl} propan-1-enoic acid to (3R, 4R) -3- (4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- Chlorophenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [4- (3-chlorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) propyl] piperidin-3-yl) propan-1-enoic acid (3 R, 3 R, 3 R) 42-) 3- {4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (4-chlorophenyl) butyl] piperidin-3 -yl} propan-1-enoic acid

166 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (2,3-dichloro-phenyl) -propyl) (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [4- (2,3-Dichlorophenyl) butyl] piperidin-3-yl} propan-1-en [

(3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (2,6-dichloro-phenyl) -propyl) (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - (4- (2,6-Dichlorophenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-methylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) 3- (4- (3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [5- (2-methylphenyl) pentyl] piperidine-3-yl} -propan (1R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenyl) -l-acid] (propyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylphenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- ( 6-methoxy-quinolin-4-yl) propyl] -1- (3- (4-methylphenyl) propyl 1] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) - 1- (4- (4-Methylphenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- (3- (R, S) -Fluoro-3- (6) -methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) propyl] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- {4- [3- (R) S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (2-methoxyphenyl) butyl] piperidin-3-yl) propan-1-enoic acid (3R, 4R) - 3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] 167

-1- [3- (3-methoxyphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [4- (3-methoxyphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) ) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (4-methoxyphenyl) butyl] piperidine-3-yl} (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid propyl] -1- [4- (2-trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3) - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (3-trifluoromethylphenyl) butyl] piperidine 3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (4-Trifluoromethylphenyl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)) -yl) propyl] -1- [4- (4-trifluoromethylphenyl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4 - [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2-fluoro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid

168 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2R, 4R) - 3- {4- [3- (2R, S) -Fluoro-3- (6-methoxyquinoline) (2-fluorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid -4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 P) R) 3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine-3- yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidin-3-yl) propan-1-enoic acid (3R, 4R) -3- (4- [3- (2R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3-difluorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) -3- {4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) o) Propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [2- (2,6-difluorophenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R) -propyl] -1- , S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenylthio) propyl] piperidin-3-y 1} Propan-1-enoic acid (3R, 4R) -3- (4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 2- (2-Chloro-phenylthio) -ethyl] -piperidin-3-yl) -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Fluoro-3- (6R) -methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-chloro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid

169 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [ 2- (4-Chloro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline) -4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3-dichlorophenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (R, S) -fluoro-3- (6-metoxychipolín-4-yl) propyl] -1- [3- (2,3-dichlorophenylthio) propyl] piperidin-3-yl} (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (2, 2-propyl) -propan-1-enoic acid 6-Dichloro-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,6-dichlorophenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S)) fluoro-3- (6-methoxy-quinoline -4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidin-3-yl} -propan-l- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3-methyl-phenylthio) -acetic acid] propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (4-Methylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid

170 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methyl-phenylthio) -propyl] piperidin-3-yl} propan-1-enoic acid {3R, 4R} -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (2-Trifluoromethylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid.

(3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-trifluoromethyl-phenylthio) -propyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (3-Trifluoromethyl-phenylthio) -ethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidin-3-yl} propan-1 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -propyl] -1- [2- (2- methoxyphenylthio) ethyl] piperidin-3-yl} propan-1-enoic acid.

(3R, 4R) -3- (4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) (propyl) piperidin-3-yl} propan-1-ynoic acid (3 R, 4 R) -3- (4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) -propyl) piperidin-3-yl} propan-1-ynoic acid (yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidin-3-yl] propan-1-ynoic acid (3R, 4R) -3- (4- (3- (2R) -propyl) -1- [2- (3-methoxyphenylthio) ethyl] piperidin-3-yl) propan-1-enoic acid , S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3-methoxyphenylthio) propyl] piperidin-3-yl} propan-1-one

(3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [2- (4-methoxy-phenylthio) -ethyl] -acetic acid piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (4-Methoxy-phenylthio) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [cyclopropylmethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (R, S)] - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropyl) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4 - [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [cyclobutylmethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) - 3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [2- (cyclobutyl) ethyl] piperidin-3-yl} -propan-1- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [cyclopentylmethyl] -piperidin-3-yl] -acetic acid {3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cy (3R, 4R) -3- {4- [3- (F, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propionyl] -ethyl] -piperidin-3-yl} -propan-1-ynoic acid propyl] -1- [cyclohexylmethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline)] n-4-yl) propyl] -1- [2- (cyclohexyl) ethyl] piperidin-3-r-yl (propan-1-ynoic acid (3R, 4R) -3- [4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclopropylthio) ethyl] piperidin-3-yl (propan-1-enoic acid (3 R, 4 R) ) -3- (4- [3- {R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (cyclopropylthio) propyl] piperidin-3-yl} propane (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- ( cyclobutylthio) ethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] 172

-1- [3- (cyclobutylthiopropyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro] -3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cyclopentylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (cyclohexylthio) -ethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) 3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (cyclohexylthio) -propyl] -piperidin-3-yl} -propan-1 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2-methyl-thioethyl] -piperidine-3- acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-methyl-thiopropyl] -yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [2-ethylthioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3-ethylthiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (n-propylthio) ethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (n-propylthio) propyl] piperidin-3-yl} -propan-1- onic acid

I (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (n-butylthio) ethyl] piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (n-Butylthio) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (thien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (thien-2-yl) butyl] piperidin-3-yl (propan-1-enoic acid)

173 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (thien-2-yl) -thioethyl] - (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [3- (Thien-2-yl) -thiopropyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (5-chlorothien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [4- (5-chloro-thienyl-2-yl) butyl] piperidine-3-yl} -propan-l (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [2- (5-chloro-thien-2) -acetic acid] (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -thioethyl) -piperidin-3-yl} -propan-1-ynoic acid propyl] -1- [3- (5-chlorothien-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S)) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorothien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) 3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl -1- [4- (3-Chlorothien-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (3-chlorothien-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- (4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (3-chloro-thienyl-2-yl) thiopropyl] piperidin-3- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (yl) -propan-1-enoic acid] 5-Methyl-thien-2-yl) -propyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline) 4-yl) propyl] 174

-1- [4- (5-methylthien-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, S)] ) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (5-methylthien-2-yl) thioethyl] piperidin-3-yl} propan-1 (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (5-methylthien-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- {4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (3-methylthieri-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (3-methylthien-2-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylthien-2-yl) thiopropyl] piperidin-3-yl} propan-1 -acetic acid (32?, 42?) - 3 - (4- (3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (thi-3-yl) propyl] piperidin-3-yl) (3R, 4R) -3- (4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1-propyl] -1- [4- (Thien-3-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) -Fluoro-3] - (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- { 4- [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-3-yl) thiopropyl] piperidin-3-yl} (32 R, 42 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, S) -Fluoro-3] - (6-Methoxyquinolin-4-yl) propyl] -1- [4- (fur-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid

175 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (fur-2-yl) -thioethyl] - (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [3- (fur-2-yl) -thiopropyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (fur-3-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3 - (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (fur-3-yl) butyl] piperidin-3-yl} propan-1-enoic acid ( 3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (fur-3-yl) -thioethyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (fur-3-yl) -thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (1-methyl-pyrrol-2-yl) -butyl 1] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (1-Methyl-pyrrol-2-yl) -thioethyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (1-methyl-pyrrol-2-yl) -propyl) -piperidin-3-yl} (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -propyl] -1- [4- (1- (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -butyl] -piperidin-3-yl} -propan-1-ynoic acid yl) propyl] 176

-1- (2- (1-methylpyrrol-3-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro] -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylpyrrol-3-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid, (3R, 4R) - 3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thiazol-2-yl) -propyl] -piperidin-3-yl} (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [4- (thiazole- 2-yl) butyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] (propyl) -1- [2- (thiazol-2-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S)] -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (thiazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (l-methylimidazol-2-yl) -propyl] -piperidin-3-yl (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (4- (1-propyl) -propanoic acid) -methylimidazol-2-yl) butyl] piperidin-3-yl} propan-1-acid to (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (1-methyl-imidazol-2-yl) (Thioethyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (1-methylimidazol-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro) -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - (4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [4- (3-methyl-imidazol-4-yl) butyl] piperidine-3-yl propan-1-enoic acid

177 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-methyl-imidazol-4-yl) (Thioethyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methylimidazol-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro] -3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (3-methyl-pyrazol-4-yl) -butyl] -piperidin-3-yl (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -propyl) -1- [2- (2-methyl-propyl) -propanoic acid] 3-Methyl-pyrazol-4-yl) -thioethyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (oxazol-2-yl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3R) , 4 R) -3- (4- (3- (R, S) -fluoro-3- (6-methyl oxyquinolin-4-yl) propyl] -1- [4- (oxazol-2-yl) butyl] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- (4- [3- [ R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (oxazol-2-yl) thioethyl) piperidin-3-yl (propan-1-enoic acid (3R, 4 R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (oxazole-2-yl) thiopropyl] piperidin-3 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3-yl] -propan-1-enoic acid - (pyridin-2-yl) propyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R _/ S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [4- (pyridin-2-yl) butyl] piperidin-3-yl (propan-1-enoic acid)

178 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) (1 R, 4 R) -3- (4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) -thioethyl] piperidin-3-yl} propan-1-ynoic acid propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, <RTIgt; S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 3 R, 3 R); 42-) 3- {4- [3- (2H, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridin-3-yl) -butyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (pyridin-3-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (32 R, 42 R) - 3- {4- [3- (2H, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridin-4-yl) -propyl] -piperidin-3-yl } -propan-l- (3 R, 4 R) -3- (4- (3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [4- (pyridine- 4-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [5- (pyridin-4-yl) pentyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- (4- [3- ( 2R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyridin-4-yl) -thioethyl] -piperidin-3-yl} -propan-1-enoic acid (32) R, 42 R) -3- {4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) thiopropyl] ] Piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (pyrimidin-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- (3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrimidin-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) - 3- (4- [3- (2R, S) -Fluoro-3- (β-methoxyquinolin-4-yl) propyl] 179

-1- [2- (pyrimidin-2-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4 - [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) propyl] piperidine-3-y1} -propan-l- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyrimidin-4-yl) -acetic acid] butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [2- (Pyrimidin-4-yl) thioethyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-4-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -propyl] -piperidin-3-yl} -propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyrimidin-5-yl) butyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyrimidin-5-yl) -thioethyl] -elino (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1-piperidin-3-yl] -propyl] -1 - [3- (pyrimidin-5-yl) -thiopropyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) propyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- (pyrazin-2-yl) butyl] piperidin-3-yl} propan-1-enoic acid ( 3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] 180

-1- [2- (pyrazin-2-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) propyl] piperidin-3-yl} -propan-l-oic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [4- (pyridazin-3-yl) butyl] (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1] piperidin-3-yl} -propan-1-enoic acid - [2- (pyridazin-3-yl) thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3] - (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-4-yl) -propyl] -piperidin-3-yl} -propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [4- (pyridazin-4-yl) butyl] piperidine -3-yl} propan-1-enoic acid and (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyridazin-4-yl)] Thioethyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (pyridazin-4-yl) -thiopropyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2-fluorophenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] 181

-1- [3- (3-Fluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro] -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine-3-yl (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3)} - propan-1-enoic acid (3-chloro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline- 4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- (4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (3-methylphenyl) prop-2-ynyl ] piperidin-3-yl (propan-1-enoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1) - [3- (4-methylphenyl) prop-2-ynyl] piperidine-3-yl} propane (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (2- (trifluoromethyl) -propyl) -acetic acid) (phenyl) prop-2-ynyl] piperidin-3-yl) propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- (3- (3- (trifluoromethyl) phenyl) prop-2-ynyl) piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [ 3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine-3-yl} -propan -1-acid

182 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-methoxy-phenyl) -prop-2] (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -inyl] -piperidin-3-yl} -propan-1-ynoic acid 1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine-3-yl} -propan-l-oic acid

(3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (4-methoxy-phenyl) -prop- (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -propan-2-yl] -propan-1-ynoic acid 1- [3- (3,4-Difluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-difluorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R) 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,4-dichlorophenyl) prop-2- Inyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (2,3-Dichloro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichlorophenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R ) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,4, β-trichlorophenyl) prop-2- inyl] piperidin-3-yl) propan-1-acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (3,5-dichloro-phenyl) -prop] (2R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) -2-ynyl] piperidin-3-yl} propan-1-ynoic acid propyl] -1- [3- (4-chloro-3-fluorophenyl) prop-2-ynyl] piperidine-3-yl} propán183

(3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (3-chloro) -acetic acid (4-Fluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (2-chloro-4-fluorophenyl) prop-2-ynyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3- {4 - [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-chloro-5-fluoro-phenyl) -prop-2-ynyl] piperidine-3 yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [ 3- (4-Chloro-2-fluoro-phenyl) -prop-2-ynyl] -piperidin-3-yl-propan-1-ynoic acid (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3) - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-4-methylphenyl) prop-2-ynyl] piperidin-3-yl] propan-1-enoic acid (3R, 4R) -3 - (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (4-chloro-3- (trifluoromethyl) phenyl) prop-2- Inyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) - 1- [3- (2-chloro-4- (tri (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinoline) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid -4-yl) propyl] -1- [3- (2-chloro-5- (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3 - {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-2-methoxy-phenyl) -prop-2-ynyl] -piperidine -3-yl} propan-1-enoic acid (3R, 4R) -3- (4- (3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl) -1- ( 3- (3,5-bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S)] -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] 184-1- [3- (3,5-dimethylphenyl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3R) 42-) - 3- (4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,4-dichloro-6-methylphenyl) (Prop-2-ynyl) piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid 42-) -3- {4- [3- (2H, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (5-chloro-thien-2-yl) -prop] -2-ynyl-piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinoline-4) -yl) propyl] -1- [3- (3-chloro-thien-2-yl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- (4-yl) - [3- (2H, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (5-methylthien-2-yl) prop-2- vinyl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4- [3- (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (3-methylthien-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3 - (2R, 5S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (shadow-3-yl) prop-2-ynyl] piperidin-3-yl} propane- (1 R, 4 R) -3- {4- [3- (2 R, 5 S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-chloro-1 H) -pyridoic acid] (methyl) pyrrol-2-yl) prop-2-ynyl] piperidin-3-yl} propan-1-enoic acid (3 R, 4 R) -3- {4- [3- (2 R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) prop yl] -1- [3- (1-methylpyrrol-3-yl) prop-2-ynyl] piperidin-3-yl) propan-1-ynoic acid (3R, 4R) -3- (4- [3] - (2R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine-3- yl} propan-1-enoic acid

185 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thiazol-4-yl)] Prop-2-ynyl-piperidin-3-yl} -propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- ( R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (1-methylimidazol-2-yl) prop-2-ynyl] piperidin-3-yl} propane -1 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (3-methyl-imidazole-4) -acetic acid] (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-1-yl) -prop-2-ynyl] -piperidin-3-yl} -propan-1-enoic acid 4-yl) propyl] -1- [3- (3-methylpyrazol-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [3- (oxazole-2-yl) prop-2-ynyl] piperidine-3-yl} -propan (1R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (oxazole-4) -ylic acid] -yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3 - {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine-3 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3-] - yl} -propan-1-enoic acid (pyridin-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-one

186 (3R, 4R) -3- (4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (pyrimidin-2-) yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (pyrimidin-4-yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid [3R, 4R) -3- {4- [ 3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrimidin-5-yl) -prop-2-ynyl] -piperidin-3-yl} -propan-1 (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyrazine-2-) -acetic acid yl) prop-2-ynyl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidin-3-yl} propan-1-en acid (3R, 4R) -3- {4- [3] - (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] piperidine-3-yl] propan-1 (3R, 4R) -3- {4- [3- (6-Methoxy-quinolin-4-yl) -propyl] -1- [3-phenyl-propen-2-yl] -piperidin-3-yl} -propan-1-yl acid (3R, 4R) -3- (4- [3- (6-Methoxyquinoline-4) -acetic acid); -yl) propyl] -1- [4-phenylbuten-3-yl] piperidin-3-yl} propan-1-ynoic acid (3R, 4R) -3- {4- [3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylpropen-2-yl] piperidin-3-yl} propan-1-enoic acid (3R, 4R) -3- {4 - [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-phenylbuten-3-yl] piperidin-3-yl [propan-1-enoic acid ( 3 R, 4 R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3-phenyl-propen-2-yl] piperidin-3- yl] propan-1-enoic acid (3R, 4R) -3- {4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4- phenylbuten-3-yl] piperidin-3-yl} propan-1-enoic acid

187 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3 - (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (2-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine (3R, 4R) -3- Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (4-Fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) ethyl] ] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidine (3R, 4R) - 3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine (3R, 4R).-3-Hydroxymethyl-4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] 1- [2- (4-Chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4- Chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidine

188 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (3-methylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (4-methylphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3- Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (3-Trifluoromethylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- ( 4-Trifluoromethylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] ] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine (3R, 4R) -3 -Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6 methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine

189 (32 R, 42 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [ 3- (6-methoxyquinolin-4-yl) piropropyl] -1- [2- (shadow-3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (shadow-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (fur-2-yl) thioethyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (6-methoxyquinolin-4-yl) propyl) -1- [3] - (fur-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (fur-3- yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (6-methoxyquinolin-4-yl) propyl) -1- (3- (fur-3-yl) thiopropyl) piperidine (32 R, 4 R) -3-Hydroxymethyl-4- (3- (6-methoxyquinolin-4-yl) propyl) -1- [2- (thiazol-2-yl) thioethyl] piperidine (32 R); (R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- '(6-methoxyquinolin-4-yl) propyl] -1- [3] - (oxazol-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridine-2-) yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine ( 32 R, 42 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (pyridin-3-yl) thioethyl) piperidine

190 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine (32R, 42R) R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-4-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (β-methoxyquinoline) n-4-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolinol) 4-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- ( pyridazin-3-yl) thiopropyl] piper (32 R, 42 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine (32 R, 42 R) R) -3-Hydroxymethyl-4- [3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-4-yl) -thiopropyl] -piperidine (32 R, 42 R) -3 -Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [ 3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6 -methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl]

1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine

191 (3F, 4R) -3-Hydroxymethyl-4- [3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (2-chloro-phenyl) -prop-2-ynyl] -piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (3-methylphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (4-methylphenyl) prop-2-ynyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (2- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] ] -1- [3- (3- (Trifluoromethyl) phenyl) prop-2-ynyl] -piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4- (Trifluoromethyl) phenyl) prop-2] -inyl] -piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine (3R) R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine ( 3 R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine (3 R) R, 4 R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (shadow-3-yl) prop-2-ynyl] piperidine (3 R), (R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl]

1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine

192 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-4-yl) prop-2-ynyl] piperidine (3R) 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-5-yl) prop-2-ynyl] piperidine (3R, 4R) - 3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl- 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3] - (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolin-4-) yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (Pyrimidin-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazine) 2-yl) prop-2 1-piperidin (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop-2-ynyl] piperidine (3R, 4R) ) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidine (3R, 4R) -3 -Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine (3R, 4R) -3-hydroxymethyl- 4- [3- (R, S) -hydroxy-3- (6-methoxy-quinoline

4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine

193 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy) Quinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (4-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (2-methylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (2-methylphenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (3-methylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxy-quinolin-4-yl) propyl] -1- [3- (3-methylphenylthio) propyl] piperidine

194 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) -propyl] -1- [2- (4-methyl-phenylthio) -ethyl] -piperidine ( 3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidine (3R, 4R) 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (2-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-trifluoromethylphenylthio) propyl] piperidine (3R, 4R) -3 -Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (2- (3-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl -4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (3- (3-trifluoromethylphenylthio) propyl) piperidine (3R, 4R) -3-hydroxymethyl-4 - [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (2- (4-trifluoromethylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [ 3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (4-trifluoromethylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3 - (R, S) -Hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- ( R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-methoxyphenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (3-methoxyphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy -3- (6-methoxyquinolin-yl) propyl] -1- [2- (4-methoxyphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3 - (6-methoxyquinolin-yl) propyl] -1- [3- (4-methoxyphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- ( 6-methoxy-quinolin-4-yl) propyl] -1- [2- (thien-3-yl) thioethyl] piperidine

195 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) -propyl] -1- [3- (shadow-3-yl) -thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (fur-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (fur-3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (fur-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (thiazol-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [2- (pyridin-3-y1) thioethyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [2- (pyridin-4-y1) thioethyl] piperidine (3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4

yl) propyl] -1- [3- (pyridin-4-yl) thiopropyl] piperidine

196 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) -propyl] -1- [2- (pyrimidin-2-yl) -thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyrazin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyrazin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridazin-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3-phenylprop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-Fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] - 1- (3- (3-Fluorophenyl) prop-2-ynyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl)] propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinoline- yl) propyl] -1- [3- (2-chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6- methoxyquinolin-yl) propyl] -1- [3- (3-chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- ( 6-methoxy-quinolin-4-yl) propyl] -1- [3- (4-chlorophenyl) prop-2-ynyl] piperidine

197 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-methylphenyl) prop- 2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (2H, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl) -1- [3- (3- methyl-phenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1 - [3- (4-Methyl-phenyl) -prop-2-ynyl] -piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinoline) -yl) propyl] -1- [3- (2- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) - hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3] - (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (4- (trifluoromethyl) phenyl) prop-2-ynyl] piperidine (32 R, 42 R) - 3-Hydroxymethyl-4- [3- (2H, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidine ( 32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3] - (6-methoxyquinolin-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2-methoxyphenyl) prop-2-ynyl] piperidine S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4 - [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (shadow-3-yl) prop-2-ynyl] piperidine (32 R, 42 R); -3-Hydroxymethyl-4- [3- (2H, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thiazol-4-) yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [ 3- (thiazol-5-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinoline-4)] yl) propyl] -1- [3- (oxazole-2-yl) prop-2-ynyl] piperidine

198 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazole- 4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6) -methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-3-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) - hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidine (3R> 4R) -3-Hydroxymethyl -4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (pyridazin-3-yl) -prop- 2-ynyl] piperidine (3 R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop- 2-Inyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2-phenylthioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-phenylthiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine (3R, 4R) 3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (3-fluorophenylthio) propyl] piperidine

199 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-fluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-fluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (4-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (4-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) prop yl] -1- (2- (2-methylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (2-methylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- (2- (3-methylphenylthio) ethyl) piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -4-fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (3-methylphenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [2- (4-methylphenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- (3- (R, S) -fluoro-3- (6-methoxyquinolin-4)) -yl) propyl] -1- [3- (4-methylphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4)] yl) propyl] -1- (2- (2-trifluoromethylphenylthio) ethyl] piperidine

200 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) -propyl] -1- [3- (2-trifluoromethyl-phenylthio) -propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (3-trifluoromethylphenylthio) ethyl] piperidine ( 3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-trifluoromethylphenylthio) propyl] piperidine (3R, 4R) 4R) -3-Hydroxymethyl-4- [3- (2H, S) -fluoro-3- (6-methoxyquinolin-yl) -propyl] -1- [2- (4-trifluoromethyl-phenylthio) -ethyl] -piperidine (32 R, 3 S); (R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) -propyl] -1- [3- (4-trifluoromethyl-phenylthio) -propyl] -piperidine (32 R); 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- (2-methoxyphenylthio) ethyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-1-yl) propyl] -1- [3- (2-methoxyphenylthio)] propyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (3-methoxyphenylthio) ) e tert] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-methoxyphenylthio) propyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- ( 4-methoxyphenylthio) ethyl] piperidine (3R, 3R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- ( 4-Methoxyphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3 - '(R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (thien) -3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thien-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (fur-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (fur-2-yl) thiopropyl] piperidine

201 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) -propyl] -1- [2- (fur-3-yl) -thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (fur-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (thiazol-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (thiazol-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (oxazol-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (oxazol-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridin-3-yl) thioethyl piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridin-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- (pyridin-4-yl)] thioethyl] piperidine

I (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinol-1-yl) -propyl] -1- [3- (pyridin-4-yl) -thiopropyl] ] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyrimidin-2-yl) thioethyl] piperidine {3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyrimidin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyrazin-2-yl)] ) thioethyl] piperidine

202 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) -propyl] -1- [3- (pyrazin-2-yl) -thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- [R, S] -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridazin-3-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridazin-3-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (pyridazin-4-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridazin-4-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3-phenylprop-2-ynyl] -piperidine ( 3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-fluorophenyl) prop-2- inyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (4-fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2- Chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- ( 3-Chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3] - (4-chlorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2-Methylphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] - 1- [3- (3-Methylphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] ] -1- [3- (4-methylphenyl) prop-2-ynyl] piperidine

203 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2- (trifluoromethyl) phenyl) (Prop-2-ynyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3- (Trifluoromethyl) phenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- (3- (4- (trifluoromethyl) phenyl) prop-2-ynyl) piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6 -methoxyquinolin-4-yl) propyl] -1- [3- (2-methoxyphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-methoxyphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (4-methoxyphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2-ynyl] -piperidine (3R, 4R) -3-hydroxymethyl -4- (3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl) -1- [3- (shadow-3-yl) -prop-2-ynyl] -piperidine (3R, 4 R) -3-hydroxy methyl 4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (thiazol-2-yl) prop-2-ynyl] piperidine (3R) 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (thiazol-4-yl) -prop-2 (vinyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (thiazole- 5-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (oxazol-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinoline-4-) yl) propyl] -1- [3- (oxazol-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (oxazol-5-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) prop-2-ynyl] piperidine

204 (3R, 4R) -3-Hydroxymethyl-4- [3- (2H, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridine- 3-yl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-4-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6R) -methoxyquinolin-4-yl) propyl] -1- [3- (pyrimidin-2-yl) prop-2-ynyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, 3 R) -pyridin-4-yl] propyl] -1- S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyrazin-2-yl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl- 4- [3- (2 R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-3-yl) prop-2-ynyl] piperidine (32 R); 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridazin-4-yl) prop -2-ynyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-fluoro-4-phenylbutyl] piperidine-3-carboxylic acid R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3,5-difluorophenylthio) ethyl] piperidine- (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,5-difluorophenylthio) propyl] piperidine-3-carboxylic acid 3-carboxylic acid ( 32 R, 42 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (2- (2,5-difluorophenylthio) ethyl] piperidine-3-carboxylic acid (32 R, 42 2) R) -4- (3- (6-Methoxyquinolin-4-yl) propyl) -1- (3- (2,5-difluorophenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) - 4 R) - (3- (6-Methoxyquinolin-4-yl) propyl) -1- (2- (2,3,4,6-tetra fluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) - 4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3,4,6-tetra fluorophenylthio) propyl] piperidine-3-carboxylic acid (32 R, 42 R) - 4 - [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoro-5-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3] - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine-3-carboxylic acid

205 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [2- (3-cyanophenophthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (3-cyanophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridine-2) (yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] piperidine-3-carboxylic acid 3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoropyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclic) (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine-3-carboxylic acid (3-hydroxybenzyl) ethyl] piperidine-3-carboxylic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3 - (6-Methoxyquinolin-4-yl) propyl] -1- [3- (tert-butylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4)] -yl) propyl] -1- [3- (2,3-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [3- (2,5-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (3,5-Difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid

206 (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,6-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2,3,5-trifluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2,3,6-trifluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) ) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3- (2-cyano-3-fluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (3-cyano-6-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2-acetamido-5-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6 (Methoxyquinolin-4-yl) propyl] -1- [3-trifluoromethoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- (3-fluoro-3-phenylpropyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-me Toxinquinolin-4-yl) propyl] -1- [4-fluoro-4-phenylbutyl] piperidine-3-carboxalic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- (3- (3,5-difluorophenylthio) propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-Methoxyquinolin-4-yl) propyl] -1- (2- (2,5-difluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,5-difluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) 1-Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (2- (2,3,4,6-tetrafluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,3,4,6-tetrafluórfenyltio) propyl] piperidine-3-carboxylic acid

207 (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoro-5-) chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] 1

-1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3 - (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S)] -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [ 3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (32) R, 42 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] (3 R, 4 R) -4- [3- (2 R, 5 S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- fl fluoropyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (Cycloheptylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl -1- [3- (tert-butylthio) propyl] piperidine-3-carboxylic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid

208 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3,6-trifluorophenyl) prop (2R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-ynyl) piperidine-3-carboxylic acid] 2-Cyano-3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] propyl] -1- [3-cyano-6-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6 -methoxyquinolin-4-yl) propyl] -1- [2-acetamido-5-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) - Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-trifluoromethoxyphenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-fluoro-3-phenylpropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-fluoro-4-phenylbutyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) ) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (3,5-Difluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,5-Difluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,5-difluorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4-) yl) propyl] -1- [3- (2,5-difluorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) 4-yl) propyl] -l- [2- (2,3,4,6-tetrafluórfenyltio) ethyl] piperidine-3-carboxylic acid

209 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3,4,6-tetrafluorophenylthio) (propyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] ^-1

-1- [2- (3-fluoro-5-chlorophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4)] -yl) propyl] -1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3 - (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -,

-1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoropyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro- 3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylic acid

210 [3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (2- (tert-butyl-thio) -ethyl) -piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (tert-butylthio) propyl) piperidine-3 carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,3-difluorophenyl) prop) carboxylic acid (2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- ( 2,5-Difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (3,5-difluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-yl) propyl] -1- (3- (2,6-difluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro 3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,3,5-trifluorophenyl) prop-2-ynyl] pip (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (3- (2,3,6) -pyridine-3-carboxylic acid) (trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid. ^1- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-cyano-3-fluorophenyl) prop- 2-Inyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-cyano- 6-Fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3-trifluoromethoxyphenyl) -prop-2-ynyl] piperidine-3-carboxylic acid

211 (3R, 4R) -4- [3- (β-Methoxyquinolin-4-yl) propyl] -1- [3-fluoro-3-phenylpropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [4-fluoro-4-phenylbutyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (β-Methoxyquinolin-4-) y1) propyl] -1- [2- (3,5-difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3,5-Difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2 5-Difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,5-difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3,4,6-tetra fluorophenylthio) ethyl] piperidine- 3-Acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3,4,6-tetra fluorophenylthio) propyl] piperidine-3- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoro-5-chlorophenylthio) ethyl] piperidin-3-o acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R, 4R) 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3) (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) -cyanophenylthio) propyl] piperidine-3-acetic acid

212 Thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3- (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] piperidine-3-acetic acid ( 3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoropyridin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) ) 4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-acetic acid (3R, 4S) -4- [3- (6- Methoxyquinolin-4-yl, 1-propyl] -1- [3- (cycloheptylthio) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [ 3- (tert-butylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3- Difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquino) lin-4-yl) propyl] -1- [3- (2,5-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (2,6-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6-Methoxyquinoline- 4-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (6-Methoxyquinoline) -4-yl) propyl] -1- [3- (2,3,6-trifluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3- (2-cyano-3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6) (Methoxyquinolin-4-yl) propyl] -1- [3-cyano-6-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (6- Methoxyquinolin-4-yl) propyl] -1- [3-trifluoromethoxy]

213 phenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-Fluoro-3-phenylpropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-Fluoro-4-phenylbutyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (3,5-Difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl 1- (3- (3,5-Difluorophenylthio) propyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline-4- yl) propyl] -1- (2- (2,5-difluorophenylthio) ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- (3- (2,5-difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- (2- (2,3,4,6-tetrafluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) ) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (3- (2,3,4,6- (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-fluoro-phenylthio) -propyl] -piperidine-3-acetic acid -fluoro-5-chlorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3- (3-Fluoro-5-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinoline) -4-ylpropyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine-3-acetic acid

214 (3R, 4R) -4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, 5S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy -3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoropyridin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-acetic acid (3R, 4R) - 4- [3- (2H, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine-3-acetic acid (R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl)] - propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (tert-butylthio) propyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3 - ( 6-Methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,5-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid t · ·.

(3R, 4R) -4- [3- (2R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop- 2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- (3- (2 R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- (3 - (2,6-Difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3 R, 4 R) -4- [3- (2 R, S) -Hydroxy-3- (6-methoxyquinoline-4) -yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (32 R, 42 R) -4- [3- (2 R, S-S)] ) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (2,3,6-trifluorophenyl) prop-2-ynyl) piperidine-3-acetic acid

215 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-cyano-3-fluorophenyl) prop (2R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-cyano-2-ynyl] piperidine-3-acetic acid 6-Fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] - 1- [3-Trifluoromethoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] ] -1- [3-Fluoro-3-phenylpropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [4-Fluoro-4-phenylbutyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] ] -1- (2- (3,5-difluorophenylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline-4-) y1) propyl] -1- (3- (3,5-difluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinoline) -4-ylpropyl] -1- (2- (2,5-difluorophenylthio) ethyl] piperidine-3-acetic acid ( 3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-y1) propyl] -1- [3- (2,5-difIuórfenyltio) propyl] piperidine-3 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (2,3,4,6-tetrafluorophenylthio) acetic acid (ethyl) piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2- 3,4,6-Tetrafluorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (3-Fluoro-5-chlorophenylthio) ethyl] piperidin-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) (propyl) -1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- (3- (R, S) -Fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine-3-acetic acid

216 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine-3- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine- (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine 3-acetic acid -3-Acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [2- (pyridin-2-yl)] thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2) (yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- ( 3-Fluoropyridin-2-yl) thioethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1 - [3- (3-Fluoropyridin-2-yl) thiopropyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) (propyl) -1- [2- (cycloheptylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fl] Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro -3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) - Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (tert-butylthio) propyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (1,6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) ) -4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-4-yl) propyl] -1- [3- (2,5-difluorophenyl) prop-2-iny1] piperidin-3 -acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop- 2-Inyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2 6-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid

217 (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop- 2-Inyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2 (3,6-Trifluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-Cyano-3-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [3-cyano-6-fluorophenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -4- [3- (R, S) 1-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-trifluoromethoxyphenyl) prop-2-ynyl] piperidine-3-acetic acid (3R, 4R) -3-Hydroxymethyl-4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (3,5-difluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (3,5-difluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1 - [2- (2,5-Difluorophenylthio) ethyl] piperidine (3R, 4R) -3- Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,5-difluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3,4,6-tetrafluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline- 4-yl) propyl] -1- [3- (2,3,4,6-tetrafluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (3-fluoro-5-chlorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3- (3-fluoro-5-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) (Ethyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3]

- (3-trifluoromethoxyphenylthio) propyl] piperidine

218 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6- methoxyquinolin-4-yl) propyl] -1- [2- (pyridin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (pyridin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3) (Fluoropyridin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3-fluoropyridin-2-yl) (Thiopropyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine (3R, 4R) -3- Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (tert-bu (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3-thienyl] propyl] piperidine

- (2,3-Difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2, 2-difluorophenyl) prop-2-ynyl] piperidine 5-Difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3]

- (3,5-Difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3]

- (2,6-Difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [3]

- (2,3,5-trifluorophenyl) prop-2-ynyl] piperidine

219 (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [- (2,3,6-trifluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [- (2-cyano-3-fluorophenyl) prop-2- inyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [cyano-6-fluorophenyl) prop-2 -inyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [trifluoromethoxyphenyl] prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (3,5-difluorophenylthio) (ethyl) -piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3, 6-methoxyquinolin-yl) propyl] 5-Difluorophenylthio) propyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (2,5-difluorophenylthio) ethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2,5-difluorophenylthio) of pyl] piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- (2,3,4,6-Tetrafluorophenylthio) ethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl -1- [3- (2,3,4,6-tetrafluorophenylthio) propyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -hydroxy-3 - ( 6-methoxyquinolin-1-yl) propyl] -1- [2- (3-fluoro-5-chlorophenylthio) ethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S)] -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-fluoro-5-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3 - ( 2- (S) -hydroxy-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- (3-trifluoromethoxyphenylthio) ethyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2H, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-trifluoromethoxyphenylthio) propyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4 - [3- (2H, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-cyanophenylthio) ethyl] piperidine

220 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-cyanophenylthio) propyl] piperidine ( 3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) -propyl] -1- [2- (pyridin-2-yl) -thioethyl] -piperidine ( 3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) -propyl] -1- [3- (pyridin-2-yl) -thiopropyl] -piperidine ( 3 R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- [2- (3-fluoropyridin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (3-fluoropyridin-2-yl)] Thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine

(3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- [3- (cycloheptylthio) propyl] piperidine (3R, 4R) 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (2- (tert-butylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (3- (tert-butylthio) propyl] piperidine (3R, 4R) -3 -Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (δ-methoxyquinolin-yl) propyl] -1- (3- (2,3-difluorophenyl) prop-2-ynyl) piperidine (3R, 4 R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-yl) propyl] -1- (3- (2,5-difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4-; (3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl) -1- (3- (3,5-difluorophenyl) prop -2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (3- (2,6) -difluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-yl) propyl] -1- (3- (2,3,5-Trifluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- (3- (R, S) -hydroxy-3- (6) methoxyquinolin-4

yl) propyl] -1- (3- (2,3,6-trifluorophenyl) prop-2-ynyl] piperidine

221 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-cyano-3) -fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [ 3-Cyano-6-fluorophenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl 1- (3-Trifluoromethoxyphenyl) prop-2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl)] propyl] -1- [2- (3,5-difluorophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinoline-4- yl) propyl] -1- [3- (3,5-difluorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinoline- 4-yl) propyl] -1- [2- (2,5-difluorophenylthio) ethyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- (6- methoxyquinolin-4-yl) propyl] -1- [3- (2,5-difluorophenylthio) propyl] piperidine (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -fluoro-3- ( 6-Methoxyquinolin-4-yl) propyl] -1- [2- (2,3,4,6-tetrafluorophenylthio) ethyl] piperidine (3R, 4R) -3- Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3,4,6-tetrafluorophenylthio) propyl] piperidine (3R) 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (3-fluoro-5-chloro) f] enylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- Fluoro-5-chlorophenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2] - (3-Trifluoromethoxyphenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (3-Trifluoromethoxyphenylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2] - (3-cyanophenylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (3-kyanofenyltio) -propyl]

222 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxy-quinolin-yl) -propyl] -1- [2- (pyridin-2-yl) -thioethyl piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (pyridine-2-) yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-1-yl) propyl] -1- [2- ( 3-Fluoropyridin-2-yl) thioethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1 - [3- (3-Fluoropyridin-2-yl) thiopropyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinolin-1-yl)] propyl] -1- [3- (cycloheptylthio) propyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinolin-yl)] propyl] -1- (2- (tert-butylthio) ethyl) piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- (3- (tert-butylthio) propyl] piperidine (3 R, 3 R); 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- (3- (2,3-difluorophenyl) prop-2- inyl) piperidine (3 R, 4 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2,5) -difluorophenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-yl) propyl] -1- (3- (3,5-Difluorophenyl) prop-2-ynyl) piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (2R, 5S) -fluoro-3- (6-methoxyquinoline- yl) propyl] -1- (3- (2,6-difluorophenyl) prop-2-ynyl) piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2 R, S) -fluoro- 3- (6-methoxyquinolin-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop-2-ynyl] piperidine (32 R, 42 R) -3-Hydroxymethyl-4- [3- (2R, 5S) -Fluoro-3- (6-methoxyquinolin-yl) propyl] -1- [3- (2,3,6-trifluorophenyl) prop-2-ynyl] piperidine (32R, 42R) - 3-Hydroxymethyl-4- [3- (2H, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2-cyano-3-fluorophenyl) prop-2- ynyl] -piperidine

223 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-cyano-6-fluorophenyl) prop -2-ynyl] piperidine (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3-trifluoromethoxyphenyl] Prop-2-ynyl] piperidine (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- (2- (6-fluoropyridin-2-yl) thioethyl) piperidine-3- (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (6-fluoropyridin-2-yl) thiopropyl] piperidine-3-carboxylic acid (3R, 4R, 4R) 4 R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- (2- (6-fluoropyridin-2-y1) thioethyl] piperidine-3 (3R, 4R) -4- (3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl) -1- [3- (6-fluoropyridin-2-yl) carboxylic acid] (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (6-fluoropyridine) thiopropyl] piperidine-3-carboxylic acid -2-yl) thioethyl] piperidine-3-carboxylic acid (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3] - (6-fluoropyridin-2-y1) thiopropyl] piperidine n-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (6-fluoropyridin-2-yl) thioethyl] piperidin-3 -acetic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [3- (6-fluoropyridin-2-yl) thiopropyl] piperidine-3-acetic acid ( 3 R, 4 R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinolin-4-yl) propyl] -1- [2- (6-fluoropyridin-2-yl) thioethyl] piperidine (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (6-fluoropyridin-2-yl) 3-acetic acid) (3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- (2- (6-) -thiopropyl) -piperidine-3-acetic acid Fluoropyridin-2-yl) thioethyl] piperidine-3-acetic acid

224 (3R, 4R) -4- [3- (R, S-Fluoro-3- (6-methoxy-quinolin-4-yl) -propyl] -1- [3- (6-fluoro-pyridin-2-yl) -thiopropyl] -piperidine -3-Acetic acid (3R, 4R) -4- [3- (R, S-Fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (6-fluoropyridine) -2-yl) thiopropyl] piperidine-3-acetic acid.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are given by way of illustration only and are not intended to limit the scope of the present invention in any way

Example 2

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid dihydrochloride

0.057 cm ^{3 of} 2-iodothiophene and 1.42 cm ^{3 of} triethylamine are added with stirring to a solution of 0.185 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1-prop-2 acid. -inyl) piperidine-3-carboxylic acid in 4 cm ^{3 of} anhydrous dimethylformamide and then 0.38 g of tetrakis (triphenylphosphine) palladium and .019 g of cuprous chloride are added. The solution is stirred for 20 hours at about 20 ° C. 75 cm ^{3 of} ethyl acetate and 75 cm ^{3 of} water are then added to the reaction mixture. After stirring, the reaction mixture is separated by settling and then neutralized to pH 6 with 0.1 N aqueous hydrochloric acid. The aqueous phase is extracted with 50 cm ^{3 of} ethyl acetate, and the extract is washed twice with 75 cm ^{3 of} saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at about 40 ° C. 0.090 g of a yellow oil is obtained, which is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particles 20-45 μm, diameter 1 cm, height 30 cm), eluting with a mixture of dichloromethane and methanol (92/8 by volume). ) and 50 cm ³ fractions are collected. Fractions 12 to 15 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The oil obtained is transferred to 1 cm @ ^{3 of a} 4 N solution

225 hydrogen chloride in dioxane. Concentration under the same conditions as above and transferring the residue to 10 cm ^{3 of} diethyl ether gave, after filtration, 0.030 g of (3R, 4R) -4- [3- (β-methoxyquinol-4-yl) propyl] dihydrochloride. -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid as a white solid.

¹ H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.15-2.10 and 3.00-3.65 (mts, 14H), 3.98 (s , 3H), 4.25-4.55 (unresolved peak,

2H), 7.16 (dd, J = 5 and 3 Hz, 1H), 7.40-7.60 (mt, 4H), 7.75 (broad d, J = 5 Hz, 1H), 7.96 (mt, 1H), 8.79 (mt, 1H), 10.50-10.70 (broad unresolved peak, IH), 12.85-13.15 (broad unresolved peak, IH).

(3R, 4R) -4- [3- (6-Methoxy-pyridin-4-yl) -propyl] -1-prop-2-ynyl] -piperidine-3-carboxylic acid can be prepared by the following procedure:

0.3 g of prop-2-ynyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1-prop-2-ynyl) piperidine-3-carboxylate in 3 cm ^{3 of} dioxane and 1.48 cm ^{3 of} 1 N sodium hydroxide are heated with stirring at about 70 ° C for 17 hours. The reaction mixture is concentrated under reduced pressure at about 50 ° C. 1.48 cm @ ^{3 of} 1 N aqueous hydrochloric acid and then 10 cm @ ^{3 of} water are added to the solid residue obtained. The solution obtained is extracted with 5 x 20 cm ^{3 of} dichloromethane. The organic extracts were combined and then concentrated under reduced pressure (5 kPa). There was thus obtained (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1-prop-2-ynyl] piperidine-3-carboxylic acid (0.189 g) as a white foam.

Prop-2-ynyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1-prop-2-ynyl) piperidine-3-carboxylate can be prepared as follows:

0.95 g of potassium carbonate is added to a solution of 0.835 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylic acid hydrochloride in 15 cm ^{3 of} anhydrous dimethylformamide, and then 0.36 cm @ ^{3 of} propargyl bromide are added. The mixture is stirred in

226 nitrogen atmosphere at 70 ° C for 18 hours. 100 cm ^{3 of} ethyl acetate and 100 cm ^{3 of} distilled water are added to the reaction mixture. The organic phase is separated by settling and then washed with 5 x 40 cm ^{3 of} water and 2 x 50 cm ^{3 of} saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and stirred under reduced pressure (5 kPa) at about 40 ° C. The oil obtained is purified by chromatography under 50 kPa of nitrogen on a silica gel column (particle size 20-45 μπι, diameter 2 cm, height 40 cm), eluting with ethyl acetate and collecting 50 cm ^{3 of} fraction. Fractions 17 to 21 are combined, concentrated under reduced pressure (5 kPa) at 40 ° C. 0.300 g of prop-2-ynyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1-prop-2-ynyl) piperidine-3-carboxylate is obtained in the form of a yellow oil. .

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] piperidine-3-carboxylic acid hydrochloride can be obtained as follows:

8.8 g of (3R, 4R) -1-benzoyl-4- [3- (6-methoxyquinol-4-yl) -propyl] piperidine-3-carboxylic acid are heated with stirring in 200 cm ^{3 of} 5 N aqueous hydrochloric acid at about 100 ° C for 48 hours. The reaction mixture is concentrated under reduced pressure (5 kPa) at about 50 ° C. The residue is taken up in 100 cm ^{3 of} acetone. The mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 60 ° C. This operation is repeated twice. The residue is finally triturated in 100 cm ^{3 of} acetone until crystallization. After filtering the crystals, and drying in a desiccator under reduced pressure (10 kPa), 7.2 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylic acid hydrochloride are obtained. in the form of a beige solid, m.p.

(3R, 4R) -1-Benzoyl-4- [3- (6-methoxy-quinol-4-yl) -propyl] -piperidine-3-carboxylic acid can be prepared as follows:

227 g of (3R, 4R) -1-benzoyl-4- [3- (6-methoxyquinol-4-yl) propyl] -3-vinylpiperidine are dissolved in a mixture of 250 cm ³ of carbon tetrachloride and 250 cm ^{3 of} acetonitrile. Then, at a temperature of about 20 [deg.] C. and with good stirring, 51.3 g of sodium meta periodate are added, followed by 0.27 g of ruthenium chloride hydrate. After addition of the reactants, a slightly exothermic reaction (temperature about 30 ° C) is maintained for 15 minutes. The mixture was then stirred at room temperature for 2 hours. The suspension obtained is filtered and the insoluble material is washed with 5 x 80 cm ^{3 of} dichloromethane. After stirring the filtrate, the organic phase is separated by settling and the aqueous phase is saturated with sodium chloride and then extracted with 2 x 300 cm ^{3 of} dichloromethane. The combined organic extracts are washed with 3 x 200 cm ^{3 of} water, dried over magnesium sulfate, filtered through filter paper and then concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 23.2 g of an oil are obtained, which is purified by chromatography on a silica gel column (20-45 µm particle size, 6.5 cm diameter, 30 cm column height), eluting with a dichloromethane / methanol mixture (97/3 by volume). ) and 400 cm ³ fractions are collected. Fractions 4 to 8 are combined and concentrated under reduced pressure (5 kPa). 11.8 g of a brown oil are obtained. This oil is dissolved in 60 cm ^{3 of} acetonitrile and heated to boiling point in the presence of activated carbon for several minutes. After filtration, the solution obtained is cooled. The product which crystallizes is filtered off and washed with 2 x 10 cm ^{3 of} acetonitrile. The solid is dried in a desiccator under vacuum in the presence of potassium hydroxide (10 kPa). 8.8 g of (3R, 4R) -1-benzoyl-4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylic acid are obtained in the form of a beige solid, m.p.

(3R, 4R) -1-Benzoyl-4- [3- (6-methoxyquinol-4-yl) propyl] -3-vinylpiperidine may be prepared as follows:

18.4 cm @ ^{3 of} triethylamine are added to a stirred solution of 20.8 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -3-vinylpiperidine in 270 cm @ ^{3 of} chloroform, and then a solution of 7.2 cm ^{3 of} benzoyl chloride in 50 cm ^{3 of} chloroform is added over 1 hour. The mixture is stirred at

The reaction mixture is added to 100 cm ^{3 of} distilled water. The organic phase is separated by settling, washed with 2 x 100 cm ^{3 of} water and then dried over magnesium sulphate. The mixture is filtered through filter paper and the solution is concentrated under reduced pressure (5 kPa) at about 40 ° C. 25 g of (3R, 4R) -1-benzoyl-4- [3- (6-methoxyquinol-4-yl) -propyl] -3-vinylpiperidine are obtained in the form of a brown oil.

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -3-vinylpiperidine can be obtained by applying the method described in patent application FR 2 354 771.

Example 3

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- [2- (3-fluorophenylthio) -2-ethyl] piperidine-3-carboxylic acid dihydride

A mixture of 0.54 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (3-fluorophenylthio) -2-ethyl] piperidine-3-carboxylate in 4 cm ^{3 of} methanol and 0.8 cm ^{3 of} 5 N aqueous sodium hydroxide are heated with stirring at 60 ° C for 20 hours. The solvents are then removed under reduced pressure (5 kPa) at a temperature of about 40 ° C and the residue is taken up in 10 cm ^{3 of} water and acidified with 0.4 cm ^{3 of} concentrated hydrochloric acid. The solution is stirred under the same conditions as above, and then the residue is triturated in a mixture of dichloromethane and methanol (90/10 by volume). The insoluble material was filtered off and washed with 5 cm ³ DII ¹ chloromethane. The filtrate is dried over sodium sulfate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is triturated in 10 cm ^{3 of} diisopropyl ether and then 1 cm ^{3 of} 5N hydrogen chloride in diisopropyl ether is added with stirring. The crystals are separated by filtration and then washed with 2x5 cm ^{3 of} diisopropyl ether. After air drying, 0.45 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine-3 acid hydrochloride is obtained. carboxylic acid in the form of a pale yellow amorphous solid, m.p.

229

Infrared (KBr): 3058 and 3012 cm ^-1 (aromatic CH v), 2935 and 2862 cm ^-1 (CH ₂ v), 3000 and 2750 (acidic OH v), 2800 and 1900 cm ^-1 (NH ⁺ v (tertiary) amine salt and quinoline salt), 1719 cm ^-1 (acidic C = O v), 1618, 1600, 1578, 1541 and 1496 cm ^-1 (aromatic core C = C vj, 1274 cm ^-1 (acidic C-0 v)) , 1251 and 1216 cm ^-1 (ether C-0 vas), 1021 cm ¹ (ether C-0 vs and alcohol C-0 v), 847 cm ^-1 (4,6-disubstituted quinoline CH γ), 781 and 729 cm ^-1 (1,3-disubstituted phenyl CH 2).

Ms (EI): m / z = 482 (M) ^+, 438 (M-CO2) ^T, 341 (M-C 7 H _6,) ⁺ base peak, 297, 341 (M-CO2) ^+, 186 (ΟΧ2Η ₁₂ ΝΟ) ⁺ , 128 (C ₆ H ₅ SE) ⁺ , 36 (HCl) ⁺ .

Methyl (3R, 4R) -4- (3- (6-methoxyquinol-4-yl) propyl) -1- (2- (3-fluorophenylthio) ethyl) piperidine-3-carboxylate can be prepared as follows:

In an analogous manner to that described in Example 4 below, methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -piperidine-3-carboxylate hydrochloride and 2-bromo-1- (3-fluorophenylthio) ethane yields 0.55 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (3-fluorophenylthio) ethyl] piperidine-3 -carboxylate in the form of a yellow viscous oil.

IR (CC1 _4): 2949 cm ¹ (aliphatic CH at).

1737 cm ^-1 (0 = 0 in), 1227 cm ^-1 (ether C-0 in), 845 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate hydrochloride was prepared using the method described in Example 6.

Example 4

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- (2- (phenyl-io) -ethyl) -piperidine-3-carboxylic acid

230

A suspension of 0.7 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (phenylthio) ethyl] piperidine-3-carboxylate in 5 cm ^{1 * 3 * 5} methanol and 2.9 cm @ ^{3 of a} 1N aqueous sodium hydroxide solution are stirred for 2 hours at a temperature of about 80 ° C. The solution obtained is neutralized with 0.18 cm ³ of acetic acid and stirred under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by atmospheric pressure chromatography on a silica gel column (particles 20-63 μπι, diameter 3 cm, height 20 cm), eluting with a mixture of dichloromethane and methanol (90/10 by volume) and collecting 20 cm ^{3 of} fractions. . Fractions 21 to 52 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.53 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (phenylthio) ethyl] piperidine-3-carboxylic acid is obtained in the form of a beige oil.

1 H-NMR spectrum (400 MHz, d 6 - (CD ₃ ) ₂ SO, δ in ppm): 1.35-1, 95 (mt, 7H), 2.28 (broad t, J = 10.5 Hz, 1H ), 2.43 (wide d,

J = 10.5 Hz, 1H), 2.59 (mt, 1H), 2.64 (t, J = 7 Hz, 2H), 2.77 (unresolved peak, 1H), 2.93 (unresolved peak, 1H), 3.03 (mt,

2H), 3.13 (mt, 2H), 3.95 (s, 3H), 7.21 (tt, J = 7.5 and 2 Hz, 1H),

7.25-7.45 (mt, 7H), 7.93 (d, J = 9Hz, 1H), 8.63 (d, J = 4.5Hz,

1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (phenylthio) ethyl] piperidine-3-carboxylate can be prepared as follows:

g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -propyl] piperidine-3-carboxylate hydrochloride and 1 g of potassium carbonate are stirred at about 20 ° C in 100 cm ^{3 of} acetonitrile for 20 minutes. A solution of 0.61 g of 2-bromo-1-phenylthioethane in 5 cm ^{3 of} acetonitrile is then added and the mixture is heated to about 60 ° C for hours. After addition of 20 cm ^{3 of} dimethylformamide and an additional 0.61 g of 2-bromo-1-phenylthioethane, heating is continued for 8.5 hours. After cooling, the reaction mixture is filtered, and the solution is concentrated under reduced pressure (5 kPa) at a temperature of ca.

231 ° C. The residue is taken up in 50 cm @ ^{3 of} ethanol and concentrated again under the same conditions. The residue is diluted with 30 cm ^{3 of} water and then extracted with 3 x 20 cm ^{3 of} dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure (5 kPa) at about 40 ° C. 1 g of an oil is obtained which is purified by chromatography on a silica gel column under reduced pressure (particle size 20-63 μπι, diameter 3.5 cm, height 20 cm), eluting with a mixture of dichloromethane and ethanol (90/10 by volume). and 20 cm ³ fractions are collected. Fractions 15 to 26 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 0.79 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (phenylthio) ethyl] piperidine-3-carboxylate is obtained in the form of a yellow oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate hydrochloride can be prepared using the method described in Example 6.

Example 6

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- (3-phenyl-prop-2-ynyl) -piperidine-3-carboxylic acid

To a solution of 0.25 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -propyl] -1- (3-phenylprop-2-ynyl) piperidine-3-carboxylate in 6 cm ³ of methanol is added 0.41 cm ³ of 5 N aqueous sodium hydroxide solution and the mixture is heated in an inert atmosphere to a temperature of about 57 DEG C. for 18.5 h. Mix it up ^! is cooled and then concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The residue is taken up in 10 cm ^{3 of} water, acidified with 2 cm ^{3 of} 1 N hydrochloric acid and concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue obtained is triturated in 10 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume) and then filtered. The insoluble material is washed with 2 x 10 cm ^{3 of} dichloromethane. The combined organic filtrates are concentrated under reduced pressure (2 kPa) at about 30 ° C. 0.22 g of residue is obtained

232 is stirred in a mixture of 20 cm @ ^{3 of} water and 15 cm @ ^{3 of} dichloromethane. The aqueous phase is separated by settling and then extracted with 3 x 10 cm ^{3 of} dichloromethane. The aqueous phase is concentrated to dryness under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is triturated in 10 cm @ ³ of dichloromethane / methanol (90/10 by volume). The insoluble material is filtered off and the filter cake is washed with 5 cm ^{3 of the} same mixture. The filtrate is dried over magnesium sulphate and then concentrated under reduced pressure under the same conditions as above, and finally dried under reduced pressure (13 kPa) at about 40 ° C for 2 hours. 0.11 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3-phenylprop-2-ynyl) piperidine-3-carboxylic acid is obtained in the form of: light yellow foam having a melting point of about 166 ° C while softening.

Infrared (KBr): 2931 and 2859 cm ^-1 (CH ₂ v), 3000 and 2750 cm ¹ (acidic OH v), 2800 and 1900 cm ^-1 (NH ⁺ v (tertiary amine salt and quinoline salt)), 1719 cm ^-1 (acidic C = 0 in), 1618, 1601,

1542 and 1492 cm ^-1 (aromatic core C = C in), 1275 cm ^-1 (acidic C-0

v), 1225 cm ^-1 (ether C-0 vas), 1022 cm ¹ (ether C-0 vs), 846 cm ^-1 (4,6-disubstituted quinoline CH γ), 761 and 693 cm ^-1 (monosubstituted phenyl) CH γ).

Mass spectrum (EI): m / z = 442 (M) ⁺ , 398 (M-CO 2) ⁺ , 327 (MC ₉ H ₇ ) ⁺ , 283, 327 (M-CO 2) ⁺ , 186 (C ₁₂ H ₁₂ O) ⁺ , 115 (C ₉ H ₇ ) ⁺ , 44 (CO ₂ ) ⁺ , 36 (HCl) ⁺ base peak.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3-phenylprop-2-ynyl) piperidine-3-carboxylate can be prepared as follows:

0.138 g tetrakis (triphenylphosphine) palladium, 0.041 g triphenylphosphine and 0.070 g copper (I) iodide are added in an inert atmosphere at about 20 ° C to a stirred solution of 0.7 g methyl (3R, 4R) -4- [3- (6-methoxyquinoline) 4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 12 cm ^{3 of} acetonitrile. 0.56 g of iodobenzene and 0.51 cm ^{3 of} triethylamine are then added successively. The mixture is stirred for

233 hours at about 20 ° C and then filtered. The filter cake is washed with 3 x 10 cm ³ acetonitrile. 100 cm ^{3 of} dichloromethane and 100 cm ^{3 of} water are added to the combined filtrates and the mixture is stirred. The organic phase is separated by settling and washed with 3 x 50 cm ^{3 of} saturated sodium chloride solution. After drying over magnesium sulfate and filtering, the organic solution is concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 1.1 g of an oil are obtained, which is purified by chromatography under argon at 50 kPa on a silica gel column (particle size 40-60 pm, diameter 3 cm, 65 g), eluting with ethyl acetate and collecting 2.5 cm ^3. fractions. Fractions 52 to 210 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 35 ° C. 0.64 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3-phenylprop-2-ynyl) piperidine-3-carboxylate is obtained. in the form of a light brown oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) -piperidine-3-carboxylate can be prepared as follows:

14.7 cm @ ^{3 of} triethylamine are added at about 20 DEG C. under an inert atmosphere to a stirred suspension of 10 g of methyl (32 R, 42 R) -4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine hydrochloride. 3-carboxylate of 100 cm ^{3 of} anhydrous dimethylformamide and after 45 minutes 3 cm ^{3 of} propargyl bromide diluted with 10 cm ^{3 of} anhydrous dimeoylformamide are added. The mixture was stirred for 15 minutes at about 20 ° C and then heated at about 45 ° C for 4 hours. After cooling, the reaction mixture is poured into a mixture of 250 cm ^{3 of} ethyl acetate and 250 cm ^{3 of} distilled water. The mixture is stirred for a few minutes and then the organic phase is separated by settling. The aqueous phase was extracted with ³ x 250 cm of ethyl acetate. The organic phases are combined, washed ³ x 200 cm of distilled water and dried over magnesium sulfate. Filtration and removal of the solvent under reduced pressure (2 kPa) at about 40 ° C afforded 7.8 g of an oil which was purified by chromatography under 50 kPa argon pressure on a silica gel column (particle size 40-63 µm, diameter 7 cm, 465 g), eluting with ethyl acetate and collecting 8 cm ^{3 of} fraction. Fractions 468-612 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. 4.7 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate are obtained in the form of an orange oil. .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate hydrochloride can be prepared as follows:

cm ^{3 of} thionyl chloride are added dropwise to a stirred suspension of 4.29 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -propyl] -1- (tert-butyloxycarbonyl) piperidine-3- of carboxylic acid in 50 cm ^{3 of} methanol cooled to about -30 ° C in an acetone-solid carbon dioxide cooling bath. The temperature of the obtained solution is adjusted to about 20 ° C and then the reaction mixture is stirred at this temperature for 16 hours. The solution is then concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C and the residue is triturated in about 30 ml of diisopropyl ether. The crystals obtained are filtered off, washed with 2 x 10 cm ^{3 of} diisopropyl ether and air-dried. 4.20 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate hydrochloride are obtained in the form of a solid, m.p.

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine-3-carboxylic acid can be prepared as follows :.

g (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -3-vinylpiperidine is dissolved in 3 cm ^{3 of} acetone. 14.5 cm @ ^{3 of} 3 M sulfuric acid, pre-cooled to 5 DEG C. in an ice / acetone bath, are then added to this solution with stirring. A solution of 4.64 g of potassium permanganate monohydrate is added over 30 minutes while maintaining the temperature between 0 and 7 ° C. The reaction mixture is stirred for 4 hours at a temperature between 10 and 17 ° C, filtered and the insoluble material is washed with 2 x 10 cm ^{3 of} water. An orange solution and a black inorganic solution are obtained

235 mass. The pH of the orange solution is then adjusted to pH 10 by the addition of 4.6 g of sodium carbonate. The mixture is filtered to give solution 1 and insoluble inorganic material 2. The black inorganic mass is stirred for 30 minutes with 20 cm ^{3 of} water and then added 2 cm ^3. The pH of the solution is adjusted to 12 by the potassium hydroxide solution. After filtering the mixture, solution 3 and the insoluble inorganic material 4 are obtained. The insoluble inorganic materials 2 and 4 are stirred for 15 minutes with 15 cm ^{3 of} water to which 3 cm ³ of potassium hydroxide solution are added. The suspension is filtered to give solution 5. The aqueous solutions 1, 3 and 5 are combined, added

2.31 g of di-tert-butyl dicarbonate and the mixture was stirred at about 20 ° C for 15 hours. The mixture is extracted with 6 x 10 cm ^{3 of} ethyl acetate. The organic phases are combined and washed with 20 cm ^{3 of} water and then with 20 cm ^{3 of} saturated sodium chloride solution. After drying over sodium sulfate, concentrating under reduced pressure (5 kPa) at about 35 ° C, 2.86 g of (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] acid is obtained. -1- (tert-butyloxycarbonyl) piperidine-3-carboxylic acid as a beige solid, which becomes a paste at 154 ° C.

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -3-vinylpiperidine can be obtained by applying the method disclosed in patent application FR 2 354 771.

Example 7

Acid, (3 R, 4 R) -4- [3- (6-méthoxyquinolin-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid

0.44 cm &lt; ^{3 &gt; of a} 5 N aqueous sodium hydroxide solution is added to a solution of 0.28 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- ( Of 2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 10 cm ^{3 of} methanol and heated to about 57 ° C for 20 hours. After cooling, the solution is concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.41 g of a residue is obtained, which is taken up in 20 cm @ ^{3 of} water, to which 3.5 cm @ ^{3 of} 1N chloro236 hydrochloric acid are added. After extraction of the aqueous phase with 5x15 cm ^{3 of} dichloromethane, the aqueous phase is concentrated to dryness under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is triturated in 10 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume). The insoluble material is filtered off and the filter cake is washed with 10 cm ^{3 of the} same mixture. The filtrate is dried over magnesium sulphate and then concentrated under reduced pressure (5 kPa) at about 40 ° C and finally dried under vacuum (13 Pa) at about 40 ° C for 2 hours. 0.15 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3- acid is obtained. carboxylic acid in the form of a yellow foam having a melting point of about 154 ° C under softening.

Infrared (KBr): 3057 cm @ ^-1 (aromatic CH3), 2933 a

2864 cm ^-1 (CH ₂ v), 3000 and 2750 cm ^-1 (acidic OH v), 2800 and 1900 cm ¹ (NH ⁺ (tertiary amine salt and quinoline salt) '), 1722 cm ^-1 (acid C = O (v), 1618, 1601, 1542 and 14 93 cm ¹ (aromatic core C = C v),

1275 cm ^-1 (acid C-0 v), 1217 cm ^-1 (ether C-0 v _as ), 1022 cm ^-1 (ether C-0 v _s ), 847 cm ^-1 (4,6-disubstituted quinoline CH γ )

765 cm ^-1 (o-disubstituted phenyl CH 2).

Mass spectrum (DCI): m / z = 461 (M + H) &lt; ^{+ &gt};.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate

0.041 g tetrakis (triphenylphosphine) palladium and 0.70 g copper (I) iodide are added at a temperature of about 20 ° C in an inert atmosphere to a stirred solution of 0.7 g methyl (3R, 4R) -4- [3- (6-methoxyquinol-4)]. -yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 14 cm ^{3 of} acetonitrile. 0.32 cm ^{3 of} 1-fluoro-2-iodobenzene and 0.51 cm ^{3 of} triethylamine are added successively. The mixture was stirred at about 20 ° C for 20 hours. The reaction mixture is filtered and the filter cake is washed three times with 10 cm ^{3 of} acetonitrile. The combined filtrates are transferred with stirring to a mixture of 10 cm ^{3 of} dichloromethane and 10 cm ^{3 of} water. The organic phase is separated by settling, washed with 3 x 50 cm ^{3 of} saturated solution

Sodium chloride, dried over magnesium sulfate and then filtered and concentrated under reduced pressure (2 kPa) at a temperature of about 35 ° C. The residue obtained is purified by chromatography under argon at 50 kPa on a silica gel column (particle size 40-63 µm, diameter 4 cm, height 14 cm), eluting with ethyl acetate and collecting 2 cm ^{3 of} fractions. Fractions 33 to 160 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.56 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2-fluorophenyl) prop-2-ynyl] piperidine- is obtained. 3-carboxylate as a light brown oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate was prepared using the method described in Example 6.

Example 8

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid dihydrochloride

10.5 cm ^{3 of a} 6 N aqueous hydrochloric acid solution are added to a solution of 0.66 g of methyl ( ³ R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -propyl] -1- [3] - (3-Fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate, heated at about 100 ° C for 3 hours, and then an additional 3.5 cm ^{3 of a} 6 N aqueous hydrochloric acid solution is added. After 4 hours, the reaction mixture is cooled to about 40 ° C and concentrated under reduced pressure (2 kPa) at about 60 ° C. The residue is taken up in 10 cm ^{3 of} water and 8 cm ^{3 of} dichloromethane and separated by settling. The aqueous phase is extracted with 2 x 6 cm ^{3 of} dichloromethane. The aqueous solution is concentrated to dryness under reduced pressure (1 kPa) at about 50 ° C. The residue obtained is dissolved in 5 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume), dried over sodium sulphate and, after filtration, the solvent is removed under reduced pressure (1 kPa) at a temperature of about 40 DEG C. The residue was taken up in a mixture of 2-propanol and diisopropyl ether, dissolved hot and filtered through paper. The filtrate

238 is cooled to about 25 ° C and concentrated under reduced pressure (1 kPa) at about 45 ° C. The residue is taken up in a mixture of 10 cm ^{3 of} dichloromethane and methanol (90/10 by volume) and concentrated again under the same conditions. 0.44 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine- dihydrochloride is obtained. 3-carboxylic acid in the form of a yellow foam, m.p.

1 H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.20-2.15 (unresolved peak, 6H), 2.35 (unresolved peak, 1H), 3.00 -3.90 (mt, 7H), 4.22 (s, 3H), 4.40 (broad s, 2H), 7.25-7.55 (mt, 4H), 7.60 (broad s, 1H), 7.75 (dd, J = 9 and 2 Hz, 1H), 7.82 (d, J = 5 Hz, 1H), 8.27 (d, J = 9 Hz, 1H), 8.97 (d, J = 5 Hz, 1H), 11.15-11.45 (broad unresolved peak, 1H).

Methyl · (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate

0.07 g of triphenylphosphine, 0.237 g of tetrakis (triphenylphosphine) palladium and 0.12 g of copper (I) iodide are added in an inert atmosphere at about 20 ° C to a stirred solution of 1.2 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 25 cm ^{3 of} acetonitrile. 0.56 cm @ ^{3 of} 1-fluoro-3-iodobenzene and 0.88 cm @ ^{3 of} triethylamine are then added successively. The mixture was stirred for 20 hours at about 20 ° C, the reaction mixture was filtered through diatomaceous earth (Celite) and the filter cake was washed with acetonitrile. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 35 ° C. The residue is taken up in a mixture of 80 cm ^{3 of} dichloromethane and 80 cm ^{3 of} water. After separation by settling, the organic phase is washed with 3 x 50 cm ^{3 of} saturated ammonium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure (2 kPa) at about 40 ° C. 1.91 g of an oil are obtained, which is purified by chromatography under argon pressure on a column of silica gel (particle size 40-63 µm, diameter 3 cm, 77 g), eluting with ethyl acetate and collecting 5 cm ^{3 of} fractions. Fractions containing the expected product

239 is concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 1.08 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3 is obtained. -carboxylate as a yellow oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate was prepared using the method described in Example 6.

Example 10

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- [2- (1,3-thiazol-2-yl-thio) -ethyl] -piperidine-3-carboxylic acid trihydrochloride

A mixture of 0.3 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidin-3 -carboxylate and 0.44 cm ^{3 of} 5 N aqueous sodium hydroxide in 2.5 cm ^{3 of} methanol are heated to about 60 ° C with stirring for 20 hours. After cooling, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C, the residue is taken up in 5 cm ^{3 of} water and acidified by addition of 1 cm ^{3 of} hydrochloric acid. The mixture is worked up under the same conditions as above and the residue is triturated in 10 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume). After filtering off the insoluble material, the filtrate is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.34 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3-thiazolylthio) ethyl] piperidine-3-carboxylic acid trihydrochloride is obtained. in the form of light yellow foam.

Infrared (KBr): 3097 cm ^-1 (thiazole CH v), 3058 and 3012 cm ¹ (aromatic CH v), 2929 and 2865 cm ^-1 (CH ₂ v), 3000 and 2750 cm ^-1 (acidic OH v) , 2800 and 1900 cm ^-1 (NH ^T (tertiary amine salt and quinoline salt)), 1715 cm ^-1 (acidic C = O v), 1617, 1600,

1543 and 1496 cm ^-1 (aromatic core C = C in), 1274 cm ^-1 (acidic C-0)

v), 1250 and 1219 cm ^-1 (ether C-0 vas), 1020 cm ^-1 (ether C-0 vs and alcohol C-0 v), 846 cm ^-1 (4,6-disubstituted quinoline CH γ),

240

740 cm ¹ (thiazole CH γ).

Mass spectrum (EI): m / z = 471 (M) ⁺ , 355 (M-C ₃ H ₂ NS 2) ⁺ , 341 (M-C ₄ H ₄ S ₂ ) ⁺ base peak, 297, 341 (M-CO 2) ⁺ , 186 (C12H) ₁₂ ON) ⁺ , 117 (C 3 H 3 NS 2) ⁺ , 44 (CO 2) ⁺ .

and

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidine-3-carboxylate

According to a method analogous to that of Example 4, methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate and 2-bromo-1- ( 1,3-thiazol-2-ylthio) ethane yields 0.31 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3- thiazol-2-ylthio) ethyl] piperidine-3-carboxylate as an orange lacquer.

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.30-1.85 (mt, 7H), 2.20-2.35 (mt, 1H), 2 35 (dd, J = 11 and 3 Hz, 1H), 2.50-2.85 (mt, 5H), 3.03 (t, J = 7 Hz, 7H), 3.25-3.40 ( mt, 2H), 3.53 (s,

3H), 3.94 (s, 3H), 7.31 (d, J = 5Hz, 1H), 7.35 (d, J = 2.5Hz,

1H), 7.40 (dd, J = 9 and 2.5 Hz, 1H), 7.63 (d, J = 3.5 Hz, 1H),

7.72 (d, J = 3.5Hz, 1H), 7.93 (d, J = 9Hz, 1H), 8.63 (d, J = 5Hz, 1H).

Example 11

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- [2- (2-fluoro-phenylthio) -ethyl] -piperidine-3-carboxylic acid hydrochloride

A mixture of 0.12 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-carboxylate and 0.6 cm ^{3 of a} 1 N aqueous solution of sodium hydroxide in 1.8 cm ^{3 of} methanol are stirred for 20 hours at a temperature of about 60 ° C. the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is taken up in 5 cm @ ^{3 of} water and acidified with 1 cm @ ^{3 of} 2 N aqueous hydrochloric acid. The mixture is reprocessed under the same conditions as above and the new residue is triturated at 5 cm ^3.

241 dichloromethane / methanol (90/10 by volume). The mixture is filtered and the filtrate is concentrated under reduced pressure (5 kPa) at 40 DEG C. and the residue is triturated in 3 cm @ ^{3 of} diisopropyl ether. The insoluble material is filtered off, washed with 2 x 1 cm ^{3 of} diisopropyl ether and air-dried. 0.14 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-carboxylic acid hydrochloride is obtained in the form of: beige solid with a melting point of about 148 ° C while softening.

Infrared spectrum (KBr): 3058 and 3013 cm ^-1 (aromatic CH v), 2934 and 2862 cm ^-1 (CH ₂ v), 3000 and 2750 cm ^-1 (acidic OH v), 2800 a

1900 cm ^-1 (NH ⁺ (tertiary amine salt and quinoline salt)), 1719 cm ^-1 (acidic C = O v), 1618, 1600, 1541 and 1497 cm ^-1 (aromatic core C = C v), 1276 cm ¹ (acid C-O v), 1251 and 1219 cm ^-1 (ether

C-0 v _as ), 1022 cm ¹ (ether C-0 v _s and alcohol C-0 v), 847 cm ^-1 (4,6-disubstituted quinoline CH γ), 760 cm ^-1 (1,2-disubstituted phenyl CH 2).

Ms (EI): m / z = 438 _(M-CO2) ^+, 355 (M-CsH4SF) ^+, 341 (M-C 7 H ₆ SF) ⁺ base peak, 297, 341 (M-CO2) ^+, 186 (C ₁₂ H ₁₂ ON) ⁺ , 128 (C ₆ H ₅ SF) ⁺ , 36 (HCl) ⁺ .

Mass spectrum (DCI): m / z = 483 (M + H) &lt; ^{+ &gt};.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3-carboxylate

According to a method analogous to that of Example 6, methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate and 2-bromo-1- (2-fluorophenylthio) ethane yields 0.17 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2-fluorophenylthio) ethyl] piperidine-3 -carboxylate in the form of an orange lacquer.

Infrared spectrum (CH ₂ Cl ₂ ): 2942 cm ^-1 (aliphatic CH v),

1727 cm -1 (C = O v), 1227 cm -1 (ether C-0 v), 848 cm -1 (quinol242 new CH?).

Example 12

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine-3-carboxylic acid dihydrochloride

0.5 cm ^{3 of} 5 N aqueous sodium hydroxide solution is added to a stirred solution of 0.34 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- ( thien-2-ylthio) ethyl] piperidine-3-carboxylate in cm ^{3 of} methanol and then heated to 60 ° C for 20 hours. After evaporation of the solvents under reduced pressure (5 kPa) at a temperature of about 40 ° C, the residue obtained is taken up in 5 cm ^{3 of} water and then acidified by adding 1 cm ^{3 of} 35% hydrochloric acid. The mixture is concentrated under the same conditions as above and the residue is taken up in 5 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume). The insoluble material is filtered off and the solution is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.35 g of 3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylic acid dihydrochloride is obtained. beige solid with a melting point of about 150 ° C while softening.

IR (KBr): 3102 cm ^{@ -1} (thiophene CH3), 3058 a

3012 cm ¹ (aromatic CH v), 2932 and 2865 cm ¹ (CH ₂ v), 3000 and 2750 cm ^-1 (acidic OH v), 2800 and 1900 cm ^-1 (NH ⁺ v (tertiary amine salt and quinoline salt) ), 1717 cm ^-1 (acidic C = O v), 1618, 1600,

1541 and 1496 cm ^-1 (aromatic core C = C in), 1276 cm ^-1 (acidic C-0

v), 1250 and 1218 cm ^-1 (ether C-0 vas), 1020 cm ^-1 (ether C-0 vs and alcohol C-0 v), 846 cm ^-1 (4,6-disubstituted quinoline CH γ),

725 cm ^-1 (thiophene CH γ).

Mass spectrum (EI): m / z = 355 (M-C ⁴ H 3 S 2) ⁴ ·, 341 (M-C ⁵ H 5 S 2) ⁴ · base peak, 297, 341 (M-CO ₂ ) ⁺ , 186 (C 12 H 12 NO) ⁺ , 115 (C 4 H) ₃ S ₂ ) ⁺ .

Mass spectrum (DCI): m / z = 471 (M + H) &lt; ^{+ &gt};.

243

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylate

According to a method analogous to that described in Example 4, methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -piperidine-3-carboxylate and 2-bromo-1- of (thien-2-ylthio) ethane yields 0.34 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] ] piperidine-3-carboxylate as a green lacquer.

^X H-NMR (300 MHz, d ₅ - (CD 3) 2 SO, δ in ppm): 1.30-1.90 (mt,

7H), 2.15-2.30 (Mt. 1H), 2.35 to 2 60 (mt, 4H), 2.65- 2.80 (mt, 2H). 3.02 (t, J = 7) Hz, 2H), 3.03 (broad t, J = 7.5 Hz, 2H), 3.54 (with, 3H), 3.95 (with, 3H), 7.06 1 ] dd, J = 5.5 and 3.5 Hz, 1H), 7.19 (Dd, J = 3.5 and 1, 5 Hz, 1H), 7 32 (d, J = 4.5Hz, 1H), 7.36 (d, J = 3 Hz, 1H) 7.42 (Dd, J = 9 and 3 Hz, 1H), 7.62 (Dd, J = 5.5 and

1.5 Hz, 1H), 7.95 (d, J = 9 Hz, 1H), 8.64 (d, J = 4.5 Hz, 1H).

Example 14

(3R, 4R) -4- [3- (6-Methoxy-quinol-4-yl) -propyl] -1- [2- (pyrid-2-yl-thio) -ethyl] -piperidine-3-carboxylic acid trihydrochloride

A solution of 0.5 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine-3-carboxylate in 7.8 cm @ ^{3 of} 6 N hydrochloric acid are heated with stirring at about 100 DEG C. for 2 hours. After concentrating the reaction mixture to dryness under reduced pressure (5 kPa) at a temperature of about 80 DEG C., the residue obtained is triturated in 10 cm @ ^{3 of} diisopropyl ether. The insoluble material is filtered off and then dried under reduced pressure (13 kPa) at a temperature of about 65 ° C. 0.55 g of (3R, 4R) -4- [3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (pyrid-2-yl-thio) -ethyl] -piperidine-3- acid is obtained. carboxylic acid in the form of a cream colored solid, m.p. about 165 ° C with softening.

¹ H-NMR spectrum (400 MHz, ds- (CD ₃ ) ₂ SO, δ in ppm): 1.20-2.40 and 3.00-3.60 (mts, 16H), 3.62 (broad t J = 7.5 Hz, 2H) 4.05 (s,

244

3Η), 7.21 (dd, J = 8 and 5 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 7.67 (broad s, 1H), 7.7.3 (dd, J) = 8 and 1.5 Hz, 1H), 7.84 (dd, J = 9 and 2.5 Hz, 1H), 7.95 (d, J = 5 Hz, 1H), 8.45 (d, J = 9 Hz, 1H), 8.49 (broad d, J = 5 Hz, 1H), 9.05 (d, J = 5 Hz, 1H), 11.25 (unresolved peak, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine-3-carboxylate

According to a method analogous to that described in Example 4, methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -piperidine-3-carboxylate and 2-bromo-1- (pyrid-2-ylthio) ethane yields 0.52 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine-3-carboxylate as a yellow oil.

Infrared spectrum (CH 2 Cl 2): 2949 cm ^-1 (aliphatic CH v), 1737 cm ^-1 (C = O v), 1227 cm ^-1 (ether C-O v), 845 cm ^-1 (quinoline CH 2).

Example 15

(3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid dihydrochloride

A solution of 0.55 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylate in 8.5 cm ³ 6 N hydrochloric acid is heated with stirring to about 100 ° C for 2 hours. The reaction mixture is cooled and then concentrated to dryness under reduced pressure (5 kPa) at a temperature of about 80 ° C. The residue is triturated in 15 cm @ ^{3 of} diisopropyl ether. The insoluble material is filtered off and the filter cake is washed with 10 cm @ ^{3 of} diisopropyl ether. The resulting solid was dried under reduced pressure (13 Pa) at about 60 ° C for 2 hours. 0.51 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid dihydrochloride is obtained in the form of a beige solid. 150 DEG C. under softening.

245 ¹ H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) 2 SO with addition of a few drops of d ₄ -CD ₃ COOD at 0 ° C, δ in ppm): 1.20-2.35 and 2.75 -3.50 (mts, 29H), 4.03 (s, 3H), 7.57 (mt, 1H), 7.60-7.75 (mt, 2H), 8.24 (d, J = 9) Hz, 1H), 8.85 (d, J = 5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylate

According to a method analogous to that of Example 4, methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) propyl] -piperidine-3-carboxylate and 2-bromo- of 1- (cyclohexylthio) ethane yields 0.57 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3 -carboxylate in the form of an orange oil.

Infrared spectrum (CH 2 Cl 2): 2934 cm ^-1 (aliphatic CH v),

1732 cm ^-1 (C = O v), 1227 cm ^-1 (ether C-O v), 848 cm ^-1 (quinoline CH v).

Example 16

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- [4-oxo-4- (thien-2-yl) butyl] bis (trifluoroacetate) piperidine-3-carboxylic acid

1.76 cm @ ^{3 of} 2- (4-chlorobutyro) thiophene are added with stirring at a temperature of about 20 DEG C. under an inert atmosphere to a solution of 1.55 g of bis (trifluoroacetate) (32 R, 42 R) -4- [ 3- (6-methoxyquinol-4-yl) -propyl] -piperidine-3-carboxylic acid in 40 cm ^{3 of} anhydrous acetone, and then 3.86 g of potassium carbonate are added. The mixture is heated to about 57 ° C for 20 hours. After cooling the reaction mixture and filtering off the insoluble material, the filter cake is washed with 10 cm ^{3 of} acetone and the filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπι, diameter 4 cm, height 35 cm), eluting with a mixture of dichloromethane and methanol (90/10 by volume) and collected at 100 cm ^3.

246 fractions. Fractions 43 to 122 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.09 g of an oil are obtained, which is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπι, diameter 4 cm, height 35 cm), eluting with a mixture of dichloromethane and methanol (90/10 by volume) and collected. , with a 100 cm ³ fraction. Fractions 125 to 216 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.48 g of an oil is obtained which is purified in the form of a bis (trifluoroacetate) prepared from 0.1 cm @ ³ of trifluoroacetic acid in a mixture of 10 cm @ ^{3 of} dichloromethane and 5 cm @ ^{3 of} methanol. After evaporation of the reaction mixture under reduced pressure (5 kPa) at a temperature of about 40 ° C, the residue is taken up in 10 cm ^{3 of} diethyl ether and the solid is filtered off. 0.35 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [4-oxo-4- (thien-2-yl) bis (trifluoroacetate) bis (trifluoroacetate) acid is obtained. butyl] piperidine-3-carboxylic acid as a beige solid with a purity of 90%.

¹ H-NMR spectrum (400 MHz, d 6 - (CD ₃ ) 2 SO with the addition of several

peak d ₄ -CD ₃ COOD at temperature 110 ’C, δ v ppm): 1 50 to 2.25 and 2.95-3.55 (mts, 20H), 3.96 (s, 3H) 7.23 (Mt. IH), 7,36 (D, J = 5 Hz, 1H), 7.40-7.50 (mt, 2H), 7.88 (d, J = 4 Hz, IH), 7 92 (d, J = 5Hz, 1H), 7.99 (d, J = 9 Hz, 1H) 8.66 (D, J = 5 Hz,

1H).

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -piperidine-3-carboxylic acid bis (trifluoroacetate)

1.75 cm @ ^{3 of} pure trifluoroacetic acid is added at a temperature of about 20 DEG C. to a stirred suspension of 1.5 g of (3R, 4R) -1- (tert-butyloxycarbonyl) -4- [3- (6-methoxyquinol-4-) acid. y1) propyl] piperidine-3-carboxylic acid in 15 cm ^{3 of} dichloromethane. The solution obtained is stirred at this temperature for 20 hours and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 2.46 g of (3R, 4R) -4- [3- (6-methoxy-quinol-4-yl) -propyl] -piperidine-3-carboxylic acid bis (trifluoroacetate) are obtained as a brown oil.

247

(3 R, 4 R) -1- (tert-Butyloxycarbonyl) -4- (3- (6-methoxyquinol-4-yl) propyl) piperidine-3-carboxylic acid was prepared using the method described in Example 6.

Example 19

(3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-3-yl) prop-2-ynyl] piperidine-3-carboxylic acid

3.9 cm ^{3 of a} 1 N aqueous solution of sodium hydroxide are added to a solution of 0.6 g of methyl ( ³ R, 4 R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-3-yl) prop-2-ynyl] piperidine-3-carboxylate in 10 cm ^{3 of} dioxane and heated at about 65 ° C for 16 hours. The reaction mixture is cooled and extracted with 3 x 50 cm ^{3 of} ethyl acetate. The aqueous phase is acidified with 3.9 cm @ ^{3 of} 1N hydrochloric acid. The solution is taken up in 10 cm ^{3 of} saturated aqueous sodium bicarbonate solution and extracted with 2 x 20 cm ^{3 of} ethyl acetate and 2 x 20 cm ^{3 of} dichloromethane, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure (2 kPa) at 45 ° C. 0.32 g of (3R, 4R) -4- [3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-3-yl) -prop-2-] - was obtained. vinyl] piperidine-3-carboxylic acid in the form of a white foam.

¹ H-Ni MR spectrum (300 M Hz, d ₆ - (CD ₃ ) ₂ SO, δ ppm (ppm): 1.20-1.90 (Mt. 7H), 2 , 43 (mt (1H), 2.50-3.00 (mt, 4H), 3.04 (broad t, J = 7.5 Hz, 2H) , 3, 55 (s, 2H), 3.93 (s, 3H), 7.15 (dd, J = 5 a 1.5 Hz, 1H), 7 , 32 (d, J = 5 Hz, 1H) 35-7.50 (mt, 2H). 7.62 (Dd, J = 5 and 3 Hz, 1H) , 7.75 (dd, J = 3) and 1.5 Hz, 1H), 7.92 (D,

J = 9 Hz, 1H), 8.62 (d, J = 5 Hz, 1H), 12.00 and 13.00 (very broad unresolved peak, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-3-yl) prop-2-ynyl] piperidine-3-carboxylate

The reaction was carried out as described in Example 2 from 1 g of methyl (3 R, 4 R) -4- (3- (6-methoxyquinol-4-yl) propyl) -1- (prop-2-ynyl) piperidine-3-carboxylate, 0.9 g of 3-iodothiophene, 0.2 g of tetrakis248 (triphenylphosphine) palladium, 0.1 g of copper iodide, 0.060 g of triphenylphosphine and 0.75 cm ^{3 of} triethylamine. Silica gel pressure (particle size 40-63 µm, diameter 3.5 cm, height 35 cm) eluting with ethyl acetate and collecting 40 cm ³ fractions. Fractions 18 to 49 were pooled and concentrated under reduced pressure. (5 kPa) at a temperature of about 40 [deg.] C. 0.6 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-3) is obtained. -yl) prop-2-ynyl] -piperidine-3-carboxylate as a brown oil.

3-Iodothiophene can be prepared as described by N. A. Petasis et al., Synlett., 1999, 141.

Example 21

(3R, 4R) -1- [2- (3-Fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylic acid dihydrochloride j

0.8 g methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy- (6-methoxyquinol-4-yl) propyl] piperidine- The 3-carboxylate in cm ^{3 of} methanol and 1.25 cm ^{3 of} 5N sodium hydroxide is heated with stirring at about 60 ° C for 4 hours. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 50 ° C. 15 cm @ ^{3 of} water and 2 cm @ ^{3 of} 5N hydrochloric acid are then added to the residue. The reaction mixture was then evaporated to dryness. The residue obtained is triturated in a mixture of dichloromethane and methanol (90/10 by volume). The sodium chloride is filtered off and the filtrate is concentrated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The foam obtained is triturated in diethyl ether and the resulting solid is filtered off. 0.75 g of a beige solid is obtained. This solid is dissolved in a mixture of 50 cm ^{3 of} chloroform and 50 cm ^{3 of} acetonitrile. The insoluble material is filtered off and the filtrate is acidified with 20 cm @ ^{3 of a} 1 N solution of hydrogen chloride in diethyl ether. The reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The residue is triturated in diethyl ether. The solid was filtered off and dried under vacuum.

249

0.7 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy- (6-methoxyquinol-4-yl) -] - is obtained. propyl] piperidine-3-carboxylic acid as a beige solid.

^X H-NMR (400 MHz, _d6 - _{(CD3) 2} SO, δ in ppm): 1.25-1.90 (mt, 8H), 2.22 (mt, 2H), 2.65- 2.90 (mt, 2H), 3.35-3.60 (mt, 4H), 3.91 and 3.93 (2 s, 3H), 4.29 (unresolved peak, 1H), 5.28 ( mt, 1H)

5.50 and 5.52 (2 d, J = 4.5 Hz, 1H), 7.07 (mt, 1H), 7.28 (dd,

J = 4 and 1 Hz, 1H), 7.35-7.45 (mt, 2H), 7.50-7.60 (mt, 2H), 7.95 (d, J = 9 Hz, 1H), 8.71 (d, J = 5Hz, 1 H).

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy- (6-methoxyquinol-4-yl) -propyl] piperidine-3-carboxylate

0.16 g of sodium borohydride is added to a solution of 1.8 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl)] with stirring. 3-oxopropyl] piperidine-3-carboxylate in 20 cm ^{3 of} methanol. The reaction mixture was stirred at room temperature for 2 hours. After evaporation of the methanol under reduced pressure (5 kPa), the mixture is stirred with 50 cm ^{3 of} dichloromethane and 50 cm ^{3 of} saturated ammonium chloride solution. The organic phase is separated by settling and then dried over magnesium sulphate. Filtration through filter paper and concentration under reduced pressure (5 kPa) at a temperature of about 40 ° C gives 1.6 g of product which is purified by chromatography on atmospheric pressure on a silica gel column (particle size 20-45 µm, diameter 3 cm, 60 g), eluting with a mixture of dichloromethane and methanol (96/4 by volume) and collecting 10 cm ^{3 of the} fraction. Fractions 30 to 45 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 1.05 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy- (6-methoxyquinol-4-yl) propyl] is obtained. piperidine-3-carboxylate as a brown oil.

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate can be prepared as follows:

250

A mixture of 6.44 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate, 3.43 g of 1-chloro-2- (3 -fluorophenylthioethane, 8.85 g of potassium carbonate and 1.24 g of potassium iodide in 100 cm ^{3 of} acetonitrile are heated at about 65 ° C for 48 hours. After cooling, the insoluble material was filtered off. The filtrate is concentrated under reduced pressure (5 kPa) at about 40 ° C. The oily residue is purified by silica gel column chromatography (particle size 20-45 µm, diameter 6 cm, 270 g), eluting with a mixture of dichloromethane, ethyl acetate and methanol (50/50/3 by volume) and collecting 50 cm ^{3 of} fractions. Fractions 19 to 25 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 2.1 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3 are obtained. -carboxylate in the form of a brown oil.

1-Chloro-2- (3-fluorophenylthio) ethane may be used. prepare as follows:

A solution of 3.75 g of sodium hydroxide pellets in 50 cm ^{3 of} distilled water is added dropwise to a solution of 10 g of 3-fluorothiophenol and 0.1 cm ^{3 of} Aliquat 336 in 125 cm ^{3 of} 1,2-dichloroethane. The temperature is raised to 33 ° C. The reaction mixture was stirred at room temperature for 5 hours. The organic layer is separated by settling, washed with 50 cm ^{3 of} 0.1 N hydrochloric acid and 50 cm ^{3 of} distilled water and dried over magnesium sulfate. After filtering through filter paper and concentrating under reduced pressure (5 kPa) at a temperature of about 40 ° C, 15 g of residue are obtained, which is purified by chromatography under atmospheric pressure on a silica gel column (particle size 20-45 µm, diameter 6 cm, 400 g) ), eluting with cyclohexane and collecting 100 cm ^{3 of} fraction. Fractions 15 to 40 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 13.6 g of 1-chloro-2- (3-fluorophenylthio) ethane are obtained in the form of a colorless oil.

Methyl (3R, 4R) -4- [3- (2R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3-phenylpropyl) piperidine-3- carboxylate

251

Sodium borohydride (0.15 g) is added portionwise at about 20 ° C in an inert atmosphere to a stirred solution of 1.59 g of methyl (3 R, 4 R) - [3- (6-methoxyquinol-4-yl) -3] oxopropyl] -1- (3-phenylpropyl) -piperidine-3-carboxylate in 25 cm ^{3 of} methanol. The mixture is then stirred for 75 minutes at about 20 ° C. 15 cm @ ^{3 of} distilled water are then added, maintaining the temperature at the same temperature. The milky appearance mixture is then concentrated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The residue is taken up in 40 cm @ ^{3 of} distilled water, to which 80 cm @ ^{3 of} dichloromethane are added, stirred and then the layers are separated by settling. The organic phase is separated, washed with 40 cm @ ^{3 of} water and dried over magnesium sulphate. Filtration through filter paper and evaporation of the solvent under reduced pressure (5 kPa) at about 40 ° C gave 1.39 g of methyl (3 R, 4 R) -4- [3- (R, S) -hydroxy- 3- (6-methoxyquinol-4-yl) propyl] -1- (3-phenylpropyl) piperidine-3-carboxylate as an orange foamy sticky solid.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (3-phenylpropyl) piperidine-3-carboxylate can be prepared as follows:

A suspension of 4.51 g of methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate and 2.3 g of potassium carbonate in 75 cm ^{3 of} acetone is heated to about 58 ° C with stirring. A solution of 2.5 cm ^{3 of} 1-bromo-3-phenylpropan-3-one in 7.5 cm ^{3 of} acetone is then added dropwise at this temperature. Heating is continued for 19 hours. After cooling, the reaction mixture is filtered and the filter cake is washed with 2 x 30 cm ^{3 of} acetone. The filtrate and washings were combined and concentrated under reduced pressure (5 kPa) at about 30 ° C. 7.2 g of product are obtained in the form of an oil which is purified by chromatography on a silica gel column (20-45 µm particle size, 7 cm diameter, 712 g), eluting with a mixture of chloroform, methanol and aqueous ammonia (12 g). (2.25 / 0.38 by volume) and 65 cm ³ fractions are collected. Fractions 9 to 14 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 30 ° C. 6.7 g are obtained

252 of an oil which was subjected to a second purification by atmospheric pressure chromatography on a silica gel column (particle size 20-45 µm, diameter 4.8 cm, 336 g), eluting with a mixture of ethyl acetate and methanol (9/1 by volume) and collected 20 cm ³ fraction. Fractions 71 to 122 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 30 ° C. 1.66 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (3-phenylpropyl) piperidine-3-carboxylate are obtained in the form of a brown oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate can be prepared as follows:

A solution of 19.4 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-carboxylic acid (80% content) in 355 cm ^{3 of} methanol are cooled to about -30 ° C. Then 7.7 cm ^{3 of} thionyl chloride are added with stirring, maintaining the temperature between -25 and -30 ° C. After the addition, the reaction mixture is maintained at a temperature of about -30 ° C for 30 minutes and then allowed to rise to about 20 ° C. The mixture was stirred at room temperature for 19 hours, then concentrated under reduced pressure (5 kPa) at about 30 ° C. The residue is taken up in 300 cm @ ^{3 of} water, to which 200 cm @ ^{3 of} dichloromethane are added and stirred. The organic phase is separated by settling and the aqueous phase is extracted again with 200 cm @ ^{3 of} dichloromethane. Thereafter, the pH of the aqueous solution is adjusted to 8 by the stepwise addition of solid sodium bicarbonate. After extraction of the obtained alkaline solution with 3 x 200 cm ^{3 of} dichloromethane, the combined organic extracts are washed with 2 x 200 cm ^{3 of} water and dried over magnesium sulfate. The mixture is filtered through filter paper and the organic solution is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 4.51 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate are obtained in the form of a brown lacquer.

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-carboxylic acid can be prepared as follows:

253

A solution of 36 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -3-vinylpiperidine in 54 cm ^{3 of} acetone is cooled to about 0 ° C. then 150 cm ^{3 of} 3M sulfuric acid are added with stirring over 15 minutes, maintaining the temperature between 0 and 5 ° C. the temperature is lowered to about 0 ° C and a solution of 32 g of potassium permanganate in 200 cm ^{3 of} distilled water is added dropwise. The reaction mixture is stirred for an additional 45 minutes at a temperature between 10 and 15 ° C and then the temperature is raised to about 20 ° C. The mixture is stirred at this temperature for 3 hours, then the reaction mixture is cooled to about 0 ° C and, at a temperature below 10 ° C, 160 cm ^{3 of a} 38% potassium hydroxide solution are slowly added. The mixture is stirred for 30 minutes at about 10 ° C and then filtered. The filter cake is transferred to 300 cm ^{3 of} water to which 15 cm ^{3 of} 38% potassium hydroxide is added and the mixture is stirred for 20 minutes. After filtering and washing the filter cake with 2 x 200 cm ^{3 of} distilled water, the filtrates are combined and 24 g of di-tert-butyl dicarbonate are added. The solution was stirred at about 20 ° C for 15 hours. After addition of 1 L of ethyl acetate and stirring, the mixture is partitioned by settling and the pH of the separated aqueous phase is adjusted to 5 by adding 38 cm ^{3 of} concentrated hydrochloric acid. The mixture is again extracted with 5x11 of ethyl acetate. The extracts were combined and washed with 2 x 11 saturated sodium chloride solution. The organic solution is dried over magnesium sulphate, filtered through filter paper and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 21.2 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-carboxylic acid are obtained in the form of a brown solid. mp 114 ° C with softening.

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -3-oxopropyl] -3-vinylpiperidine can be obtained by applying the method described in patent application FR 2,354,771.

Example 22

(3R, 4R) -1- [2- (3-Fluorophenylthio) ethyl] -4254 acid dihydrochloride

- [3- (R, S) -Fluoro-3- (6-methoxy-quinol-4-yl) -propyl] -piperidine-3-carboxylic acid

0.9 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] of piperidine-3-carboxylate in cm ^{3 of} methanol and 1.4 cm ^{3 of} 5N sodium hydroxide is heated with stirring at about 60 ° C for 4 hours. The reaction mixture is concentrated under reduced pressure (5 kPa) at about 50 ° C. 15 cm @ ^{3 of} water are added to the residue, followed by 2.1 cm @ ^{3 of} 5N aqueous hydrochloric acid. The reaction mixture was again evaporated to dryness. The residue is taken up in a mixture of dichloromethane and methanol (90/10 by volume). The sodium chloride is filtered off and the filtrate is concentrated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The foam obtained is triturated in diethyl ether. The resulting solid was filtered off to give 0.9 g of a beige solid. This solid is dissolved in a mixture of 50 cm ^{3 of} chloroform and 50 cm ^{3 of} acetonitrile. The insoluble material is filtered off and the filtrate is acidified with 20 cm @ ^{3 of a} 1N solution of hydrogen chloride in diethyl ether. The reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The residue is triturated in diethyl ether. The resulting solid was filtered off and dried under vacuum. 0.9 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) acid] hydrochloride is obtained. propyl] piperidine-3-carboxylate as a beige solid.

¹ H-NMR spectrum (600 MHz, d ₆ - (CD ₃ ) ₂ SO with the addition of a few drops of d ₄ -CD ₃ COOD at 110 ° C, δ in ppm): 1, 40-2.25 and 2.65-3 65 (mts, 16H), 3.96 (s, 3H), 6.31 (mt, _JHF = 47Hz, 1H), 7.03 (mt, 1H), 7.25 (mt, 2H), 7.30-7.45 (mt, 2H), 7.53 (mt, 1H), 7.57 (mt, 1H), 8.09 (d, J = 9Hz, 1H), 8.82 (d , J = 5 Hz, 1 H).

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] piperidine-3- carboxylate

1.7 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate

255 is dissolved in 17 cm ^{3 of} dichloromethane under argon. 0.53 cm ^{3 of} diethylaminosulfur trifluoride are added dropwise with stirring at 20 ° C. The mixture is stirred at room temperature for 2 hours, then the reaction mixture is cooled to 15 [deg.] C. and 20 cm &lt; ^{3 &gt; of} saturated sodium bicarbonate solution are added dropwise. The organic phase is separated by settling and the aqueous phase is extracted with 2 x 50 cm ^{3 of} dichloromethane. The combined organic extracts are washed with 2 x 50 cm ^{3 of} distilled water and dried over magnesium sulfate. The mixture is filtered through filter paper and the solution is evaporated under reduced pressure (5 kPa) at a temperature of about 30 ° C. 1.6 g of an oil are obtained, which is purified by double column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 µm, diameter 3 cm, 60 g), eluting with a mixture of dichloromethane and methanol (98/2 by volume) and 10 cm ³ fractions are collected. Fractions 15-25 are combined for the first purification. Fractions 18-30 are combined for the second purification and concentrated under reduced pressure (5 kPa). 0.92 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl)] was obtained. propyl] piperidine-3-carboxylate as a brown oil.

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3- The carboxylate is obtained using the method described in Example 21.

Example 23

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (1,3-thiazol-2-ylthio) dihydrochloride ) ethyl] piperidine-3-carboxylic acid

A mixture of 0.21 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3-thiazole) 2-ylthio) ethyl] piperidine-3-carboxylate and 0.33 cm ^{3 of} 5 N aqueous sodium hydroxide in 3 cm ^{3 of} methanol are heated with stirring at about 60 ° C for 18 hours. After cooling, the reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C, the residue is taken up in 6 cm ^{3 of} water and

256 is then washed with 6 cm ^{3 of} ethyl acetate. The aqueous phase is evaporated to dryness under reduced pressure (5 kPa) at a temperature of about 80 ° C. The residue is triturated in 5 cm @ ^{3 of} dichloromethane and then acidified by the addition of 1 cm @ ^{3 of a} 3.3 N solution of hydrogen chloride in diisopropyl ether. The insoluble material is filtered off and washed with 2 x 3 cm ³ of dichloromethane / methanol (90/10 by volume). The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. There was thus obtained (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1, 2, 4R, 4R) -hydrochloride, 0.19 g. 3-thiazol-2-ylthio) ethyl] piperidine-3-carboxylic acid as a beige amorphous solid at about 75 ° C with softening.

³ H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) ₂ SO with addition of a few drops of d ₄ -CD ₃ COOD at 100 ° C, δ in ppm): 1.35-2.15 and 2.50 -3.70 (mt, 16H), 3.94 (s, 3H), 5.28 (mt, 1H), 7.40-7.75 (mt, 5H), 7.99 (d, J = 9 Hz) (1H), 8.72 (d, J = 5Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (1,3-thiazol-2-ylthio)] ethyl] piperidine-3-carboxylate

Analogously to Example 5, but using methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (1,3-thiazole) -2-ylthio) ethyl] piperidine-3-carboxylate and sodium borohydride gave 0.17 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4)]. -yl) propyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidine-3-carboxylate as a viscous yellow oil.

IR (CC1 _4): 2949 cm ^-1 (aliphatic CH at).

1736 cm ^-1 (C = O), 1228 cm ^-1 (ether C-0), 1031 cm ^-1 (alcohol C-0), 854 cm ¹ (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidine-3-carboxylate can be prepared analogously to Example 4 from methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate and 2- (2- chloroethylthio) thiazole.

257

2- (2-Chloroethylthio) thiazole can be prepared as follows:

1.2 cm @ ^{3 of} 1-bromo-2-chloroethane are added at a temperature of about 20 DEG C. to a stirred solution of 1.47 g of 2-mercaptotriazole and 1.95 g of potassium carbonate in 12.5 cm @ ^{3 of} dimethylformamide. The mixture is then stirred for 2 hours at about 20 ° C. The insoluble material is filtered off and washed with 2 x 5 cm ^{3 of} dimethylformamide. The filtrate is added to a mixture of 50 g of crushed ice and 50 cm ^{3 of} distilled water, then 50 cm ^{3 of} diethyl ether are added and the mixture is stirred. The aqueous phase is separated by settling and then extracted with 2 x 25 cm ^{3 of} diethyl ether. The combined ether phases are washed with 2 x 25 cm ^{3 of} water and dried over magnesium sulfate. After filtration through filter paper, the organic solution is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 2.11 g of 2- (2-chloroethylthio) thiazole are obtained in the form of a yellow oil.

Example 24

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine dihydrochloride -3-carboxylic acid i

A mixture of 0.45 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-2- ylthio) ethyl] piperidine-3-carboxylate, 3.5 cm ^{3 of} methanol and 0.54 cm ^{3 of} 5 N aqueous sodium hydroxide are heated with stirring at about 60 ° C for 20 hours. After evaporation of the solvent under reduced pressure (5 kPa) at a temperature of about 40 DEG C., the residue is taken up in 3 cm @ ^{3 of a} 6N hydrochloric acid solution. The solution is evaporated under the same conditions and the residue obtained is triturated in a mixture of dichloromethane and methanol (90/10 by volume). The insoluble material is filtered off and washed with 2x1 cm ^{3 of} this mixture. The filtrate is dried over magnesium sulfate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. After air drying, 0.16 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylic acid in the form

258 beige solid with a melting point of about 148 ° C while softening.

@ 1 H NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO with the addition of a few kva- d ₄ -CD ₃ COOD,, v ppm): 1.35-2.30 and 2.80-3.75 (mts, 16H), 3, 98 and 4.00 (2 s, 3H), 5.40-5.63 (mt, 1H), 7.05-7.15 (Mt. 1H), 7.25-7.40 (mt, 1 H), 7.50-7.80 (mt, 3H), 8.00 (mt, 1H), 8.24 (wide d, J = 9 Hz, 1H), 9.05 (d, J) = 5 Hz, 1 H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine 3-carboxylate

Analogously to Example 21 except that methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (thien-2-) is used. ylthio) ethyl] piperidine-3-carboxylate and sodium borohydride gave 0.95 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] 1- [2- (Shadow-2-ylthio) ethyl] piperidine-3-carboxylate as an orange oil.

Infrared spectrum (CH ₂ Cl ₂ ): 3600-3150 cm ^-1 (alcohol OH n), 2951 cm ^-1 (aliphatic CH v), 1732 cm ¹ (C = O v), 1228 cm ^-1 (ether)

C-0 v), 1031 cm ^-1 (alcohol C-0 v), 847 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylate can be prepared analogously as described in Example 4, from methyl 3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate and

2- (2-chloroethylthio) thiophene.

2- (2-Chloroethylthio) thiophene can be prepared as follows:

4.72 cm ^{3 of} thiophene-2-thiol are added to a stirred solution of 8.25 cm ^{3 of} 20% aqueous sodium hydroxide solution and 14.6 cm ^{3 of} 1-bromo-2-chloroethane at a temperature of about 20 ° C. The mixture was stirred at about 20 ° C for 6 hours. then 40 cm ^{3 of} diethyl ether are added and the organic phase is washed with water and dried over magnesium sulphate. After filtering through filter paper, the organic solution was evaporated

259 at a reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 50 kPa of nitrogen on a silica gel column (particle size 20-45 μπι, diameter 4.5 cm, 250 g), eluting with a mixture of cyclohexane and ethyl acetate (95/5 by volume). 7.27 g of 2- (2-chloroethylthio) thiophene are obtained in the form of a yellow oil.

Example 25

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] dihydrochloride ] piperidine-3-carboxylic acid

2.1 cm ^{3 of} 5N aqueous sodium hydroxide is added to a solution of 1.3 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) - propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 15 cm ^{3 of} dioxane and the solution is heated to about 60 ° C for 16 hours. After cooling, the solution obtained is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue obtained is purified by chromatography under argon pressure of 50 kPa on an Amicon silica gel column (particle size 20-45 μπι, diameter 4 cm, height 24 cm), eluting with a mixture of chloroform, methanol and ammonia (24/12/1 by volume) and collected. with 30 cm ³ fractions. Fractions 41 to 58 are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 1.0 g of foam is obtained, which is dissolved in 8 cm @ ^{3 of} acetone. This solution is added to 5 cm ^{3 of a} 1 N solution of hydrogen chloride in

I I ether. The mixture is stirred for 5 minutes, the solid is filtered off and dried to constant weight under reduced pressure (2 kPa) at a temperature of about 40 ° C. 820 mg of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop] dihydrochloride are obtained. -2-ynyl] piperidine-3-carboxylic acid as a hygroscopic solid.

^X H-NMR (300 MHz, D6 (CD _{3) 2} SO with a few drops of _{d4-CD 3} COOD, δ in ppm): from 1.35 to 2.30 and 2.90 to 3.65 (mts 12H), 3.99 (s, 3H), 4.20-4.50 (mt, 2H), 5, 40-5, 60 (mt, 1H), 7.25-7.70 (mt,

260

5Η), 7.70-7.80 (mt, 1H), 7.99 (mt, 1H), 8.20 (d, J = 9Hz, 1H), 9.01 (broad d, J = 5Hz) , 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] ] piperidine-3-carboxylate

Sodium borohydride (0.193 g) is added in two portions at about 20 ° C under an inert atmosphere to a stirred solution of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 30 cm ^{3 of} methanol. The mixture is then stirred at a temperature of about 20 ° C. 10 cm @ ^{3 of} distilled water are then added, maintaining the temperature at the same temperature. The mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is taken up in 25 cm @ ^{3 of} distilled water. The mixture is extracted with a total of 150 cm ^{3 of} dichloromethane. The organic phases are combined, washed with 30 cm @ ^{3 of} water and dried over magnesium sulphate. After filtration through filter paper and evaporation of the solvent under reduced pressure (5 kPa) at a temperature of about 40 ° C, 1.8 g of foam is obtained, which is purified by chromatography on an Amicon silica gel column (particle size 20-45 μηη, diameter 3). cm, height 30 cm), eluting with ethyl acetate and collecting 50 cm ³ fractions. Fractions 17 to 28 are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 1.4 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) -propyl] are obtained. enyl) prop-2-ynyl] piperidine-3-carboxylate in the form of a light yellow foam.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate can be obtained by following these steps:

0.404 g of tetrakis (triphenylphosphine) palladium, 0.118 g of triphenylphosphine and 0.91 g of copper iodide are added in an inert atmosphere at a temperature of about 20 ° C to a stirred solution of 1.97 g of methyl (3R, 4R) -4- [3- (6) -methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 40 cm ^{3 of} acetonitrile. Then it is added gradually

261

0.90 cm ^{3 of} 3-fluoroiodobenzene followed by 1.40 cm ^{3 of} triethylamine. The mixture was stirred for 15 hours at about 20 ° C and then filtered through diatomaceous earth. The filter cake is washed with 3 x 10 cm ³ acetonitrile. The combined filtrates are concentrated under reduced pressure (2 kPa) at about 40 ° C. 4.3 g of an oil are obtained, which is purified by chromatography on a silica gel column (particle size 20-45 µm, diameter 3 cm, height 60 cm), eluting with ethyl acetate and collecting 50 cm ^{3 of} fractions. Fractions 21 to 42 are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 35 ° C. 2 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine are obtained. -3-carboxylate as a yellow oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-carboxylate can be obtained as follows: :

19.6 cm ^{3 of} triethylamine are added at a temperature of about 20 ° C to a stirred suspension of 15 g of methyl ( ³ R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine dihydrochloride 3-carboxylate in 150 cm ^{3 of} anhydrous dimethylformamide under an inert atmosphere and after 45 minutes followed by the addition of 3.95 g of propargyl bromide diluted with 5 cm ^{3 of} anhydrous dimethylformamide. The mixture was stirred for 15 minutes at about 20 ° C and then heated at about 45 ° C for 4 hours. After cooling, the mixture is poured into a mixture of 150 cm ^{3 of} ethyl acetate and 150 cm ^{3 of} distilled water. The mixture is stirred for a few minutes and then the organic phase is separated by settling. The aqueous layer is extracted with 2 x 150 cm ^{3 of} ethyl acetate. The organic phases are combined, washed with 3 x 200 cm ^{3 of} distilled water and dried over sodium sulfate. Filtration and evaporation of the solvent under reduced pressure (2 kPa) at a temperature of about 40 ° C afforded 13.8 g of an oil which was purified by chromatography under an argon pressure of 50 kPa on a silica gel column (particle size 40-63 μιη, diameter 5 cm). height 34 cm), eluting with a mixture of ethyl acetate and cyclohexane (9/1 by volume) and then ethyl acetate and collecting 50 cm ^{3 of} fraction. Fractions 23 to 70 are added

262 are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 45 ° C. 8.2 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-carboxylate are obtained in the form of an orange. oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate dihydrochloride can be prepared as described in Example 21.

Example 26

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2] -hydrochloride -inyl] piperidine-3-carboxylic acid cm ^{3 of} 5N aqueous sodium hydroxide is added to a solution of 1.3 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol- 4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in 13 cm ^{3 of} dioxane and the solution is heated to about 60 ° C for 13 hours. After cooling, the solution is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue is taken up in 75 cm ^{3 of} distilled water. The aqueous phase is washed with a total of 75 cm ^{3 of} dichloromethane. The aqueous phase is concentrated to a volume of about 10 cm ³ , cooled to about 5 ° C, and then acidified to about pH 1 by addition of 5 N hydrochloric acid. The mixture is stirred for 12 hours at a temperature of about 12 ° C, the aqueous phase is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue is taken up in 50 cm ^{3 of} acetone. The solution obtained is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue obtained is purified by chromatography under argon pressure of 50 kPa on a silica gel column (particle size 20-45 µm, diameter 3 cm, height 30 cm), eluting with a mixture of chloroform, methanol and ammonia (24/12/1 by volume) and collected. 15- cm ³ fraction. Fractions 19 to 53 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.8 g of foam is obtained, which is dissolved in 7 cm @ ^{3 of} dichloromethane. This solution is added to 9 cm ^{3 of} 1 N hydrochloric acid solution

263 ethers. The mixture is stirred for 5 minutes at a temperature of about 20 ° C, the solid is filtered off, washed with a total of 50 cm ^{3 of} diethyl ether and then dried to constant weight under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.92 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2) -hydrochloride] is obtained. -yl) prop-2-ynyl] piperidine-3-carboxylic acid in the form of off-white crystals.

1 H-NMR spectrum (400 MHz, d ₄ -CD ₃ OD, δ in ppm): 1.50-2.30 (mt, 7H), 3.06-3.11 (2 mts, 1H), 3.15-3 , 95 (mt, 4H), 4.03 and 4.04 (2 s,

3H), 4.15-4.45 (mt, 2H), 5.55 and 5.66 (2 mts, 1H), 7.04 (mt, 1H), 7.37 (mt, 1H), 7, 51 (d, J = 5 Hz, 1H), 7.62 and 7.69 (2 broad s, IH), 7.77 (dd, J = 9 and 2 Hz, IH), 8.10-8.20 (mt, 2H), 8.92 and 8.94 (mt, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2- ynyl] piperidine-3-carboxylate

Sodium borohydride (0.15 g) is added in one portion at about 20 ° C under an inert atmosphere to a stirred solution of methyl (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) -3- (6-methoxyquinolin-4-yl) -3] - oxopropyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in 15 cm ^{3 of} methanol. The mixture is then stirred for 2.5 hours at about 25 ° C. 15 cm ^{3 of} distilled water are added dropwise over a period of about 10 minutes while maintaining the temperature at 15 ° C. The mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is taken up in 20 cm @ ^{3 of} distilled water. Mix. extracted cel · ^"1" metal 1 100 cm ³ of dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The solid obtained is purified by chromatography under argon pressure of 50 kPa on a silica gel column (particle size 20-45 µm, diameter 3 cm, height 35 cm), eluting with a mixture of ethyl acetate and cyclohexane (8/2 by volume) and collected 15 cm ^3. fractions. Fractions 38 to 59 are combined and concentrated under reduced pressure at about 40 ° C. 1.3 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3264] are obtained.

- (Thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in the form of a foam.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3-

- (Thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate can be obtained as follows:

0.404 g of tetrakis (triphenylphosphine) palladium, 0.118 g of triphenylphosphine and 0.191 g of copper (I) iodide are added in an inert atmosphere at about 20 ° C to a stirred solution of 1.97 g of methyl (3R, 4R) -4- [3- (6-methoxyquinoline). -4-yl-3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 40 cm ^{3 of} acetonitrile. 0.84 cm @ ^{3 of} 2-iodothiophene are then added, followed by 1.40 cm @ ^{3 of} triethylamine. The mixture was stirred at about 20 ° C for 48 hours and then filtered through diatomaceous earth. The filter cake was washed with acetonitrile. The combined filtrates are concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 4.2 g of an oil are obtained, which is purified by chromatography under argon at 50 kPa on a silica gel column (particle size 20-45 pm, diameter 3 cm, height 60 cm), eluting with a mixture of ethyl acetate and hexane (8/2 by volume). and 15 cm ³ fractions are collected. Fractions 16 to 32 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 35 ° C. 1.6 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (thien-2-yl) prop-2-] are obtained. inyl] piperidine-3-carboxylate as an orange oil.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-carboxylate can be obtained as described in Example 25.

Example 27

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2] -hydrochloride -inyl] piperidine-3-carboxylic acid;

2.5 cm ^{3 of} aqueous sodium hydroxide is added to a solution of 1.6 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] 265

1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in 16 cm ^{3 of} dioxane and the solution is then heated to about 60 ° C for 50 hours. After cooling, the solution obtained is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue is taken up in 50 cm ^{3 of} acetone and the concentrate is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue obtained is purified by chromatography under argon pressure of 50 kPa on a silica gel column (particle size 20-45 μπι, diameter 3,5 cm, height 34 cm), eluting with a mixture of chloroform, methanol and ammonia (24/12/1 by volume) and 15 cm ³ fractions are collected. Fractions 16 to 28 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The solid is taken up in acetone and the concentrate is under reduced pressure (2 kPa) at a temperature of about 45 ° C. 0.72 g of foam is obtained, which is dissolved in 8 cm @ ^{3 of} dichloromethane. This solution is added to 8 cm @ ^{3 of} 1N HCl in ether. The mixture is stirred at a temperature of about 20 ° C, the solid obtained is filtered off and dried to constant weight under reduced pressure (2 kPa) at a temperature of about 40 ° C. 0.74 g of (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2) acid] hydrochloride is obtained. -yl) prop-2-ynyl] piperidine-3-carboxylic acid in the form of off-white crystals, m.p. 166 ° C.

¹ H-NMR spectrum (400 MHz, dg- (CD 3) 2 SO at 110 ° C, δ in ppm): 1.68 (mt, 2H), 1.87 (mt, 1H), 1.89 (mt, 1H), 2.05-2.25 (mt, 3H), 3.05-3.45 (mt, 5H), 3.98 (s, 3H), 4.25 (limit AB, 2H), 6, 31 (mt, J _HF = 16 Hz, 1H), 7.12 (dd, J = 5 and 3.5 Hz, 1H), 7.35-7.45 (mt, 2H), 7.45-7, 55 (mt, 2H); 7.64 (d, J = 5Hz, 1H);

8.05 (d, J = 9Hz, 1H); 8.80 (d, J = 5Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2- ynyl] piperidine-3-carboxylate

A solution of 1.14 cm ^{3 of} dimethylaminosulfurtrifluoride in 10 cm ^{3 of} dichloromethane is added dropwise over 15 minutes to a solution of 3.4 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3] in an inert atmosphere. (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in 50 cm ^{3 of} dichloromethane. The mixture is stirred for 9 hours at about 20 DEG C., the reaction mixture is cooled to about 10 DEG C. and 60 cm @ ^{3 of} saturated sodium bicarbonate solution are added over about 15 minutes. The organic phase is separated by settling and then washed with a total of 300 cm ^{3 of} distilled water. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under argon pressure of 50 kPa on a silica gel column (particle size 20-45 µm, diameter 4 cm, height 35 cm), eluting with a mixture of ethyl acetate and cyclphexane (1/1 by volume) and collecting 15 cm ³ fractions. . Fractions 34 to 65 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The solid is taken up in acetone and then concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. 1.8 g of methyl (3 R, 4 R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien- 2-yl) -prop-2-ynyl] piperidine-3-carboxylate as a yellow oil.

Methyl (3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop The 2-ynyl] piperidine-3-carboxylate can be prepared as described in Example 26.

Example 28

(3R, 4R) -4- [3- (2R, S) -Fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop- 2-ynyl] piperidine-3-carboxylic acid ethyl ester _(, '

A solution of 1.48 g of methyl (3 R, 4 R) -4- [3- (2 R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3- Fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 15 cm ^{3 of} dioxane and 2.4 cm ^{3 of} aqueous sodium hydroxide is heated to about 60 ° C for 17 hours. After cooling, the solution obtained is concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue is taken up in 50 cm ^{3 of} acetone and then concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. The residue is purified by column chromatography

267 silica gel (particle size 20-45 μτη, diameter 2.8 cm, volume 150 cm ³ ) at atmospheric pressure, eluting with a mixture of dichloromethane, methanol and ammonia (120/20/3 by volume) and collecting 20 cm ^{3 of} fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The solid is taken up in 25 cm ^{3 of} acetone and then 5 cm ^{3 of} 1N hydrogen chloride in ether and 20 cm ^{3 of} diethyl ether are added. The mixture is stirred for 2 hours at about 20 ° C and the solid obtained is filtered off and dried to constant weight under reduced pressure (2 kPa) at about 40 ° C. 0.6 g of (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3- fluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid as a solid.

H-NMR spectrum (400 MHz, _d6 - (CD3) ₂ SO at 100, the δ

ppm) : 1.55-1, 95 (int (3H), 2.00-2.30 (mts, 4H); ), 3.15-3.50 (Mt. 5H), 3.99 (s, 3H), 4.31 (AB limit, 2H), 6.38 (mt, J _HF = 47) Hz, IH), 7.25-7.55 (Mt. 5H), 7.55 (dd, J) = 9 and 2.5 Hz, 1H), 7.60 (D, J = 5 Hz, IH) 8, 12 (d, J = 9Hz, IH) , 8.84 (d, J = 5Hz, IH) •

Methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate

A solution of 1.4 cm ^{3 of} diethylaminosulfurtrifluoride in 5 cm ^{3 of} dichloromethane is added dropwise over 15 minutes to a solution of 4.2 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3) in an inert atmosphere. - (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 75 cm ^{3 of} dichloromethane cooled to about 15 ° C. The mixture is stirred for 9 hours at a temperature of about 25 ° C, 100 cm ^{3 of} saturated sodium bicarbonate solution are added, the temperature of the reaction mixture not exceeding 25 ° C. The organic phase is separated by settling and then washed with a total of 100 cm ^{3 of} distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography on a silica gel column (particle size 2)

268

20-45 µm, diameter 4 cm, height 42 cm) eluting with ethyl acetate and collecting 70 cm ³ fractions. Fractions 19 to 35 are combined and then evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The solid is taken up in acetone and the concentrate is under reduced pressure (2 kPa) at a temperature of about 45 ° C. 3.1 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl)] are obtained. prop-2-ynyl] piperidine-3-carboxylate as a yellow oil.

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3-fluorophenyl) prop-2-ynyl] piperidine-3-carboxylate can be prepared as described in Example 25.

Example 29 (3R, 4R) -3-Hydroxymethyl-4- [3- (R, S) -hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-2-yl) ) prop-2-iny1] piperidine

4.2 cm @ ^{3 of a} 20% solution of diisobutylaluminium hydride in toluene are added with stirring to a mixture of 0.5 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-). yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylate in 10 cm ^{3 of} toluene cooled to 0 ° C. Stirring at this temperature is continued for 3 hours and then 15 cm ^{3 of} saturated ammonium chloride solution are added, the mixture is stirred for 15 minutes and the temperature is raised to about 20 ° C. The aqueous phase is separated by settling, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue obtained is purified by column chromatography under 50 kPa of nitrogen pressure on silica gel (particle size 20-45 μπι, diameter 2 cm, height 20 cm), eluting with dichloromethane and then with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 30% of the residue. cm ³ fraction. Fractions 14 to 16 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is taken up in 5 cm @ ^{3 of} dichloromethane and filtered. The filtrate is concentrated to dryness under reduced pressure (2 kPa). 0.17 g of (3R, 4R) -3-hydroxymethyl-4- [3- (R, S) -hydroxy-3269 is obtained.

- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine as a gum.

^X H-NMR (400 MHz, D6 (CD _{3) 2} SO, δ in ppm): 1.25-1.90 (mt,

8H), 2.22 (Mt. 2H), 2.65-2.90 (mt, 2H) , 3.35-3.60 (Mt. 4H), 3, 91 and 3.93 (2 with, 3H), 4,29 (unresolved peak, 1H), 5.28 (Mt. 1H), ' 5.50 and 5, 52 (2 d, J = 4.5 Hz, 1H) 7.07 (mt, 1H), 7.28 (Dd, J = 4 and 1 Hz, 1H), 7.35 and 7.45 (mt, 2H), 7.50- • 7.60 (Mt. 2H),

7.95 (d, J = 9Hz, 1H); 8.71 (d, J = 5Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop- 2-Inyl] piperidine-3-carboxylate was obtained as described in Example 26.

Example 30 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -3-hydroxymethyl-1- [2- (1,3-thiazole) 2-ylthio) ethyl] piperidine

The preparation is carried out analogously to Example 5, but using methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2 - ( 1,3-1 thiazol-2-ylthio) ethyl] piperidine-3-carboxylate and sodium borohydride to give 0.33 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3] - (6-Methoxyquinol-4-yl) propyl] -3-hydroxymethyl-1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidine as an oil.

^X H-NMR '(300 MHz, _d6 - _{(CD3) 2} SO, δ in ppm): from 1.10 to 2.20,

2.55-2.90 a 3, 30-3.60 (mts, 16H); , 60 (t, J = 6.5 Hz, 2H) 3.93 and 3.94 (2 with, 3H), 4.26 Ný peak, 1 H), 5.27 (mt, 1H), 5.50-5.60 (Mt. 1H), 7.35-7.45 (mt, 2H) , 7.56 (mt, 1 H), 7.63 (D, J = 3 Hz 1H), 7.71 (d, J = 3Hz, 1H) , 7.95 (d, J = 9Hz, 1H), 8.72 (d, J) = 5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidine-3-carboxylate prepared analogously to Example 4 from methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate and

270

2-bromo-l- (1,3-thiazol-2-ylthio) ethane.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (1,3-thiazol-2-ylthio) ethyl] piperidin-3 The carboxylate was prepared as described in Example 21.

Example 32

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (shadow-3-yl) -prop-2-yl] -acid ynyl] piperidine-3-carboxylic acid

A solution of 0.73 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (shadow-3-yl) 1-Prop-2-ynyl] piperidine-3-carboxylate, 7.6 cm @ ^{3 of} dioxane and 1.22 cm @ ^{3 of a} 5 N aqueous sodium hydroxide solution are heated at about 60 DEG C. for 3.5 hours. After cooling to about 20 ° C, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue obtained is purified by chromatography under argon pressure on a column of silica gel (particle size 40-63 µm, diameter 5 cm, silica gel volume 120 cm ³ ), eluting first with 1120 cm ^{3 of a} mixture of dichloromethane, methanol and acetonitrile (92/8 / 7 by volume). The elution is then carried out with 224 cm ^{3 of the} same mixture (but with 92/12/7 by volume) and then with 224 cm ^{3 of the} same mixture (but with 92/16/7 by volume) and then with 400 cm ³ of dichloromethane / methanol (50 / 50 by volume) and finally 400 cm @ ^{3 of} pure methanol. First, 112 cm ³ fractions are collected and then 7 cm ³ fractions. Fractions 173 to 468 are combined and evaporated under reduced pressure (2 kPa) at a temperature of about 35 ° C. A foam is obtained which is dried under reduced pressure (30 Pa) at about 30 ° C for 4-5 hours. 0.33 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (shadow-3-) is obtained. yl) prop-2-ynyl] piperidine-3-carboxylic acid as a beige foam, m.p. 113-115 ° C.

³ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) 2 SO, δ in ppm). The presence of two diastereoisomers was found: 1.40-1.95 and 2.30-2.95 (mts,

12H), 3.53 and 3.55 (2 s, 2H overall), 3.90 and 3.92 (2 s, 3H)

271 in total), 5.24 (mt, 1H), 5.35-5.65 (broad unresolved peak, 1H), 7.14 (d, J = 5 Hz, 1H), 7.30-7.45 ( mt, 2H), 7.53 and 7.55 (2 d, J = 5 Hz, 1H overall), 7.60 (dd, J = 5 and 3 Hz, 1H), 7.74 (mt, 1H), 7.94 (d, J = 9.5 Hz, 1H); 8.70 (d, J = 5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (shadow-3-yl) prop- 2-ynyl] piperidine-3-carboxylate

The preparation is carried out as in the preparation of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (shadow-3-yl) prop-2- vinyl] -piperidine-3-carboxylate, from 1.2 g of methyl (3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 20 cm ^{3 of} acetonitrile, 0.067 g of triphenylphosphine, 0.227 g of tetrakis (triphenylphosphine) palladium, 0.115 g of copper iodide and 10 cm ^{3 of} acetonitrile and then 0.84 cm ^{3 of} triethylamine 0.95 g of 3-iodothiophene and 5 cm ^{3 of} acetonitrile. The reaction mixture is filtered and the filter cake is washed with 30 cm ^{3 of} acetonitrile. The filtrate is evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The residue is taken up in 100 cm @ ^{3 of} dichloromethane. The resulting organic solution is washed with 3 x 50 cm ^{3 of} saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure using the conditions described above. The residue is purified by chromatography under argon pressure (55 kPa) on a silica gel column (particle size 40-63 µm, diameter 4 cm, silica gel volume 220 cm ³ ), eluting with ethyl acetate. A 180 cm ³ fraction was collected and then 10 cm ³ fractions were collected. Fractions 73 to 300 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. 0.96 g of product is obtained which is reacted with 0.76 g of 3-iodothiophene, 0.092 g of copper iodide, 0.054 g of triphenylphosphine, 0.67 cm ^{3 of} triethylamine and 0.181 g of tetrakis (triphenylphosphine) palladium in 27 cm ^{3 of} acetonitrile at at about 20 ° C for 16 hours. The reaction mixture is filtered and the filter cake is washed with 30 cm ^{3 of} acetonitrile. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 40 ° C. The residue obtained is dissolved in 50 cm ^{3 of} dichloromethane, washed with 3 x 25 cm ^{3 of} saturated sodium chloride solution, separated by settling and dried.

272 over sodium sulfate, filtered, and concentrated under reduced pressure (2 kPa) at about 35 ° C. 1.15 g of a residue is obtained, which is purified by chromatography on an argon pressure of 55 kPa on a silica gel column (particle size 40-63 µm, diameter 4 cm, silica gel volume 120 cm ³ ), eluting with ethyl acetate. A 110 cm fraction was collected first and then 8 cm fractions were collected. Fractions 68 to 260 are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 45 ° C. There was obtained 0.73 g of methyl (3 R, 4 R) -4- [3- (7 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien) 3-yl) prop-2-ynyl] piperidine-3-carboxylate as a yellow foam.

IR (CC1 _4): 3600-3200 cm ¹ (OH), 2950 cm ^-1 (aliphatic CH H), 1739 cm ^-1 (C-O H), 1241 cm ¹ (C-ether at 0).

626 cm ¹ (thiophene CH γ).

Methyl (3 R, 4 R) -4- [3- (7 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3- carboxylate

A suspension of 2.45 g of methyl (3 R, 4 R) -4- [3- (7 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate, 2.1 g of potassium carbonate, 0.99 g of potassium iodide and 0.6 cm ^{3 of} propargyl bromide in 50 cm ^{3 of} acetonitrile are stirred under an inert atmosphere for 40 hours at a temperature of about 20 ° C. After filtering the reaction mixture, the filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by silica gel column chromatography (particle size 20-45 µm, diameter 2.5 cm, weight 50 g), eluting with ethyl acetate and collecting 60 cm ^{3 of} fraction. Fractions 6 to 12 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 1.35 g of methyl (3R, 4R) -4- [3- (7R, 5S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-) are obtained. inyl) piperidine-3-carboxylate as a gum.

Infrared spectrum (CCl ₄ ): 3600-3200 cm ^-1 (OH v), 3311 cm (acetylene CH v), 2950 cm -1

v), 1242 cm ^-1 (ether C-O v).

(aliphatic CH v), 1740 cm -1 (C = O

273

3-Iodothiophene can be prepared as described by N. A. Petasis et al., Synlett., 1988, 141.

Example 33

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine-3-carboxylic acid diastereoisomer A, and (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylic acid , diastereoisomer B

1.36 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) acid] Ethyl] piperidine-3-carboxylic acid dissolved in 100 cm ^{3 of} dichloromethane is chromatographed on a 35 cm 6 cm diameter column packed with 700 g of silica (particle size 5-15 μπι) from Daiso. Elution is carried out using a mixture of dichloromethane and methanol (92/8 by volume) containing 0.05% triethylamine. The flow rate is 90 cm ³ per minute and detection is by ultraviolet radiation at 280 nm. This procedure results in two diastereoisomers. The fractions corresponding to the first are concentrated to dryness under reduced pressure (5 kPa) at a temperature of about 40 ° C and the residue obtained is dried in an oven under reduced pressure (13 Pa) at a temperature of about 40 ° C. 0.28 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine acid is obtained. -3-carboxylic acid diastereoisomer A ([α] D ²⁰ = -73.8 ° ± 1.4 ', in dichloromethane at 0.5%) as a yellow foam. The fractions corresponding to the second diastereoisomer are worked up as described above. There was obtained 0.46 g of (3R, 4R) -4- [3-hydroxy-3- (β-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine- 3-carboxylic acid diastereomer B ([α] D ²⁰ = + 71.2 ° ± 1.2, in dichloromethane at 0.5%) as a yellow foam.

Diastereoisomer A: 1 H-NMR spectrum (300 MHz, d ₅ - (CD ₃ ) ₂ SO, δ in ppm): 1.35-1.75 and 1.94 (mts, 7H), 2.22 (mt, 1H) 1.36 (broad d, J = 10.5 Hz, 1H), 2.50-2.65 (mt, 1H), 2.61 (t, J = 7 Hz, 2H),

274

2.76 (mt, 1 H), 2.85-3.05 (mt, 1 H), 2.98 (mt, 2H), 3.9! 5 (s, 3H), 5.22 (mt, 1 H), 5.51 (broad d, J = 4.5 Hz, 1H), 7.07 (dd, J = 5 and 4 Hz, 1H), 7.22 (broad d, J = 4 Hz (1H), 7.36 (Mt. 1H), 7.35-7.45 (mt, 2H), 7.64 (broad d, J = 5 Hz, 1 H), 7.95 (D, J = 9.5 Hz, 1 H) 8.72 (d, J = 5Hz) 1H). diastereomer B: ^{1 * 34 4} H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ Sat, δ v

ppm): 1.20-1.95 (mts, 7H), 2.22 (mt, 1H), 2.39 (broad d,

J = 10.5 Hz, 1H), 2.50-2.95 (mt, 3H), 2.60 (t, J = 7 Hz, 2H), 2.97 (mt, 2H), 3.92 ( s, 3H), 5.25 (mt, 1H), 5.51 (unresolved peak, 1H), 7.06 (dd, J = 5 and 3.5 Hz, 1H), 7.20 (dd, J = 3.5 and 1.5 Hz, 1H), 7.40 (mt, 2H), 7.53 (d, J = 5 Hz, 1H), 7.63 (dd, J = 5 and 1.5 Hz, 1H), 7.93 (d, J = 10Hz, 1H), 8.70 (d, J = 5Hz, 1H).

Example 34

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (tert-butylthio) -ethyl] -piperidine-3-dihydrochloride carboxylic j ^cm3 of 5 N sodium hydroxide solution was added under stirring and in an inert atmosphere to a solution of 0.26 g of methyl (3 R, 4 R) -4- [3- (R, S) -hydroxy-3- (6-metoxychinol- 4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3-carboxylate in 5 cm ^{3 of} methanol. The solution is heated to about 60 ° C and then cooled to room temperature and the reaction mixture is evaporated under reduced pressure (2.8 kPa) at about 60 ° C. The residue is taken up in 5 cm ^{3 of} distilled water and then 5 cm ^{3 of} concentrated hydrochloric acid (d = 1.18) are added. The mixture is evaporated under reduced pressure (2.8 kPa) at a temperature of about 60 ° C. The residue obtained is taken up in cm ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume). The white precipitate obtained is filtered off and washed with 2 x 2 cm ^{3 of the} same mixture. The filtrate is concentrated under reduced pressure (2.8 kPa) at a temperature of about 40 ° C. The product obtained is dried under reduced pressure (16 Pa) at a temperature of about 60 ° C. 0.29 g of dihydrochloride is obtained

275 (3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (tert-butylthio) -ethyl] -piperidine 3-carboxylic acid as a beige solid, m.p. 169 ° C with softening.

1 H-NMR spectrum (400 MHz, d 6 - (CD ₃ ) ₂ SO at 110 ° C, δ in ppm). Two diastereoisomers were found: 1.34 and 1.36

(2s, 9H overall), 1.40 to 2.35 (wide t, J = 8 Hz, 2H), 3.26 5.40 (mt, 1H), 7.55 -7.70 (mt, J = 9 Hz 1H), 8.88 (d, J = undifferentiated peak 1H).

α 2.90-3.70 (mts, 12H), 3.00 (t, J = 8Hz, 2H), 4.01 (s, 3H),

2H), 7.82 (mt, 1H), 8.22 (d,

Hz, 1H), 10.90-11.45 (broad

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (tert-butylthio) ethyl] piperidine-3- carboxylate

0.717 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate in 15 cm ^{3 of} acetonitrile and 15 cm ^{3 of} methanol with stirring, for about 16 hours, is heated to about boiling under an inert atmosphere with 0.43 g of 2-chloroethyl tert-butylsulfide in the presence of 0.33 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to about 20 ° C, insoluble material was filtered off. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 100 kPa of nitrogen pressure on a silica gel column (particle size 40-63 µm, diameter 3.5 cm, height 35 cm), eluting with a mixture of dichloromethane and methanol (97/3 by volume) and collected. cm ³ fraction. Fractions 54 to 70 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.265 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (tert-butylthio) ethyl] was obtained. piperidine-3-carboxylate as a brown lacquer.

IR (CC1 _4): 3550-3100 cm ^-1 (OH alcohol);

2959 cm ^-1 (aliphatic CH v), 1736 cm ^-1 (C = O v), 1242, 1228 cm ^-1 (ether C-0 v), 1034 cm ^-1 (alcohol C-0 v), 853 cm -1 ¹ (quinoline CH γ).

276

2-Chloroethyl tert-butylsulfide can be prepared by applying the method described in EP 136878.

Example 35

(3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine- dihydrochloride 3-carboxylic cm ^{3 of} 5N aqueous sodium hydroxide are added under stirring in an inert atmosphere to a solution of 0.48 g of methyl (32 R, 42 R) -4- [3- (2 R, S) -hydroxy-3- (6 -methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-carboxylate in 10 cm ^{3 of} methanol. After heating the mixture to about 60 ° C for 16 hours, the reaction mixture is evaporated under reduced pressure (2.9 kPa) at about 60 ° C and the residue is taken up in 4.3 cm ^{3 of} distilled water to which it is added 4.3 cm ³ 28% hydrochloric acid. The remaining insoluble material was filtered off and the filtrate was evaporated under the same conditions as above. The residue obtained is stirred in a mixture of dichloromethane and methanol (90/10 by volume). The resulting precipitate is filtered off and washed with 3 x 2.5 cm ^{3 of the} same mixture. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.48 g of (3R, 4R) -4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2R, 5S) -hydrochloride is obtained. cyclopentylthio) ethyl] piperidine-3-carboxylic acid in the form of a green foam, m.p.

¹ H-NMR spectrum (400 MHz, dg- (CD 3) 2 SO at 100 ° C, δ in ppm). Two diastereoisomers were found: 1.45-2.30 and

2 90 to 3.60 (Mts, 20H ), 2.98 (broad t, J = 7.5Hz, 2H) 3.22 (Mt. IH ), 3.30 (T, J = 7.5 Hz, 2H), 4 , 00 (s, 3H) 5.37 (Mt. IH) 1 50 to 7.65 (Mt. 2H), 7.77 (mt, 1H), 8 17 (d, J = 9Hz) IH), 8.85

(d, J = 5Hz, 1H).

Methyl (3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] -piperidine- 3-carboxylate

277

0.717 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate in 15 cm ^{3 of} acetonitrile and 15 cm ^{3 of} methanol The mixture is heated at reflux for about 3.5 hours with 0.439 g of 2-chloroethylcyclopentyl sulfide in the presence of 0.332 g of potassium carbonate and 0.4 g of potassium iodide while stirring under an inert atmosphere. After cooling the reaction mixture to about 20 ° C, the insoluble material was filtered off and then washed with acetonitrile. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 100 kPa of nitrogen pressure on a silica gel column (particle size 40-63 pm, diameter 3.5 cm, height 45 cm), eluting with a 95/5 by volume mixture of dichloromethane and methanol and collecting 35 cm. ³ fractions. Fractions 25 to 45 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.48 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (cyclopentylthio) ethyl] is obtained. ] piperidine-3-carboxylate as a dark brown lacquer.

IR (CC1 _4): 3550-3100 cm ¹ (OH alcohol);

2951 cm ^-1 (aliphatic CH v), 1736 cm ^-1 (C = O v), 1242, 1228 cm ¹ (ether C-0 v), 1034 cm ¹ (alcohol C-0 v), 853 cm ¹ (quinoline CH γ).

2-Chloroethylcyclopentyl sulfide can be prepared by applying the method described in patent application FR 2 395 260.

I

Example 36

(3R, 4R) -1- [2- (3-Fluorophenylthio) ethyl] -4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine-3-acetic acid dihydrochloride

A mixture of 0.48 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate in 10 cm ³ of dioxane, to which 0.78 cm ^{3 of a} 5N aqueous hydrochloric acid solution was added, was stirred for 20 hours at a temperature of about 60 ° C. After cooling to about 20 ° C, the reaction mixture was evaporated at room temperature

278 vacuum at about 40 ° C and then diluted with 10 cm ^{3 of} water. The pH is adjusted to 4 by the addition of sufficient aqueous citric acid. The mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C and then the residue is taken up in 70 cm ^{3 of} water and 20 cm ^{3 of} ethanol. The pH of the mixture is then adjusted to 9 and the mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 50 ° C. The residue is taken up in 50 cm ^{3 of a} mixture of chloroform, methanol and aqueous ammonia (12/3 / 0.5 by volume) and the inorganic salts are filtered off. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.2 g of product are obtained, which product is purified by atmospheric pressure chromatography on a silica gel column (particles 20-45 gm, diameter 2 cm, height 25 cm), eluting with a mixture of chloroform, methanol and aqueous ammonia (12/3 / 0.5 volume) and first 100 cm ³ fractions are collected and then approximately 15 cm ³ fractions are collected. Fractions 8 to 18 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.31 g of a pale yellow foam is obtained, which is stirred with 13 cm @ ^{3 of} 0.1 N aqueous hydrochloric acid for 2 hours at a temperature of about 20 DEG. After addition of 5 cm ^{3 of} dioxane and stirring for a further 2 hours at about 20 ° C, the dioxane is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The solution obtained is frozen and then lyophilized. 0.35 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid dihydrochloride is obtained in the form of: white lyophilisate.

^ -MR spectrum (400 MHz, dg- (CD3) 2SO at 110 ° C, δ in

ppm): 1.45-1.95 (mt , 8H), 2 33 (dd, J = 16 and 5.5 Hz, IH), 2.45-2.60 (mt, 1H), 2.90-3.55 (mt 10H) 4.00 (with, 3H), 7.06 (wide t, J = 8Hz, 1H), 7.28 (d, J = 8Hz, 2H), , 7.41 (Mt. IH), 7.46 (d, J = 5Hz, 1H), 7.48 (d, J = 2.5 Hz, IH), 7, 51 (Dd, J = 9.5 and 2.5 Hz, 1H), 8.07 (d, J = 9.5) Hz, IH), 8.72 (D,

J = 5 Hz, 1H).

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinolone) 279

4-yl) propyl] piperidine-3-acetate

A mixture of 0.76 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate and 0.42 g of 2- (3-fluorophenylthio) ethyl-1- chloride in 15 cm ^{3 of} acetonitrile, to which 1.4 g of potassium carbonate and 0.15 g of potassium iodide were added, with stirring under an inert atmosphere, at a temperature of about 70 ° C for 20 hours. After adding 0.15 g of potassium iodide and heating for an additional 5 hours, the reaction mixture is cooled to 20 ° C, diluted with 15 cm ^{3 of} water and extracted with 2 x 20 cm ^{3 of} ethyl acetate. The combined extracts are washed with 30 cm @ ^{3 of} 1N aqueous hydrochloric acid. The acidic solution was separated and then basified (pH 8-9) with a sufficient amount of saturated aqueous sodium bicarbonate solution. The mixture is extracted with 2 x 30 cm ^{3 of} ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at about 40 ° C. 0.71 g of an oil is obtained, which is purified by chromatography at atmospheric pressure on a silica gel column (particle size 20-45 μπι, diameter 2.5 cm, silica gel volume 120 cm ³ ), eluting with a mixture of dichloromethane and methanol (99/1). volume). First, collected 500 cm ³ fractions and then taken about 15 cm ³ fractions. Fractions 10 to 20 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.48 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate is obtained as a yellow solid. oil.

Infrared (CH ₂ Cl ₂ ): 2934, 2861 cm ^-1 (aliphatic CH v), 2807, 2767 cm ^-1 (N (CH ₂ ) ₂ CH ₂ v), 1730 cm ¹ (ester C = O v), 1242 .

1227 cm ^-1 (ether C-O v), 848 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate

A mixture of 2.8 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid in 100 cm ^{3 of} anhydrous methanol to which 1 cm ^{3 of} 95% sulfuric acid was added

280 is heated with stirring to approximately boiling for 2 hours. After cooling to about 20 ° C, the reaction mixture is evaporated under reduced pressure (5 kPa) at about 40 ° C and then 20 cm ^{3 of} saturated aqueous sodium bicarbonate solution are added to the residue. The mixture is extracted with 4 x 20 cm ^{3 of} dichloromethane. The combined extracts were dried, over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at about 40 ° C. 2.25 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate is obtained as a brown oil.

Infrared (CH ₂ Cl ₂ ): 2954, 2865 cm ^-1 (aliphatic CH v), 2788 cm ^-1 (N (CH ₂ ) ₂ CH ₂ v), 1736 cm ¹ (ester C = 0 v), 1242,

1227 cm ^-1 (ether C-O v), 848 cm ^-1 (quinoline CH γ).

(3R, 4R) -4- (3- (6-Methoxyquinol-4-yl) propyl) -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid

1.48 g of potassium permanganate previously dissolved in 45 cm ^{3 of} distilled water and then 220 cm ^{3 of} acetone are added under stirring and under an inert atmosphere at about 20 ° C to a solution of 2 g of (3R, 4R) -4- [3- (6) -methoxyquinol-4-yl) propyl] -1- (tert-butoxycarbonyl) piperidine-3-acetaldehyde in 100 cm ^{3 of} acetone. The mixture obtained is stirred for 2 hours at a temperature in the region of 20 DEG C. and then, after cooling to a temperature between 0 DEG and 5 DEG C., a solution of sodium sulfite in 150 cm @ ^{3 of} water is added. The brown manganese dioxide precipitate is filtered off through diatomaceous earth and then the acetone is evaporated off under reduced pressure (5 kPa) at a temperature of about 40 ° C. Sufficient citric acid is added to the reaction mixture to achieve a pH of 4-5. The reaction mixture is extracted with 2 x 100 cm ^{3 of} ethyl acetate. The combined extracts are dried over magnesium sulphate, filtered and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 2.8 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid are obtained in the form of a white foam.

IR (KBr): 2977, 2932, 2868 cm @ -1 (aliphatic CH

281

v), 3000-2200 cm ¹ (acid OH v), 1734 cm ^-1 (acid C = O v), 1689 cm ¹ (carbamate C = 0 v), 1391, 1365 cm ¹ (CH ₃ δ _as ), 1246 cm ^-1 , (ether C-0 v), 1170 cm ¹ (carbamate C-0 v), 848 cm ^-1 (quinoline CH

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetaldehyde

5.6 cm ^{3 of} dimethylsulfoxide dissolved in 80 cm ^{3 of} dichloromethane, then 13.5 g of (3R, 4R) -3- (2-hydroxyethyl) -4- [3- (6-methoxyquinol-4-yl) propyl] -1 - (tert-butyloxycarbonyl) piperidine dissolved in 80 cm ^{3 of} dichloromethane and finally 26.5 cm ^{3 of} triethylamine dissolved in 80 cm ^{3 of} dichloromethane are gradually added under stirring under argon to a solution of 3.5 cm ^{3 of} oxalyl chloride in 80 cm ^{3 of} dichloromethane cooled to temperature -60 ° C. The resulting solution is maintained at about -60 ° C for 1 hour and then at about 20 ° C for 3.5 hours. After diluting with 150 cm ^{3 of} dichloromethane, the reaction mixture is washed with 2 x 300 cm ^{3 of} water. The organic solution is separated by settling, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 12.7 g of a brown oil are obtained, which is taken up in 400 cm @ ^{3 of} diethyl ether. The resulting solution is washed with 2 x 300 cm ^{3 of} water, then with 300 cm ^{3 of a} 5% aqueous citric acid solution and finally with 2 x 300 cm ^{3 of} water. The organic solution is dried over magnesium sulfate and concentrated under reduced pressure (5 kPa) at about 40 ° C. 7.73 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetaldehyde is obtained in the form of a yellow sticky gum.

IR (CC1 _4): 2978, 2932, 2864 cm ^-1 (aliphatic

CH v), 2717 cm ^-1 (aldehyde CH v), 1729 cm ¹ (aldehyde C = O v),

1694 cm ^-1 (carbamate C = O in), 1391, 1366 cm ^-1 (CH ₃ 5 _and), 1242 cm ^-1, (the ether C-0); 1158 ^cm-1 (carbamate C-0), 844 cm ¹ (quinoline CH γ).

282 (3R, 4R) -3- (2-Hydroxyethyl) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine

A solution of 2 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) -3-vinylpiperidine and 0.72 cm ^{3 of} triethylamine borane complex in 10 cm ^{3 of} toluene is stirred under reduced pressure in an inert atmosphere at a temperature of about 110 ° C for 10 hours. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 60 ° C. 2.1 g of an orange foam are obtained, which is dissolved in 9 cm @ ^{3 of} acetone, to which 1.9 cm @ ^{3 of} 5% aqueous hydrochloric acid are added. The mixture is stirred for 20 minutes at about 20 ° C and the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue is taken up in 7.5 cm ^{3 of} tetrahydrofuran, 6.2 cm ^{3 of a} 30% aqueous sodium hydroxide solution and 7.5 cm ^{3 of a} 30% aqueous hydrogen peroxide solution. The mixture is heated to about boiling for about 3 hours. After cooling, the reaction mixture is stirred with 30 cm ^{3 of} chloroform at a temperature of about 20 ° C. The aqueous phase is separated by settling, the organic phase is washed with 3 x 30 cm ^{3 of} water and then with 1 x 20 cm ^{3 of} saturated sodium chloride solution. After drying over magnesium sulfate, the organic solution is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.7 g of a brownish-yellow oil are obtained, which is purified by chromatography on a silica gel column (particle size 40-63 pm, diameter 3.5 cm, weight 60 g), eluting with a 95/5 by volume mixture of dichloromethane and methanol. ) and 20 cm ³ fractions are collected. Fractions 4 and 5 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.95 g of (3R, 4R) -3- (2-hydroxyethyl) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine is obtained in the form of an orange-yellow foam.

Infrared spectrum (KBr): 3550-3100 cm ^-1 (alcoholic OH),

2972, 2931, 2865 cm ^-1 (aliphatic CH v), 1690 cm ^-1 (carbamate

C = 0 v), 1391, 1365 cm ^-1 (CH ₃ δ ₃₅ ), 1244, 1228 cm ^-1 , (ether C-0 v), 1158 cm ^-1 (carbamate C-0 v), 1031 cm ¹ ( alcohol C-O v), 845 cm ^-1 (quinoline CH γ).

283 (3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) -3-vinylpiperidine cm ^{3 of} triethylamine followed by 3.15 g of di-tert-butyl dicarbonate added with stirring at about 20 ° C to a suspension of 5 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -3-vinylpiperidine hydrochloride in 50 cm ^{3 of} dichloromethane. After 45 minutes, the solution obtained is washed with 2 × 30 cm ^{3 of} water, dried over magnesium sulfate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 6 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) -3-vinylpiperidine are obtained as a brown oil.

Infrared spectrum (CH 2 Cl 2): 2972, 2933, 2860 cm ^-1 (aliphatic CH v), 1680 cm ^-1 (carbamate C = O v), 1391, 1365 cm ¹ (CH ₃ δ _as ), 1244, 1228 cm ^-1 , (ether C-0 v), 1165 cm ^-1 (carbamate C-0 v), 845 cm ^-1 (quinoline CH γ).

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -3-vinylpiperidine hydrochloride can be prepared by applying the method described in patent application FR 2,354,771.

Example 37

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetic acid dihydrochloride

A mixture of 0.3 g of methyl (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetate in 8 cm ^{3 of} dioxane with stirring in the presence of 0.5 cm ^{3 of} 5 N aqueous sodium hydroxide solution at a temperature of about 60 ° C for 20 hours. After cooling to about 20 ° C, the reaction mixture is evaporated under reduced pressure (5 kPa) at about 40 ° C. A yellow foam was obtained which was purified by silica gel column chromatography (20-45 µm particle size, 1.6 cm diameter, 40 cm ³ silica gel) eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (12%). (3 / 0.5 by volume) and collected first

284

125 cm ³ fractions and then approximately 10 cm ³ fractions are collected. Fractions 3 to 7 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.27 g of lacquer is obtained, which is taken up in 5 cm @ ^{3 of} dioxane, 11 cm @ ^{3 of} 0.1 N aqueous hydrochloric acid and 14 cm @ ^{3 of} distilled water. The dioxane is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C and then the remaining solution is lyophilized. 0.29 g of (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetic acid dihydrochloride is obtained in the form of white lyophilisate.

^X H-NMR (400 MHz, DG-(CD 3) 2 SO at 110 DEG C., the δ

ppm): 1.25-2.05 (Mt. 18H), 2.33 (dd, J = 16 and 5.5 Hz, 1H), 2.50-2.60 (mt, 1 H) 2.83 (mt, 1H), 2.95-3.30 (mt, 10H); 4.00 (with, 3H), 7.45 (d, J = ^: 5 Hz, 1H), 7.48 (d, J = 2Hz, 1 H), 7.51 (Dd, J = 9.5 and 2 Hz, 1H), 8.08 (D, J = 9.5 Hz, 1H) 8.72 (D,

J = 5 Hz, 1 H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetate

A mixture of 1.2 g of methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) propyl] -piperidine-3-acetate and 0.65 g of 2-chloroethylcyclohexylsulfide in 25 cm ^{3 of} acetonitrile, to which 2.3 g of potassium carbonate and 0.55 g of potassium iodide were added, heated under stirring in an inert atmosphere at 80 ° C for 4 hours. After cooling to about 20 ° C, 30 cm ^{3 of} water are added to the reaction mixture and then extracted with 2 x 200 cm ^{3 of} ethyl acetate. The combined organic extracts were washed with 2 x 40 cm ^{3 of} 1 N aqueous hydrochloric acid. After separation by settling, the combined acidic extracts are basified with saturated aqueous sodium bicarbonate solution and then extracted with 2 x 100 cm ^{3 of} ethyl acetate. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.80 g of a brown oil is obtained, which is purified by silica gel column chromatography (20-45 µm particle size, 2.5 cm diameter, 120 cm ³ silica gel volume),

285 was eluted with dichloromethane and methanol (99/1 by volume) was collected and the first 250 cm ³ fractions, and then eluted with a mixture of dichloromethane and methanol (90/10 by volume) and collected with 200 ^cm3 fractions. Finally, it is eluted again with a mixture of dichloromethane and methanol (99/1 by volume) and approximately 10 cm ^{3 of} fractions are collected. Fractions 10 to 33 are combined, concentrated under reduced pressure (5 kPa) to give 0.30 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-acetate as a colorless oil.

IR (CC1 _4): 2932, 2855 cm ^-1 (aliphatic CH at).

2800, 2763 cm ¹ (N (CH ₂ ) 3 CH ₂ v), 1737 cm ¹ (ester C = O v), 1241,

1227 cm &^lt; -1 ^&gt; (ether C-O), 844 cm &^lt; -1 ^&gt; (quinoline CH [gamma]).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate can be prepared as described in Example 36.

Example 38

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -hydrochloride piperidine-3-carboxylic acid i

A solution of 0.2 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2- Ytlthio) ethyl] piperidine-3-carboxylate in 3 cm @ ^{3 of} 6N hydrochloric acid is heated with stirring at about 100 DEG C. for 7 hours and then evaporated under reduced pressure (5 kPa) at a temperature of about 50 DEG. The residue is stirred in 10 cm @ ^{3 of} diisopropyl ether, the crystals are filtered off, washed with 2.times.5 cm @ ^{3 of} diisopropyl ether and dried under reduced pressure (13 Pa) at a temperature of about 60 ° C. 0.22 g of (3R, 4R) -4- [3- (R, 5) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2) -hydrochloride] is obtained. -ylthio) ethyl] piperidine-3-carboxylic acid as a beige solid with a melting point of about 140 ° C while softening.

¹ H-NMR spectrum (400 MHz, d 6 - (CD 3) ₂ SO with the addition of a few drops of d ₄ -CD ₃ COOD at 100 ° C, δ in ppm). The presence of two diastereomers was found: 1.55-2.30 and 3.10-3.50 (mts, 15H),

3.10 (broad s, 1H), 3.98 (s, 3H), 6.31 (mt, J _HF = 48 Hz, 1H),

7.10 (mt, 1H); 7.29 (broad d, J = 4 Hz, 1H); 7.35-7.45 (mt,

1H), 7.45-7.60 (mt, 2H), 7.64 (broad d, J = 5.5 Hz, 1H), 8.06 (d, J = 9 Hz, 1H), 8.82 (d, J = 5Hz, 1 H).

Methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine- 3-carboxylate

0.16 cm @ ^{3 of} diethylaminosulfurtrifluoride dissolved in 2 cm @ ^{3 of} dichloromethane are added under an inert atmosphere to a stirred solution of 0.5 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinoline). 4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-carboxylate in 8 cm ^{3 of} dichloromethane cooled to about 10 ° C. The mixture was stirred at this temperature for 10 minutes and then allowed to rise to 20 ° C and stirring was continued for 18 hours. After addition of 8 cm ^{3 of} saturated aqueous sodium bicarbonate solution and stirring for 15 minutes, the organic phase is separated by settling. The aqueous phase is extracted with 1 x 5 cm ^{3 of} dichloromethane and the organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.5 g of a red oil is obtained which is purified by chromatography under a nitrogen pressure of 100 kPa on a silica gel column (particle size 40-63 μτη, diameter 3.5 cm, silica gel height 35 cm), eluting with a mixture of dichloromethane and methanol (97). , 5 / 2.5 by volume) and 30 cm ³ fractions are collected. Fractions 25 to 29 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.2 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-) was obtained. ylthio) ethyl] piperidine-3-carboxylate as an orange oil.

The infrared 'range (CC1 _4): 2950 cm ¹ (aliphatic CH H), 2804,

2767 cm ^-1 (N (CH ₂ ) ₃ CH ₂ v), 1737 cm ^-1 (ester C = O v), 1243, 1229 cm ¹ , (ether C-0 v), 852 cm ¹ (quinoline CH γ) .

287

Example 39

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-acetic acid dihydrochloride

0.8 cm ^{3 of a} 5 N aqueous solution of sodium hydroxide is added to an stirred solution of 0.43 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [ 3- (thien-2-yl) prop-2-ynyl] -piperidine-3-acetate in 10 cm ^{3 of} dioxane. The mixture is heated to about 60 ° C for 20 hours and, after cooling to about 20 ° C, the reaction mixture is evaporated under reduced pressure (5 kPa) at about 45 ° C. 0.8 g of product is obtained, which product is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-44 µm, diameter 3 cm, height silica gel 30 cm), eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (12%). (3 / 0.5 by volume) and 25 cm ³ fractions are collected. Fractions 14 to 29 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.350 g of a white solid is obtained, the hydrochloride of which is prepared as follows: the solid obtained is dissolved in 5 cm @ ^{3 of} dichloromethane and then, under stirring under an inert atmosphere, the solution obtained is added to 10 cm @ ^{3 of a} 1 N solution of hydrogen chloride in ether. The mixture is diluted with 100 cm ^{3 of} anhydrous ether. A white suspension is obtained which is stirred for 3 hours at a temperature of about 20 ° C. The crystals are filtered off, washed with 5 x 10 cm ^{3 of} diethyl ether and dried under reduced pressure (10 kPa) at a temperature of about 20 ° C. 0.430 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3 acid hydrochloride is obtained. -acetic acid in the form of a white solid, m.p.

1 H-NMR spectrum (400 MHz, dg- (CD ₃ ) 2 SO, δ in ppm): 1.35-3.80 (mts, 16H), 4.00 (s, 3H), 4.38 and 4.43 (unresolved peak, 2H total),

7.16 (mt, 1H), 7.46 (d, J = 3.5Hz, 1H), 7.53 (mt, 1H), 7.64 (mt, 2H), 7.74 (d, J) = 5 Hz, IH), 8.12 (d, J = 9.5 Hz, IH), 8.86 (unresolved peak, IH), 9.95 and 10.45 (2 broad unresolved peaks,

IH overall), 12.20-12.55 (broad unresolved peak, IH).

288

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] -piperidin-3- acetate

0.027 g of triphenylphosphine, 0.091 g of tetrakis (triphenylphosphine) palladium, and then 0.044 g of copper (I) iodide are added at about 20 ° C under an inert atmosphere to 0.44 g of methyl (37 R, 47 R) -4- [3- (6)]. -methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-acetate in 15 cm ^{3 of} anhydrous acetonitrile. The solution is stirred for 15 minutes and 0.2 cm ^{3 of} 2-iodothiophene and 0.32 cm ^{3 of} triethylamine are added. The mixture is stirred at about 20 ° C for 12 hours, the reaction mixture is filtered through diatomaceous earth and the filter cake is washed with 5 x 10 cm ^{3 of} acetonitrile. The combined organic extracts were evaporated under reduced pressure (5 kPa) at about 40 ° C. 1.1 g of an oil are obtained, which is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 µm, diameter 4 cm, height of silica gel 28 cm), eluting with ethyl acetate and collecting 30 cm ^{3 of} fractions. Fractions 14 to 27 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.430 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine is obtained. -3-acetate as a yellow viscous oil.

Infrared (CH 2 Cl 2): 2936, 2862 cm ^-1 (aliphatic OH v), 2806, 2763 cm ^-1 (N (CH ₂ ) 3 CH ₂ v), 1731 cm ^-1 (ester C = O v), 1242,

1227 cm ^-1 , (ether C-O v), 848 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) -piperidine-3-acetate

1.28 cm @ ^{3 of} triethylamine and then 0.26 cm @ ^{3 of} 97% propargyl bromide are added at a temperature of about 20 DEG C. and in an inert atmosphere to a stirred solution of 0.8 g of methyl (32 R, 47 R) -4- [3- (6)]. -methoxyquinol-4-yl) -propyl] piperidine-3-acetate in 15 cm ^{3 of} anhydrous dimethylformamide. The temperature is adjusted to 45 ° C and after 6 hours the mixture is cooled to about 20 ° C. After diluting with 150 cm ^{3 of} water, the mixture is extracted with 5 x 50 cm ^{3 of} ethyl acetate. The combined extracts were washed

289 x 50 cm ^{3 of} water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at 40 ° C. 1 g of an oily residue is obtained, which is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπι, diameter 3 cm, height of silica gel 27 cm), eluting with pure ethyl acetate and collecting 50 cm ^{3 of} fractions. Fractions 7-10 are combined and then evaporated under reduced pressure (5 kPa) at about 40 ° C. 0.45 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-acetate is obtained as a colorless viscous oil.

Infrared (CH ₂ Cl ₂ ): 3302 cm ^-1 (acetylene CH v),

2936, 2863 cm ^-1 (aliphatic OH), 2808, 2764 cm ¹ (N (CH _{2) 3} CH _2), 1731 cm ^-1 (ester C-O H), 1242, 1227 cm ^-1, (the ether C-0 (v),

848 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate was prepared according to the procedure described in Example 36.

Example 40

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylic acid dihydrochloride, diastereoisomer A, and dihydrochloride (3R, 4R) -4- (3-Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (cycloheptylthio) -ethyl] -piperidine-3-carboxylic acid, diastereoisomer B ', ', I

A mixture of 1.8 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine The 3-carboxylate in 36 cm @ ^{3 of} dioxane with 2.8 cm @ ^{3 of a} 5N aqueous sodium hydroxide solution is heated at about 60 DEG C. for 24 hours. After cooling the reaction mixture to about 20 ° C and concentrating under reduced pressure (5 kPa) at about 40 ° C, the residue obtained is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπ, diameter 4 cm, weight 180) g) eluting with a mixture of dichloromethane, methanol and 28%

290 aqueous ammonia (40/5 / 0.5 by volume) and 50 cm ³ fractions are collected. Three portions are obtained, which are evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C: part A (0.48 g) corresponding to diastereomer A, part B (0.6 g corresponding to diastereomer B and part C (0). 5 g) of the corresponding mixture of the two diastereoisomers Part A is purified as follows: after dissolution in 15 cm @ ^{3 of} dichloromethane and addition to 10 cm @ ^{3 of a} 1 N solution of hydrogen chloride in diethyl ether, the gummy mixture obtained is evaporated under reduced pressure (5 kPa) at a temperature of ca. 40 DEG C. The residue is taken up in 40 cm @ ^{3 of} acetonitrile and 2 cm @ ^{3 of} 0.5 N hydrochloric acid and the solution is evaporated under the same conditions as above to give a white solid which is dried for 16 hours under reduced pressure. After stirring in 100 cm ^{3 of} diethyl ether and filtration, 0.514 g of (32 R, 42 R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) acid dihydrochloride is obtained. propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylic acid, dia stereoisomer A ([α] D ²⁰ = -58.3 ° ± 1.00, in methanol at 0.5%) as a white solid. Portions B and C are treated in the same way. Specifically, in the case of Part B, 0.650 g of (32 R, 42 R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cycloheptylthio) acid dihydrochloride is obtained. Ethyl] piperidine-3-carboxylic acid diastereoisomer B ([α] D ²⁰ = +120, 4 ° ± 1.7, in methanol at 0.5%) as a white solid.

Diastereoisomer A: ¹ H-NMR spectrum (400 MHz, dg- (CD 3) 2 SO, δ in ppm): 1.40-2.35 and 2.70-3.85, (mts, 29H), 4.01 (s, 3H), 5.50 (mt, 1H), 5.60-6.40 (broad unresolved peak, 1H), 7.55 (mt, 1H), 7.75 (broad d, J = 9 Hz, 1H), 7.99 (d, J = 5 Hz, IH), 8.30 (d, J = 9 Hz, IH), 9.04 (d, J = 5 Hz, IH), 10, 80 (unresolved peak,

IH).

Diastereoisomer B: ¹ H-NMR spectrum (400 MHz, dg- (CD 3) 2 SO, δ in ppm): 1.35-2.25 and 2.70-3.80 (mts, 29H), 4.00 (s , 3H), 5.49 and

5.55 (2 mts, IH overall), 5, 75-6, 20 (wide unresolved peak,

IH), 7.56 and 7.62 (2 broad s, IH overall), 7.71 (broad d,

291

J = 9Hz, 1H), 7.92 (mt, 1H), 8.24 (d, J = 9Hz, 1H), 9.00 (d, J = 4Hz, 1H), 10.56 (unresolved) peak, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3- carboxylate

0.221 g of sodium borohydride is added in portions at about 20 ° C to a mixture of 2.5 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] under stirring and in an inert atmosphere. ] -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylate in 20 cm ^{3 of} methanol. After the addition, the mixture is stirred for 2 hours at about 20 ° C. The reaction mixture is evaporated under reduced pressure (5 kPa) and the residue is taken up in 50 cm ^{3 of} dichloromethane and 30 cm ^{3 of} saturated aqueous ammonium chloride solution. The organic phase is separated by settling, dried over magnesium sulphate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 2.5 g of product are obtained, which product is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπι, diameter 4 cm, weight 150 g), eluting with a 95/5 by volume mixture of dichloromethane and methanol and collected. with 50 cm ³ fractions. The fractions containing the desired product are combined and then evaporated under reduced pressure (65 kPa) at a temperature of about 40 ° C. 1.95 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cycloheptylthio) ethyl] was obtained. piperidine-3-carboxylate in the form of a viscous oil.

IR (CC1 _4): 3500-3100 cm ¹ (OH alcohol) ',

2930 cm ^-1 (aliphatic OH v), 2805, 2772 cm ^-1 (N (^ 2) 3 (¾ v),

1736 cm ^-1 (ester C = O v), 1242, 1228 cm ^-1 , (ether C-O v),

1034 cm ^-1 (alcohol C-O v), 854 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- (3- (6-methoxyquinol-4-yl) -3-oxopropyl) -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylate

Mixture containing 3.06 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-carboxylate, 1.79 g of 2-chloroethylcycl292 loheptylsulfide, 5.39 g of potassium carbonate and 1.29 g of potassium iodide in 75 cm ^{3 of} acetonitrile are heated under stirring in an inert atmosphere to a temperature of about 72 ° C for 24 hours. After cooling to about 20 ° C, the reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 μm, diameter 4 cm, weight 150 g), eluting with a mixture of ethyl acetate and methanol (95/5 by volume) and collecting 50 cm ^{3 of} fractions. Fractions containing the desired product are combined and then concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 2.6 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (cycloheptylthio) ethyl] piperidine-3-carboxylate are obtained in the form of: viscous oil.

IR (CC1 _4): 2930 cm * ¹ (aliphatic OH), 2805,

2767 cm ^-1 (N ((^ 2) 3 (¾ v), 1740 cm ^-1 (ester C = O v), 1693 cm ¹ (ketone C = O v), 1241, 1228 cm -1 ⁾ (ether C- 0 v), 850 cm ^-1 (quinoline CH γ).

2-Chlóretylcykloheptylsulfid

5.11 cm ^{3 of} thionyl chloride are added dropwise with stirring under an inert atmosphere at about 20 ° C to a solution of 1.74 g of 2-hydroxyethylcycloheptylsulfide in 30 cm ^{3 of} chloroform. After the addition, the reaction mixture is first stirred for 15 minutes at the same temperature and then for 1 hour at a temperature of about 60 ° C. The mixture is evaporated to dryness under reduced pressure (5 kPa) at a temperature of about 40 ° C and then the residue is dissolved in 100 cm ^{3 of} diethyl ether and washed with 2 x 50 cm ^{3 of} water and then 1 x 50 cm ^{3 of} saturated sodium bicarbonate solution. The organic phase is separated by settling, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.89 g of 2-chloroethylcycloheptylsulfide are obtained in the form of an oil.

IR (CC1 _4): 2930, 2855 cm '(CH _2), 1459,

293

1445 cm ^-1 (CH ₂ δ), 1210 cm ^-1 , (C-Cl ω), 702 cm ^-1 (C-Cl v).

2-Hydroxyetylcykloheptylsulfid

2.32 g of 2-mercaptoethanol previously dissolved in 10 cm ^{3 of} dimethylformamide are slowly added to a stirred suspension of 0.91 g of 60% sodium hydride in 10 cm ^{3 of} anhydrous dimethylformamide at a temperature of about 20 ° C and under inert atmosphere. The mixture is stirred for 20 minutes and 3.5 g of bromocycloheptane dissolved in 10 cm @ ^{3 of} dimethylformamide are added. After stirring at about 20 ° C for 1.5 hours, the reaction mixture is poured into 150 cm ^{3 of} water, to which 100 cm ^{3 of} diethyl ether have been added. The organic phase is separated by settling and the aqueous phase is extracted with 1 x 50 cm ^{3 of} diethyl ether. The organic phases are combined and then washed with 2 x 100 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 3.2 g of 2-hydroxyethylcycloheptylsulfide are obtained in the form of a yellow oil.

IR (CH2 Cl2): 3608, 3457 cm @ ^-1 (free and bound)

OH v), 2927, 2855 cm ^-1 (aliphatic OH v), 1057 cm ^-1 (C-O v).

Example 41

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -propyl] -1- (2- (thien-2-ylthio) ethyl) piperidine-3-acetic acid dihydrochloride

A mixed mixture of 0.598 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate in 13 cm ^{3 of} dioxane with 1 cm ^{3 of} 5 N aqueous sodium hydroxide solution are heated in an inert atmosphere at a temperature of about 60 ° C for 20 hours. Evaporation of the reaction mixture under reduced pressure (5 kPa) at about 50 ° C affords a yellow foam which is purified by silica gel column chromatography (particle size 20-45 µm, diameter 3 cm, height silica gel 21 cm), eluting with a mixture of chloroform, methanol and 28% ammonia and collecting 50 cm ^{3 of} fraction. Fractions 4 to 7 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. It will be obtained

294

0.49 g of product is dissolved in 5 cm @ ^{3 of} dichloromethane. Addition of 10 cm @ ^{3 of a} 1 N solution of hydrochloric acid in ether gives a pasty precipitate which is diluted with 100 cm @ ^{3 of} diethyl ether. The mixture is stirred at about 20 ° C. The white suspension obtained is filtered off and washed with 3 x 30 cm ^{3 of} diethyl ether. The resulting white solid is dried under reduced pressure (10 kPa) at a temperature of about 40 ° C to constant weight. 0.55 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3 acid hydrochloride is obtained. -acetic acid in the form of a white foam, m.p.

^X H-NMR (400 MHz, d _e - (CD _{3) 2} SO to 110 ° C, δ in ppm): 1.40-1.95 (mt, 8H), 2.30 (dd, J = 16 and 5.5 Hz, IH),

2.45-2, 60 (mt, 1H), 3.00-3.35 (mt, 10H), 4.00 (s, 3H), 7.08 (dd,

J = 5 and 3.5 Hz, 1H), 7.28 (broad d, J = 3.5 Hz, 1H), 7.45-7.55 (mt, 2H), 7.56 (dd, J = 9.5 and 3 Hz, 1H), 7.62 (broad d,

J = 7 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H), 8.75 (d, J = 5 Hz, 1H).

Example 41A

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate

4.06 g of potassium carbonate and then 1 g of potassium iodide are added, under an inert atmosphere, to a stirred solution of 2.1 g of methyl (32 R, 42 R) -4- [3- (6-methoxyquinol-4-yl) propyl] piper idine-3-acetate and 1.15 g of 2- (2-chloroethyl) thiophene in 50 cm ^{3 of} acetonitrile. The mixture was heated at 70 ° C for 20 hours. After cooling to about 20 ° C, the reaction mixture is diluted with 100 cm ^{3 of} ethyl acetate and 100 cm ^{3 of} water. The mixture is stirred, the organic phase is separated by settling and the aqueous phase is extracted with 2 x 50 cm ^{3 of} ethyl acetate. The organic phases are combined and extracted with 3 x 50 cm ^{3 of} 1 N aqueous hydrochloric acid. The acidic solutions were combined and the pH adjusted to 8 with sufficient sodium bicarbonate. The resulting oil is extracted with 3 x 100 cm ^{3 of} ethyl acetate. The combined extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure

295 pressure (5 kPa) at about 40 ° C. 1.5 g of an orange oil are obtained, which is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 gm, diameter 3 cm, height of silica gel 55 cm), eluting with pure ethyl acetate and collecting 50 cm ^{3 of} fractions. Fractions 12 to 30 are combined and then evaporated under the same conditions as above. 0.60 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate is obtained in in the form of a colorless viscous oil.

Infrared (CH ₂ Cl ₂ ): 2933, 2861 cm ^-1 (aliphatic OH v), 2803, 2766 cm ^-1 (N (CH ₂ ) 3 CH ₂ v), 1730 cm ¹ (ester C = O v), 1242 .

1277 cm ^-1 , (ether C-O v), 847 cm ^-1 (quinoline CH γ).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate was prepared according to the procedure described in Example 36.

Example 43

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid, diastereoisomer A, and ( 3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid diastereoisomer B g of (3R, 4R) 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid dissolved in 100 cm ³ The mixture of dichloromethane, ethanol and tetrahydrofuran (65/15/20 by volume) is chromatographed on a 35 cm long column with an 8 cm diameter packed with 1.2 kg Kromasil® silica gel (particle size 10 gm). Elution is performed with the same mixture as used to prepare the solution. The flow rate is 150 cm ³ per minute for the first 30 minutes and then 200 cm ³ per minute. Detection is performed using ultraviolet radiation at 280 nm. Two diastereoisomers are obtained by this procedure. The fractions corresponding to the first are concentrated to dryness under reduced pressure

296 (5 kPa) at about 40 ° C. The resulting solid residue was taken up in diethyl ether, filtered and air dried at about 20 ° C. 1.5 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid are obtained, diastereoisomer A ([α] _D ²⁰ = -47.1 ° ± 0.9, in dichloromethane at 0.5%) as a beige solid. The fractions corresponding to the second diastereoisomer are worked up as described above. 1.7 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid are obtained, diastereoisomer B ([α] _D ²⁰ = + 98.7 ° ± 1.6, in dichloromethane at 0.5%) as a beige solid.

Diastereoisomer A: ¹ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.10-2.05 (mts, 17H), 2.33 (very broad t, J = 10 Hz,

1H), 2.45 (broad d, J = 10 Hz, 1H), 2.59 (unresolved peak, 1H), 2.60-2.80 (mt, 5H), 2.90 (broad d, J = 10 Hz, 1H), 3.06 (broad d, J = 10 Hz, 1H), 3.96 (s, 3H), 5.22 (very broad d, J = 7 Hz, 1H), 5.40- 5.70 (broad unresolved peak, 1H), 7.30-7.45 (mt, 2H), 7.57 (d, J = 4.5 Hz, 1H), 7.94 (d, J = 9 Hz) 1H, 8.72 (d, J = 4.5 Hz, 1H), 12.50-13.40 (very broad unresolved peak, 1H).

Diastereoisomer B: ¹ H-NMR spectrum (300 MHz, d 6 - (CD ₃ ) ₂ SO, δ in ppm): 1.10-2.00 (mts, 17H), 2.33 (mt, 1H), 40-2.55 (mt, 1 H),

2.57 (broad s, 1H), 2.60-2.80 (mt, 5H), 2.82 (mt, 1H), 2.99 (mt, 1H), 3.92 (s, 3H), 5.25 (mt, 1H), 5.40-5.70 (broad unresolved peak, 1H), 7.35-7.45 (mt, 2H), 7.53 (d, J = 4.5 Hz,

1H), 7.94 (d, J = 10Hz, 1H), 8.71 (d, J = 4.5Hz, 1H),

12.40-13.50 (very broad unresolved peak, 1H).

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylic acid is prepared from its hydrochloride according to the following procedure.

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (cyclohexylthio) -ethyl] -piperidine-3-carboxylic acid dihydrochloride j

297

0.4 g methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine- The 3-carboxylate in 3 cm ^{3 of} methanol to which 0.48 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added was kept under an inert atmosphere for 16 hours. After concentrating the reaction mixture under reduced pressure (5 kPa) at about 40 ° C, the residue is taken up in 5 cm ^{3 of} 6 N hydrochloric acid and then 2.5 cm ^{3 of} methanol. The brown solution obtained was evaporated under the same conditions as described above. The residue is taken up in 5 cm ^{3 of} diisopropyl ether, filtered and washed with 2 x 3 cm ^{3 of the} same solvent. The solid obtained is dried under reduced pressure (13 Pa) at a temperature of about 60 ° C. 0.37 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] dihydrochloride is obtained. piperidine-3-carboxylic acid as a brown solid, m.p. 170 ° C, softening.

^X H-NMR (400 MHz, _d6 - _(CD3) 2SO at 110 ° C, δ in ppm). Two diastereoisomers were found: 1.20-2.25 and 2.80-3.40 (mts, 25H), 3.28 (t, J = 8 Hz, 2H), 4.00 (s, 3H), 5.36 (mt, 1H), 7.50-7.65 (mt, 2H), 7.70 (mt, 1H), 8.13 (broad d,

J = 9 Hz, 1 H), 8.81 (d, J = 5 Hz, 1 H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] piperidine-3-carboxylate

A mixed mixture of 0.54 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate, 0.295 g

Of 2-chloroethylcyclohexylsulfide, 0.23 g of potassium carbonate and 0.27 g of potassium iodide in 9 cm @ ^{3 of} acetonitrile and 1 cm @ ^{3 of} methanol are heated under reflux for 20 hours under an inert atmosphere. The reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue obtained is purified by chromatography under argon pressure of 80 kPa on a silica gel column (particle size 40-63 µm, height 35 cm), eluting with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 35 cm ^{3 of} fractions. Fractions 23 to 40 are combined and then concentrated under reduced pressure (5

298 kPa) at a temperature of about 40 ° C. 0.4 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclohexylthio) ethyl] is obtained. piperidine-3-carboxylate as a brown lacquer.

IR (CC1 _4): 3600-3200 cm ^-1 (OH), 2932,

2854 cm ^-1 (aliphatic OH v), 1736 cm ¹ (C = 0 v), 1242 cm ¹ , (ether C-0 v).

Example 44

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2-ynyl] -piperidine-3- acid carboxylic acid, diastereoisomer A, and (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2- (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (vinyl) -piperidine-3-carboxylic acid diastereoisomer B g (thien-2-yl) prop-2-ynyl] piperidine-3-carboxylic acid dissolved in 100 cm ^{3 of a} mixture of dichloromethane, methanol and acetonitrile (85/8/7 by volume) is chromatographed on a column 35 cm long and 8 cm diameter packed 1.2 kg Kromasil® silica gel (particle size 10 μιη). Elution is performed with the same mixture as used to prepare the solution. Detection is performed using ultraviolet radiation at 280 nm. Two diastereoisomers are obtained by this procedure. The fractions corresponding to the first are concentrated to dryness under reduced pressure (5 kPa) at a temperature of about 40 ° C. The resulting solid residue is dried under reduced pressure (23 Pa) at a temperature of about 20 ° C. 0.612 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] acid is obtained. piperidine-3-carboxylic acid, diastereoisomer A ([α] D ²⁰ = -67.5 ° ± 1.3, in dichloromethane at 0.5%) as a white foam. The fractions corresponding to the second diastereoisomer are worked up as described above. 0.596 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] acid is obtained. piperidine-3-carboxylic acid diastereoisomer B

299 ([α] ₀ ^2θ = + 106,0 ° ± 1,6, in dichloromethane at 0,5%) in white foam,

Diastereomer A: ¹ H-NMR (300 MHz, d _p - (CD _{3) 2} SO, ppm): 1, 40 to 1.95 (mt, 7H), 2.40 (mt, 1H), 2.50 -2.60 (mt,

2.60-2.80 (mt, 2H), 2.90 (unresolved peak, 1H), 3.63 (s,

3.94 (s, 3H), 5.24 (mt, 1H), 5.52 (mt, 1H), 7.08 (dd, J = 4Hz, 1H), 7.31 (dd, J = 4) a 1 Hz, 1H), 7.35 (d, J = 3 Hz, 7.40 (dd, J = 9 and 3 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.59 J = 5 and 1 Hz, 1H), 7.95 (d, J = 9 Hz, 1H), 8.71 (d, J = 4, 1H).

Diastereoisomer B: ¹ H-NMR spectrum (300 MHz, d 6 - (CD ₃ ) ₂ SO, ppm): 1.20-1.95 (mt, 7H), 2.38 (mt, 1H), 2.50- 2.75 (mt,

2.71 (unresolved peak, 1H), 3.58 (s, 2H), 3.90 (s, 3H), (mt, 1H), 5.52 (mt, 1H), 7.07 (dd, J) = 5 and 3.5 Hz, 1H), (broad d, J = 3.5 Hz, 1H), 7.30-7.45 (mt, 2H), 7.53 J = 4.5 Hz, 1H) 7.58 (broad d, J = 5 Hz, 1H), 7.94 J = 10 Hz, 1H), 8.70 (d, J = 4.5 Hz, 1H).

form δ in 1H), 2H), = 5 and 1H), (dd,

Hz, δ in 3H), 5.25 7.29 (d, (d,

Example 45

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (5-chloro-thien-2-yl) -ethyl] -acetic acid ] piperidine-3-carboxylic acid

A solution of 0.460 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (5-chlorothien-2-yl) Ethyl] piperidine-3-carboxylate in 5 cm ^{3 of} dioxane to which 0.51 cm ^{3 of} 5 N aqueous sodium hydroxide solution was added was stirred at about 60 ° C for 48 hours. After an additional 1 cm ^{3 of} 5N sodium hydroxide was added, the mixture was again heated to 70 ° C for 72 hours. The reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 45 ° C and then the residue obtained is purified by chromatography under a nitrogen pressure of 40 kPa on a silica gel column (particle size 40-63 μπι, diameter 3 cm, silica gel height 27 cm). eluting with a mixture of dichloromethane, methanol and 28% ammonia (14/4 / 0,6 by volume) and

300 cm ³ fractions are collected. Fractions 7 to 16 are evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.30 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (5-chloro-thien- 2-yl) ethyl] piperidine-3-carboxylic acid as a white foam.

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm). Two diastereoisomers were found: 1.40-3.10 (mts, 16H), 3.92 and

3.95 (2 s, 3H total), 5.23 (mt, 1H), 5.50 (mt, 1H), 7.05-7.15 (mt, 2H), 7.30-7, 45 ( mt, 2H), 7.52 and 7.54 (2 d, J = 5 Hz, 1H overall), 7.94 (mt, 1H), 8.70 (d, J = 5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (5-chlorothien-2-yl) ethyl] piperidine-3-carboxylate

A solution of 1 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate in 40 cm ^{3 of} acetonitrile and 10 cm ³ of methanol is stirred at a temperature in the region of 20 DEG C. and then 1.16 g of potassium carbonate and 0.5 g of potassium iodide are added. 1 g of 2-chloro-5- (2-chloroethylthio) -thiophene is added to the suspension obtained. The mixture was stirred at about 80 ° C for 72 hours. The reaction mixture is poured into 75 cm ^{3 of} ethyl acetate and then washed with 3 x 70 cm ^{3 of} water. The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 45 ° C. The residue obtained is purified by chromatography under a pressure of 40 kPa on a silica gel column (particle size 20-40 μιη, diameter 3.5 cm, height of silica gel 31 cm), eluting with ethyl acetate and collecting 30 cm ^{3 of} fractions. Fractions 24 to 52 are combined and concentrated under reduced pressure (5 kPa) at about 40 ° C. 0.48 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (5-chlorothien- 2-yl) ethyl] piperidine-3-carboxylate as a brown oil.

Mass spectrum (CI): m / z = 535 (M + H) &lt; ^{+ &gt};.

2-Chloro-5- (2-chloroethylthio) thiophene

301 cm @ ^{3 of a} 5 N aqueous sodium hydroxide solution are added with stirring to a solution of 17.9 g of 2-chlorothiophenethiol in 30 cm @ ^{3 of} 1-chloro-2-bromoethane cooled to about 5 DEG C. and then adjusted to 20 DEG C. and stirring was continued for another 20 hours. The reaction mixture is diluted with 300 cm ^{3 of} ethyl acetate and washed with 3 x 150 cm ^{3 of} water. The organic solution is dried over sodium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 45 ° C. 20.6 g of 2-chloro-5- (2-chloroethylthio) -thiophene are obtained in the form of a brown oil.

Mass spectrum (DCI): m / z = 535 (M + H) &lt; + &gt;.

2-Chloro-5-thiophenethiol can be prepared as described by E. Jones and M. Moodie, Tetrahedron, 21, 1333-1336 (1965).

Example 46

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- (3-fluoro-3-phenylpropyl) piperidine-3-carboxylic acid

A mixture of 0.4 g of methyl (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- (3- (R, S) -fluoro-3-phenylpropyl) piperidine-3- of carboxylate and 0.18 g of lithium hydroxide monohydrate in 2 cm ^{3 of} water and 10 cm ^{3 of} acetone are stirred for 3 days at about 20 ° C and then evaporated under reduced pressure (5 kPa) at about 40 ° C. The residue is purified by chromatography under argon pressure of 50 kPa on a silica gel column (particle size 20-45 μmη, diameter 3 cm, 50 g), eluting with a 95/5 by volume mixture of dichloromethane and methanol and first collecting the 910 cm ³ fraction. Elution is then continued using a mixture of dichloromethane and methanol (90/10 by volume) and 13 cm ³ fractions are collected. Fractions 47 to 69 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The evaporated residue was taken up in dichloromethane, filtered and concentrated under the same conditions as above. The product obtained is stirred for 10 minutes in 10 cm @ ^{3 of} diisopropyl ether. The crystals are filtered off, washed with 1 x 5 cm ^{3 of} diisopropyl ether and 3 x 5 cm ^{3 of} pentane. obtained

302 to 0.102 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3-fluoro-3-phenylpropyl) piperidine-3-carboxylic acid as a gray solid with mp 60 ° C, which corresponds to one of the diastereomers. [.alpha.] _D @ ²⁰ = + 37.5 DEG. + -. 0.9, in methanol at 0.5%.

¹ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.45-3.10 (mts, 16H), 3.02 (broad t, J = 7 Hz, 2H ), 4.04 (s, 3H), 5.59 (mt, J _HF = 48Hz, 1H), 7.32 (d, J = 4.5Hz, 1H), 7.35-7.50 ( mt, 7H), 7.42 (d, J = 9Hz, 1H), 8.62 (d, J = 4.5Hz, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3- (R, S) -fluoro-3-phenylpropyl) piperidine-3-carboxylate

0.425 cm &lt; ^{3 &gt; of} diethylaminosulfurtrifluoride is added under an inert atmosphere at about 20 [deg.] C. to a stirred solution of 1.18 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3). - (R, S) -hydroxy-3-phenylpropyl) piperidine-3-carboxylate in 17.7 cm ^{3 of} dichloromethane. The mixture is stirred for 3 hours and then poured into 32 cm @ ^{3 of a} saturated aqueous solution of sodium bicarbonate. 15 cm ^{3 of} dichloromethane are added and the mixture is stirred for a further 10 minutes. After separation of the phases by settling, the organic phase is separated, while the aqueous phase is extracted with 3 x 10 cm ^{3 of} dichloromethane. The organic extracts are combined, washed with 3 x 20 cm ^{3 of} water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.11 g of a residue are obtained, which is purified by chromatography under argon at 50 kPa on a silica gel column (particle size 20-45 pm, diameter 2.8 cm, 45 g), eluting with a mixture of ethyl acetate and methanol (98/2 by volume). ) and 15 cm ³ fractions are collected. Fractions 10 to 20 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.6 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3- (R, S) -fluoro-3-phenylpropyl) piperidine-3 is obtained. -carboxylate in the form of a light yellow viscous oil.

Infrared (ΟΗ ₂ Ο _{1 2} ): 2951, 1732, 1621, 1509, 1473,

1227, 1167, 1031 and 848 cm ^-1 .

303

Methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2 R, S) -hydroxy-3-phenylpropyl) piperidine-3-carboxylate can be prepared analogously to Example 1.

Example 47

(3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2-ylthio) trihydrochloride) ethyl] piperidine-3-carboxylic acid i

1.33 cm &lt; ^{3 &gt; of a} 5 N aqueous solution of sodium hydroxide is added to a solution of 0.33 g of methyl ([beta], 42 [beta]) -4- [3- (2 [beta], S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyridin-2-ylthio) ethyl] piperidine-3-carboxylate in 6.66 cm ^{3 of} methanol while maintaining the temperature at about 20 ° C. The resulting solution was heated to about 60 ^{° C} for 16 hours. The reaction mixture is evaporated to dryness under reduced pressure (5 kPa) at a temperature of about 60 ° C. The residue is taken up in 3.4 cm ^{3 of} distilled water and then 3.43 cm ^{3 of} 36% concentrated aqueous hydrochloric acid are added. A yellow solution is obtained which is evaporated under the same conditions as above. The evaporation residue is taken up in a mixture of dichloromethane and methanol (80/20 by volume). The insoluble material is filtered off and washed with 2 x 2.5 cm ³ of dichloromethane / methanol (90/10 by volume). The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.40 g of (3R, 4R) -4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (2R, 4S) -hydrochloride is obtained. pyrid-2-ylthio) ethyl] piperidine-3-carboxylic acid as a beige solid, m.p. 155 ° C.

^X H-NMR (400 MHz, d _p - _(CD3) 2SO at 110 ° C, δ in ppm). The presence of two diastereoisomers was found: 1.50-2.30 and

3.15-3.65 (mts, 16H), 4.00 (s, 3H), 5.38 (mt, 1H), 7.18 (broad dd, J = 8 and 5 Hz, 1H), 7, 38 (d, J = 8Hz, 1H), 7.55-7.65 (mt, 2H), 7.69 (t, J = 8 and 2Hz, 1H), 7.80 (mt, 1H), 8.20 (broad d, J = 10 Hz, 1H), 8.48 (dmt, J = 5 Hz, 1H), 8.35 (broad d,

J = 5 Hz, 1 H).

304

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine- 3-carboxylate

A stirred solution of 0.77 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine The 3-carboxylate in 15 cm ^{3 of} methanol is cooled to about 0 ° C under an inert atmosphere. Sodium borohydride (0.063 g) was then added and after stirring for 15 minutes the mixture was brought to 20 ° C and stirring was continued for 16 hours. After addition of saturated aqueous ammonium chloride solution, the mixture is stirred for 10 minutes and then evaporated under reduced pressure (5 kPa) at about 40 ° C. The residue is taken up in 10 cm @ ^{3 of a} mixture of dichloromethane and methanol (95/5 by volume) and then filtered. The insoluble material is washed with 2x5 cm ^{3 of the} same mixture. The filtrate was evaporated under the same conditions as above. A foam is obtained which is purified by chromatography under 100 kPa of nitrogen pressure on a silica gel column (particle size 40-63 µm, diameter 3.5 cm, height of silica gel 35 cm), eluting first with a mixture of dichloromethane and methanol (96/4 by volume). and 35 cm ³ fractions are collected. After collecting the first 50 fractions, elution is carried out with a mixture of dichloromethane and methanol (90/10 by volume). Fractions 61 to 90 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.33 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (pyrid-2- ylthio) ethyl] piperidine-3-carboxylate as a beige lacquer.

Infrared (CH ₂ Cl ₂ ): 2596, 2951, 1622, 1579, 1508,

1455, 1415, 1242, 1228, 1125, 1031, 856 and 831 cm ^-1 .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine-3-carboxylate

A mixture of 1.35 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (2-chloroethyl) piperidine-3-carboxylate dihydrochloride in 20 cm ^{3 of} acetonitrile is stirred in an inert atmosphere at a temperature of about 20 ° C. Then 1.37 g of potassium carbonate, 0.456 g are added

305 of potassium iodide and finally 0.367 g of 2-mercaptopyridine and 1 cm ^{3 of} methanol. A red suspension is obtained which is heated to about 80 ° C for 1.5 hours. After cooling the reaction mixture to about 20 ° C, the insoluble material was filtered off and washed with acetonitrile. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The evaporation residue is purified by chromatography under a nitrogen pressure of 100 kPa on a silica gel column (particle size 40-63 µm, diameter 3.5 cm, silica gel height 35 cm), eluting with a mixture of ethyl acetate and methanol (95/5 by volume) and collected. cm ³ fraction. Fractions 19 to 40 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.77 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (pyrid-2-ylthio) ethyl] piperidine-3 is obtained. -carboxylate in the form of a red viscous oil.

IR (CH2 Cl2): 2952, 2809, 1733, 1692, 1620,

1580, 1455, 1415, 1243, 1125, 1029 and 853 cm ^{@ -1} .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (2-chloroethyl) piperidine-3-carboxylate was prepared according to the method described in Example 5.

Example 48

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine-3-acetic acid dihydrochloride, diastereoisomer A, and (3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3- acetic, diastereomer B

1.2 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) acid] Ethyl] piperidine-3-acetic acid is chromatographed on a 35 cm long, 6 cm diameter column packed with 700 g of Kromasil®-CN silica gel (particle size 10 μπι). Elution is carried out using a mixture of dichloromethane, ethanol and triethylamine (98/2 / 0.1 by volume). The flow rate is 70 cm ³ per

306 minute. Detection is by ultraviolet radiation at 265 nm. After several preparative injections, fractions corresponding to diastereoisomer A are collected. These fractions are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.34 g of product is obtained, which is converted into the salt as follows: 0.3 g of this product is taken up in 30 cm ^{3 of} ether, filtered and then dissolved in 25 cm ^{3 of} acetone. The solution obtained is poured into 5 cm @ ^{3 of a} 5N solution of hydrogen chloride in ether. After concentrating the mixture under reduced pressure under the same conditions as described above, the residue is taken up in 20 cm @ ^{3 of} water and the solution is lyophilized. 0.190 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine acid dihydrochloride is obtained. -3-acetic, diastereoisomer A, in the form of an orange lyophilisate. During the preparative separation of the two diastereomers, the fraction mixture is concentrated as mentioned above for reprocessing. The separation conditions are as follows: column length 35 cm, diameter 6 cm, filled with 700 g Kromasil® silica gel (particle size 10 µm). Elution is carried out using a mixture of dichloromethane, acetonitrile, methanol and triethylamine (60/40/4 / 0.1 by volume). The flow rate is 80 cm ³ per minute. After three preparative injections, fractions corresponding to diastereoisomer B are collected. These fractions are concentrated under the same conditions as above. 0.34 g of (3 R, 4 R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (2- (thien-2-ylthio) ethyl) acid is obtained. piperidine-3-acetic acid, diastereoisomer B, as a yellow foam ([.alpha.] _D @ ²⁰ = +55.4 DEG + 1.1., in dichloromethane at 0.5%).

Diastereomer A: ^X H-NMR (400 MHz, D6 _(CD3) 2 SO with a few drops of d4 ~ CD ₃ COOD to 100 ° C, δ in ppm): 1.40-1.90 and 2.20 -2.55 (mts, 10H), 2.95-3.35 (mt, 8H), 3.99 (s, 3H), 5.40 (mt, 1H), 7.07 (dd, J = 5) , 5 and 3.5 Hz, 1H), 7.27 (broad d, J = 3.5 Hz, 1H), 7.55-7.65 (mt, 3H), 7.85 (d, J = 4) 1.5 Hz, 1H), 8.17 (d, J = 9 Hz, 1H), 8.88 (d, J = 4.5 Hz, 1H).

307

Diastereoisomer B: ¹ H-NMR spectrum (250 MHz, dg- (CD ₃ ) ₂ SO, ppm): 1.20-2.80 (mts, 16H), 2.88 (broad t, J = 7 Hz, 2H ), (s, 3H), 5.27 (mt, 1H), 7.04 (dd, J = 5.5 and 3.5 Hz, 1H), (dd, J = 3.5 and 1.5 Hz) (1H), 7.30-7.45 (mt, 2H), 7.54

J = 4.5 Hz, 1H), 7.60 (dd, J = 5.5 and 1.5 Hz, 1H), 7.94

J = 9.5 Hz, 1H), 8.71 (d, J = 4.5 Hz, 1H).

δ v 3, 92 7.17 (d, (d,

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine -3-acetic acid

A mixture of 0.22 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-) dihydrochloride Ytlthio) ethyl] piperidine-3-acetate in 5 cm ^{3 of} dioxane to which was added 0.683 cm ^{3 of} 5 N aqueous sodium hydroxide solution was stirred for 20 hours at a temperature of about 60 ° C. After evaporation under reduced pressure (5 kPa) at about 40 ° C, the residue obtained is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 µm, diameter 1 cm, silica gel volume 20 cm ³ ), eluting with a chloroform mixture , methanol and aqueous ammonia (12/3/1 by volume). Fractions 1-3 are combined and concentrated under the conditions outlined above. The product obtained is dried in an oven to constant weight under reduced pressure (10 kPa) at a temperature of about 40 ° C. 0.179 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) acid is obtained. ethyl] piperidine-3-acetic acid as a white foam which is a mixture of two diastereoisomers.

¹ H-NMR spectrum presence of two (broad t, J = 7 (unresolved peak, (dd, J = 3.5 and 17.60 (broad d,

(300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ v ppm). She found out i sa diastereoisomers: 1, 15 to 2.80 (mts, 16H) 2.88 Hz, 2H), 3.91 and 3.92 (2 sec, 3H total) 5.26 1H), 7.04 (dd, J = 5,5 a 3.5 Hz, 1H) 7.16 Hz, 1H), 7.30-7.45 (mt, 2H), 7.54 (mt, 1H), J = 5.5 Hz, 1H), 7.94 (d, J = 9Hz, 1H) 8.70

(d, J = 4.5Hz, 1 H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxy-308-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] dihydrochloride piperidine-3-acetate drop of 5 N aqueous sodium hydroxide solution and then portionwise 0.17 g of sodium borohydride are added to a solution of 0.84 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4)] with stirring. -yl) -3-oxopropyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate in 12 cm ^{3 of} methanol, maintaining the temperature at about 20 ° C. After addition of 10 cm ^{3 of} water, the methanol is evaporated off under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is extracted with 3 x 20 cm ^{3 of} dichloromethane and then the combined extracts are washed with 2 x 30 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at about 40 ° C. An oil is obtained which is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μη, diameter 2.5 cm, silica gel volume 150 cm ³ ), eluting with a mixture of dichloromethane and methanol (99/1 by volume). Fractions -56-115 are pooled and then concentrated as above. An oil is obtained, the hydrochloride of which is prepared as follows: the oil is dissolved in 20 cm @ ^{3 of} diethyl ether and then poured into 2 cm @ ^{3 of a} 1 N solution of hydrochloric acid in ether. The resulting precipitate was filtered off and dried under reduced pressure at about 40 ° C. 0.3 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2) -hydrochloride is obtained. -ylthio) ethyl] piperidine-3-acetate as a white solid.

¹ H-NMR spectrum (400 MHz, d 6 - (CD ₃ ) ₂ SO at 110 ° C, δ in ppm). The presence of two diastereoisomers was found: 1.40-2.00 and 2.25-2.70 (mts, 10H total), 2.90-3, 40 (unresolved peak, 4H), 3.27 (mt, 4H) ), 3.61 and 3.63 (2 s, 3H total), 4.00 (s, 3H), 5.38 (mt, 1H), 7.10 (dd, J = 5 and 3.5 Hz, 1H), 7.29 (broad d, J = 3.5 Hz, 1H), 7.55-7.60 (mt, 2H), 7.65 (d, J = 5 Hz, 1H), 7.76 (mt, 1H), 8.16 (d, J = 9.5 Hz, 1H), 8.85 (d, J = 4.5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate

309

1.5 g of 2- (2-chloroethyl) thiophene and then 5.2 g of potassium carbonate and 2.5 g of potassium iodide are added to a solution of 2.8 g of methyl (3R, 4R) at a temperature of about 20 ° C. -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate in 60 cm ^{3 of} acetonitrile. The mixture is heated to about boiling for about 20 hours and then cooled to about 20 ° C. 130 cm ^{3 of} water and 50 cm ^{3 of} ethyl acetate are added to the reaction mixture. After separating the mixture by settling, the organic phase is washed with 150 cm ^{3 of} water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The oil obtained is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 μm, diameter 2.5 cm, silica gel volume 100 cm ³ ), eluting with a 95/5 by volume mixture of dichloromethane and methanol. First, 30 cm ^{3 of} fraction is collected and then 10 cm ^{3 of} fraction is collected. Fractions 1-4 are combined and then evaporated as described above. 2.3 g of a brown oil are obtained, which is subjected to one more purification by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μιτι, diameter 2.5 cm, silica gel volume. 300 cm ³ ), eluting with a mixture of dichloromethane and methanol (99/1 by volume) and 10 cm ³ fractions are collected. Fractions 21 to 30 are combined and then concentrated under the conditions outlined above. There was obtained 0.84 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (thien-2-ylthio) ethyl] piperidine- 3-acetate as light yellow oil.

Infrared (CH 2 Cl 2): 2937, 2806, 2765, 1731; 1693,

1620, 1505, 1243 and 849 cm ^-1 .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate

A solution of 10.8 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid in

460 cm ^{3 of} anhydrous methanol, to which 4.3 cm ^{3 of} concentrated sulfuric acid (d = 1.83) was added, was heated at about 65 ° C for 2 hours. After cooling to about 20 ° C

310 the reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C and then the residue is taken up in 200 cm ^{3 of} water and basified by the addition of sodium bicarbonate until a pH in the range 8 to 9 is obtained. 200 cm ^{3 of} ethyl acetate. The aqueous phase is basified to pH 11 by adding the necessary amount of sodium carbonate. The mixture is extracted with 2 x 200 cm ^{3 of} ethyl acetate. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 6.84 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate is obtained as a brown oil.

IR (CC1 _4): 2935, 2812, 1738, 1692, 1620, 1504, 1242, 1032 and 851 cm ^"first

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid

A solution of 0.85 g of potassium permanganate in 25 cm ^{3 of} water and 120 cm ^{3 of} acetone is added over a period of about 1 hour with stirring at about 25 ° C to a solution of 1.2 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetaldehyde in 60 cm ^{3 of} acetone. The mixture is stirred for 3 hours at the same temperature and then cooled to about 10 ° C. A solution of 5 g of sodium sulfite in 200 cm @ ^{3 of} water is added to the reaction mixture and the mixture is filtered through diatomaceous earth. The acetone contained in the filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C and the residue is then taken up in 200 cm ^{3 of} water and washed with 200 cm ^{3 of} diethyl ether. The aqueous phase is separated by settling, acidified with solid citric acid to pH 3-4 and extracted with 200 cm ^{3 of} diethyl ether. The ether solution is separated by settling, dried over magnesium sulphate, filtered and evaporated under the conditions already mentioned. 0.74 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetic acid is obtained as a yellow solid. .

311

Infrared (KBr): 2932, 2588, 1730, 1690, 1620, 1431, 1246, 1165, and 857 cm ^{@ -1} .

(3 R, 4 R) -4- [3- (6-methoxyquinoline-4-yl) -3-oxo-propyl] -1- (tert-butyloxycarbonyl) piperidin-3-acetaldehyde

A mixture of 13.7 g of dimethyl sulfoxide in 65 cm ^{3 of} dichloromethane is added slowly and with stirring under an inert atmosphere to a solution of 8.3 cm ^{3 of} oxalyl chloride in 65 cm ^{3 of} dichloromethane cooled to -60 ° C. The mixture was stirred for 15 minutes, and 10 g of (3R, 4R) -3- (2-hydroxyethyl) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) was added slowly. 1-Propyl] -1- (tert-butyloxycarbonyl) piperidine dissolved in 65 cm ^{3 of} dichloromethane. The mixture is stirred for 30 minutes and finally 61.7 cm ^{3 of} triethylamine dissolved in 65 cm ^{3 of} dichloromethane are added dropwise. The mixture is stirred at about -60 DEG C. for a further 3 hours and then poured into 400 cm @ ^{3 of} an ice / water mixture. After settling, the organic phase is washed with 400 cm @ ^{3 of a} 10% by weight aqueous citric acid solution and then dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. There was obtained 9.95 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) piperidine-3-acetaldehyde as a brown oil.

IR (CC1 _4): 2932, 2720, 1729, 1694, 1430, 1244, 1164 and 850 cm ^1st

(3R, 4R) -3- (2-Hydroxyethyl) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyloxycarbonyl) piperidine

33.4 cm &lt; ^{3 &gt; of} triethylamine borane complex is added with stirring at about 20 [deg.] C. to a solution of 52.6 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1 - (tert-butyloxycarbonyl) -3-vinylpiperidine in 500 cm ^{3 of} toluene and then heated to about 110 ° C for 18 hours. The reaction mixture is concentrated under reduced pressure (5 kPa) at about 45 ° C and the residue is taken up in 500 cm ^{3 of} tetrahydrofuran. About 63 cm ^{3 of} water are added over 20 minutes to the solution obtained and then

312 was added portionwise over approximately 1 hour 47.5 g of sodium perborate. The mixture is stirred for 4 hours at about 20 DEG C. and then 300 cm @ ^{3 of} saturated ammonium chloride solution are added. The organic solution is separated by settling, dried over magnesium sulphate and concentrated under the same conditions as above. The residue obtained is purified by silica gel column chromatography (particle size 20-45 μmη, diameter 9 cm, silica gel volume 2500 cm ³ ), eluting first with a mixture of dichloromethane and methanol (97.5 / 2.5 by volume) and collecting 1 liter. fractions followed by a mixture of dichloromethane and methanol (95/5 by volume) and 1 liter fractions were collected. Fractions 30 to 35 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. Finally, it is eluted with a mixture of dichloromethane and methanol (90/10 by volume) and 1 liter fractions are collected. Fractions 36 to 41 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 20 g of (3R, 4R) -3- (2-hydroxyethyl) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (tert-butyl) are obtained. -butyloxycarbonyl) -piperidine as an oil.

Infrared (CH 2 Cl 2) 3612, 2480, 2937, 1680, 1432, 1243, 1163 and 859 cm ^-1 .

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) -3-vinylpiperidine

To a stirred solution of 126 g (37 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -3-vinylpiperidine in 1700 cm ^{3 of} dichloromethane was added at a temperature of about 20 min. 2 ° C was added 162 cm ³ of triethylamine and then, in the course of about 2 hours was added 85 g of di-t-butyldicarbonate dissolved in 300 cm ³ of dichloromethane. The mixture is stirred for 16 hours at a temperature in the region of 20 DEG C. and then 400 cm @ ^{3 of} water are added. The organic phase is separated by settling, dried over magnesium sulphate, filtered and evaporated under reduced pressure (3 kPa) at a temperature of about 40 ° C. The oily residue obtained is taken up in 1000 cm ^{3 of} ethyl acetate and washed with 2 x 200 cm ^{3 of} water, 1 x 250 cm ^{3 of} saturated citric acid solution and 2 x 200 cm ^{3 of water.}

313 water. The organic solution was dried over magnesium sulfate, filtered, and concentrated under the conditions outlined above. 148 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (tert-butyloxycarbonyl) -3-vinylpiperidine are obtained as a brown oil.

Infrared (CH ₂ Cl ₂ ): 2979, 1683, 1431, 1246, 1164 a

853 cm ¹ .

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) -3-oxopropyl] -3-vinylpiperidine can be prepared as described in patent application FR 2,354,771.

Example 49

(3R, 4R) -1- [2- (3-Fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer A, and (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer B

0.7 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] acid The piperidine-3-acetic acid is chromatographed on a 35 cm long, 6 cm diameter column packed with 700 g Kromasil® silica gel (10 µm particle size). Elution is carried out using a mixture of dichloromethane, acetonitrile, methanol and triethylamine (56/40/4 / 0.5 by volume). The flow rate is

I · 1, J cm ³ per minute. Detection was by ultraviolet radiation at 265 nm. After several preparative injections, the two diastereoisomers are separated. The fractions corresponding to the first, diastereoisomer A, are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The crystals obtained are dried in an oven under reduced pressure at a temperature of about 20 ° C. 0.185 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] piperidine-3-acetic acid is obtained, diastereoisomer A, in the form of an off-white solid ((a) _D ²⁰ = -55, 9 ° + 1.2, in methanol at

314

0.5%). The fraction mixture is concentrated under the same conditions as above. New injections are made to obtain the second diastereoisomer. Preparative injections make it possible to obtain fractions corresponding to diastereoisomer B. These fractions are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The crystals obtained are dried in an oven under reduced pressure (10 Pa) at a temperature of about 20 ° C. 0.200 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] piperidine-3-acetic acid is obtained. , diastereoisomer B as an off-white solid ([α] _D ²⁰ = + 41.0 ° ± 1.0, in methanol at 0.5%).

Diastereoisomer A: ¹ H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.15-1.85 and 1.95-2.20 (2 mts, 11H total), 2.40-2.60 (mt, 3H), 2.65-2.80 (mt, 2H), 3.08 (t, J = 7Hz, 2H), 3.92 (s, 3H), 5 27 (mt, 1H), 5.52 (unresolved peak, 1H), 6.98 (dt, J = 8.5 and 2.5 Hz, 1H), 7.10-7.20 (mt, 2H) 7.25-7.45 (mt, 3H), 7.55 (d, J = 4.5Hz, 1H), 7.94 (d, J = 9Hz, 1H), 8.71 (d, J = 4.5Hz, 1H).

Diastereoisomer B: ¹ H-NMR spectrum (400 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.30-1.90 and 1.95-2.15 (2 mts, 10H total), 2.40-2.60 (mt, 3H), 2.75 (mt, 1H), 2.95-3.15 (unresolved peak, 2H), 3.10 (t, J = 7 Hz, 2H), 3.93 (s, 3H), 5.28 (mt, 1H), 5.53 (d, J = 5Hz,

1H), 6.97 (dt, J = 8.5 and 2.5 Hz, 1H), 7.10-7.20 (mt, 2H), 7.35 (mt, 1H), 7.35-7 45 (mt, 2H), 7.55 (d, J = 4.5Hz, 1H), 7.95 (d, J = 9.5Hz, 1H), 8.72 (d, J = 4, 5 Hz, 1H), 11.0-12.5 (very broad unresolved peak, 1H). ¹

(3R, 4R) -1- [2- (3-Fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidin-3 acid acetic acid

A solution of 1.3 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] piperidine-3-acetate in cm ^{3 of} dioxane, to which 2 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added, was heated with stirring at about 60 ° C for 20 hours. The reaction mixture was evaporated under reduced pressure

315 (5 kPa) at about 40 ° C and the residue is taken up in 30 cm ^{3 of} water and 5 cm ^{3 of} methanol and acidified with citric acid. The solvents are evaporated under the same conditions as above and the residue is taken up in 70 cm @ ^{3 of a} mixture of dichloromethane and methanol (80/20 by volume). The citric acid crystals are filtered off, the filtrate is evaporated as described above and the residue is taken up in 30 cm @ ^{3 of} diethyl ether, filtered and air-dried. 1.1 g of (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] piperidine-3- acid are obtained. acetic acid in the form of a cream colored solid.

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) 2 SO, δ in ppm). Detected

tomnosť two diastereoisomers: 1.15-1.90, 2 00 to 2.25 and 2.35 to 2.95 (Mts, 16H overall), 3.13 (broad t, J = 7 Hz, 2H), 3.92 (s, 3H), 5.27 (mt, 1H); 5.54 (mt, 1H) FROM 7.00 (Dt, J = 8.5Hz . IH), 7.10-7.25 (mt, 2H); 7.30-7.50 (mt, 3H), 7.55 (mt, lH) 7, 94 (d, J = 9 Hz, 1H), 8.71 (d, J = 4. 5 Hz, IH),

11.50-13.50 (very broad unresolved peak, 1H (

Example 49A

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate

0.28 g of sodium borohydride is added portionwise to a stirred solution of 3.2 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl)]. (3-Oxopropyl) piperidine-3-acetate in 50 cm ^{3 of} methanol to which 2 drops of 5 N aqueous sodium hydroxide solution were added while maintaining the temperature at about 20 ° C. The mixture is stirred for 4 hours at about 20 ° C. 30 cm ^{3 of} water are added and the mixture is extracted with 2 x 30 cm ^{3 of} dichloromethane. The combined organic phases are washed with 60 cm ^{3 of} water, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residual oil is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 gm, diameter 4 cm, silica gel volume 520 cm ³ ), eluting with a mixture of dichloromethane and methanol (99/1 by volume) and collecting approximately 60 cm. ³ fractions. Fractions 40 to 72 are combined and then evaporated under the conditions outlined above. 1.7 g of an oil are obtained, from which the hydrochloride is prepared as follows: 0.30 g of an oil in 5 cm @ ^{3 of} diethyl ether is poured into 5 cm @ ^{3 of a} 5 N solution of hydrogen chloride in ether. The gel obtained is diluted with 10 cm ^{3 of} ether, stirred for 15 minutes at a temperature of about 20 ° C and then evaporated under reduced pressure (5 kPa) at a temperature of about 30 ° C. The residue obtained is dissolved in 30 cm @ ^{3 of} water and then lyophilized. 0.26 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl)] was obtained. propyl] piperidine-3-acetate as a cream colored lyophilisate.

^X H-NMR (400 MHz, D6 (CD _{3) 2} SO with a few drops of _{d4-CD 3} COOD to 100 ° C, δ in ppm). The presence of two diastereoisomers was found: 1.45-2.00 and 2.25-2.60 (mts, 10H overall), 3.05-3.45 (mts, 8H), 3.60 and 3.63 (2 s, 3H total), 3.97 and 3.98 (2 s, 3H total), 5.39 (mt, 1H), 7.03 (mt, 1H),

7.23 (mt, 2H), 7.37 (mt, 1H), 7.50-7.65 (mt, 2H), 7.80 (mt, 1H),

8.12 (d, J = 9.5 Hz, 1H); 8.84 (d, J = 5 Hz, 1H).

Methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinolin-4-yl) -3-oxopropyl] piperidine-3-acetate

2.26 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate dissolved previously in 50 cm ^{3 of} acetonitrile are stirred at room temperature. A solution of 4 g of 1- (2-chloroethylthio) -3-fluorobenzene in 50 cm @ ^{3 of} acetonitrile is added dropwise to a temperature of about 20 DEG C. and then 6.91 g of potassium carbonate and 2 g of potassium iodide are added. The mixture is heated to about 70 ° C for 18 hours. After adding an additional 0.3 g of potassium iodide and further heating to about 70 ° C for 4 hours, the reaction mixture is cooled to about 20 ° C, 200 cm ^{3 of} water are added and extraction is carried out with 2 x 150 cm ^{3 of} ethyl acetate. The combined extracts are washed with 300 cm ^{3 of} water, dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C.

317

The residue obtained is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 µm, diameter

5.2 cm, silica gel volume 950 cm ³ ), eluting with a dichloromethane / methanol (99/1 by volume) mixture and collecting approximately 6 cm ^{3 of} fraction. Fractions 24 to 36 are combined and concentrated under the conditions outlined above. 3.3 g of methyl (3R, 4R) -1- [2- (3-fluorophenylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidin-3-yl is obtained. acetate as a yellow oil.

Infrared (CH ₂ Cl ₂ ): 2936, 2806, 1731, 1692, 1620,

1505, 1474, 1243, 881 and 853 cm ^-1 .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate was obtained as described in Example 48.

Example 50

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (3,5-difluoro-phenyl) -prop-2- ynyl] piperidine-3-carboxylic acid

A mixture of 0.89 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (3,5- Difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 9 cm ^{3 of} dioxane to which 1.41 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added was stirred for 18 hours at a temperature of about 60 ° C. After cooling to about 20 ° C, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue is purified by chromatography under 50 kPa of nitrogen on a silica gel column (particle size 20-45 μπι, diameter 3.3 cm, weight 56 g), eluting first with a mixture of dichloromethane and methanol (95/5 by volume). First, 100 cm ³ fractions are collected and then 16 cm ³ fractions are collected. Fractions 1 to 36 are separated. Subsequently, elution is carried out with a mixture of dichloromethane and methanol (75/25 by volume). A first fraction of 200 cm ^{3 is obtained} , followed by a second fraction of 150 cm ³ and a third fraction of 100 cm ³ . The last two fractions are combined and concentrated as above. The residue is carried over

318 into dichloromethane and filtered. The filtrate was evaporated as above and the new residue obtained was triturated in a mixture of diisopropyl ether and pentane (50/50 by volume). The product which crystallizes is filtered off and washed with 2 x 10 cm ^{3 of the} same mixture and then 3 x 10 _; cm ^{3 of} pentane. 0.53 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3-

- (3,5-Difluorophenyl) -prop-2-ynyl] piperidine-3-carboxylic acid as a cream colored solid, m.p. 106 ° C.

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm). Two diastereoisomers were found: 1.40-1.95 (mt, 7H), 2.30-3.00 (mt, 5H), 3.57 and 3.59 (2 s, 2H overall), 3.90 and 3.93 (2 s, 3H total), 5.25 (mt, 1H), 5.55 (unresolved peak, 1H), 7.22 (mt, 2H), 7.25-7.45 (mt, 3H), 7.56 (mt, 1H), 7.94 (d, J = 9 Hz, 1H), 8.70 (d, J = 4.5 Hz, 1H), 12.10-12.80 ( broad unresolved peak, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3,5-difluorophenyl) -prop-2 ynyl] piperidine-3-carboxylate

0.138 g of tetrakis (triphenylphosphine) palladium, 0.046 g of potassium iodide and 0.42 cm ^{3 of} 1-bromo-3,5-difluorobenzene are added at about 20 ° C under an inert atmosphere to a stirred mixture of 0.95 g of methyl (3R, 4R) ) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 9.5 cm ^{3 of} triethylamine . The mixture is heated to about 80 ° C for 3 hours. After cooling to about 20 ° C, the reaction mixture is taken up in 30 cm ^{3 of} ethyl acetate and 30 cm ^{3 of} water and stirred for 5 minutes. The organic phase is separated by settling and the aqueous phase is extracted with 2 x 30 cm ^{3 of} ethyl acetate. The organic extracts are combined, washed with 3 x 30 cm ^{3 of} water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (20-45 [mu] m particle diameter)

2.3 cm, 40 g) eluting with pure ethyl acetate. First, two 100 cm ³ fractions are collected and then 20 cm ³ are collected

319 fraction. Fractions 8 to 40 are combined and evaporated under the conditions outlined above. There was obtained 0.967 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3,5- difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate as an orange foam.

Infrared (KBr): 3424, 2948, 1734, 1618, 1586, 1432, 1242, 1122, 1028, 990, and 373 cm ^-1 .

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate can be prepared as described in Example 32.

Example 51

(3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,5-difluorophenyl) prop] 2-ynyl] piperidine-3-carboxylic acid

A mixture of 0.874 g of methyl (3R, 4R) -4- [3- (2R, 5S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2R, 4R, 4S)]. 5-difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 8.8 cm ^{3 of} dioxane to which was added

3.37 cm ^{3 of} 5 N aqueous sodium hydroxide solution is stirred for hours at about 60 ° C. After cooling to about 20 ° C, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The oil obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 µmη, diameter 3 cm, 25 g), eluting with a mixture of dichloromethane and methanol (85/18 by volume) and firstly. 100 cm ^{3 of} fraction is collected and 50 cm ^{3 of} fraction is collected. Fractions 3 and 4 were combined and concentrated as above. The evaporation residue is taken up in dichloromethane and filtered. The filtrate is concentrated under the conditions outlined above and the product obtained is stirred in 40 cm @ ^{3 of} a pentane / diisopropyl ether (50/50 by volume) mixture at about 20 DEG C. for 16 hours. The crystals obtained are filtered off and washed with 2 x 10 cm ^{3 of the} same mixture and then with 3 x 20 cm ^{3 of} pentane. 0.392 g of (3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,5) -hydroxy acid is obtained. difluorophenyl) 320

-prop-2-ynyl] piperidine-3-carboxylic acid as a light yellow solid, m.p. 109 ° C, which is a mixture of two diastereoisomers.

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm). Two diastereoisomers were found: 1.40-2.00 (mts, 7H), 2.30-3.00 (mt, 5H), 3.64 and 3.65 (2 s, 2H overall), 3.90 and 3.92 (2 s, 3H total), 5.26 (unresolved peak, 1H), 5.56 (unresolved peak, 1H), 7.25-7.50 (mt, 5H), 7.56 (mt) (1H), 7.94 (d, J = 9Hz, 1H),

8.71 (d, J = 4.5 Hz, 1H), 12.40-12.70 (unresolved peak, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,5-difluorophenyl) -prop-2 -iny1] piperidine-3-carboxylate

A mixture of 1.1 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine- 3-carboxylate, 11 cm ^{3 of} triethylamine, 0.16 cm ^{3 of} tetrakis (triphenylphosphine) palladium, 0.053 g of copper iodide and 0.47 cm ^{3 of} 1-bromo-2,5-difluorobenzene are stirred for 3 hours and 15 minutes under an inert atmosphere at about 80 ° C. After cooling to about 20 ° C, 30 cm ^{3 of} ethyl acetate and 30 cm ^{3 of} water are added to the reaction mixture with stirring. The organic phase is separated by settling and the aqueous phase is extracted with x 30 cm ^{3 of} ethyl acetate. The organic extracts are combined, washed with x 25 cm ^{3 of} water, dried over sodium sulphate and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The product obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 µm, diameter 3.3 cm, 50 g), eluting with ethyl acetate and first collecting a 300 cm ³ fraction and then collecting 32 cm ³ fractions. Fractions 7 to 22 are combined and concentrated under the conditions outlined above. 0.91 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,5-) - is obtained. difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in the form of an off-white foam.

IR (CC1 _4): 3614, 2950, 1738, 1622, 1497, 1249, 1163, 1033 and 873 cm ^1st

321

Diastereoisomer A:

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate prepared as in Example 43.

Example 52

(3R, 4R) -1- [2- (Cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer A, and ( 3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer B

1.3 g of (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid is chromatographed on a 35 cm long, 6 cm diameter column packed with 700 g Kromasil® silica gel (10 µm particle size). Elution is carried out using a mixture of dichloromethane, acetonitrile, methanol and triethylamine (56/40/4 / 0.5 by volume). The flow rate is 70 cm ³ per minute. Detection was by ultraviolet radiation at 265 nm. Two preparative injections lead to separation of the two diastereoisomers. The fractions corresponding to the first, diastereoisomer A, are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The evaporation residue obtained is dried in an oven under reduced pressure (10 Pa) at a temperature of about 20 ° C. 0.310 g of (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer A, is obtained. , in the form of a beige foam ([.alpha.] D @ ²⁰ = -43.6 DEG. + -. 1.0, in dichloromethane at 0.5%). The fractions corresponding to the other, diastereoisomer B, are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The evaporation residue obtained is dried in an oven under reduced pressure (10 Pa) at a temperature of about 20 ° C. 0.260 g of (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid, diastereoisomer B, is obtained. , in the form of a beige foam ([.alpha.] D @ ²⁰ = +55.4 DEG. + -. 1.1, in dichloromethane at 0.5%).

¹ H-NMR (300 MHz, _d6 - _{(CD3) 2} SO, δ in

322 ppm): 1.10-2.20 and 2.30-2.80 (2 mts, 29H total), 3.93 (s, 3H),

5.28 (broad dd, J = 7.5 and 3 Hz, 1H), 5.30-5.70 (broad unresolved peak, 1H), 7.35-7.45 (mt, 2H), 7.56 (d, J = 4.5Hz,

1H), 7.94 (d, J = 9.5Hz, 1H), 8.72 (d, J = 4.5Hz, 1H).

Diastereoisomer B: ^X H-NMR (300 MHz, D6 (CD _{3) 2} SO, δ in ppm): 1.10-2.10 and 2.30-2.80 (2 mts, 29H in total), 3 92 (s, 3H), 5.27 (broad dd, J = 7.5 and 3 Hz, 1H), 5.30-5.75 (broad unresolved peak, 1H), 7.35-7.45 ( mt, 2H), 7.54 (d, J = 4.5Hz, 1H), 7.94 (d, J = 9.5Hz, 1H), 8.71 (d, J = 4.5Hz, 1H).

(3R, 4R) -1- [2- (Cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid

2.96 cm @ ^{3 of a} 5 N aqueous sodium hydroxide solution are added, with stirring at about 20 DEG C., to a solution of 1.9 g of methyl (32 R, 42 R) -1- [2- (cyclohexylthio) ethyl] -4- [ 3-hydroxy-3- (6-methoxyquinol-4-yl) -propyl] piperidine-3-acetate in 35 cm ^{3 of} dioxane. The solution is heated to about 60 ° C for 16 hours. The reaction mixture is evaporated under reduced pressure (5 kPa) at a temperature of about 50 DEG C. and then the residue is taken up in 50 cm @ ^{3 of} acetone and evaporated again. The residue obtained is taken up in 50 cm ^{3 of} diethyl ether and concentrated under the conditions outlined above to give a yellow solid, to which 20 cm ^{3 of} water are added and acidified with an amount of citric acid sufficient to produce a yellow solid. The mixture is extracted with 50 cm ^{3 of} dichloromethane. The organic extract is concentrated under reduced pressure (5 kPa) at a temperature of about 50 ° C. The evaporation residue is washed with 2 x 100 cm ³ of dichloromethane / methanol (90/10 by volume) and the insoluble material is filtered off. The combined filtrates are concentrated as above and then the residue is taken up in 50 cm ^{3 of} diethyl ether and evaporated under the conditions outlined above. The crystals obtained are taken up in 50 cm ^{3 of} diethyl ether, filtered and washed with 2 x 50 cm ^{3 of} ether. The product is finally dried under reduced pressure, first at 5 kPa and then in an oven at 10 Pa at a temperature of about 60 ° C. 1.9 g of (32 R, 42 R) -1- [2- (cyclohexylthio) 323 are obtained

ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetic acid as a yellow solid.

^X H-NMR (300 MHz, D6 (CD 3) ₂ SO, δ in ppm). Two diastereoisomers were detected: 1.00-2.95 (mts, 29H), 3.92 (s,

3H), 5.27 (mt, 1H), 5.54 (unresolved peak, 1H), 7.30-7.45 (mt, 2H), 7.55 (mt, 1H), 7.95 (d, J = 9.5 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 10.80-11.90 (very broad unresolved peak, IH).

Example 52A

Methyl (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-acetate dihydrochloride

Sodium borohydride (0.42 g) is added portionwise to a solution of 3.5 g of methyl (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3] while stirring under an inert atmosphere over approximately 1 hour. - (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate in 50 cm ^{3 of} methanol to which a drop of sodium hydroxide solution cooled to 15 ° C was added. The mixture was stirred at this temperature for 2 hours and then cooled to about 10 ° C. 10 cm ^{3 of} water are added dropwise. The mixture is concentrated under reduced pressure (5 kPa) at a temperature of about 45 ° C. To the residue obtained, 100 cm ^{3 of} water are added and the mixture is extracted with 2 x 100 cm ^{3 of} ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated as above. An oil is obtained which is purified by chromatography under nitrogen pressure, 50 kPa on a silica gel column (particle size 20-45 μηα, diameter 3 cm, height 35 cm), eluting with ethyl acetate and collecting 30 cm ^{3 of} fractions. Fractions 19 to 42 are combined and concentrated under the conditions outlined above. 2.44 g of product are obtained, from which it is prepared

hydrochloride in the following way : 0.5 g product the dissolve in 10 cm ^{3 of} diethyl ether and then solution pour to 5 cm ³ 1 N HCl in the ether. Add 10 cm ³ of ether and mixture is left

react for 1 hour at about 20 ° C. The mixture is filtered and the filter cake is washed with 2 x 10 cm ^{3 of} diethyl ether and dried

324 at a reduced pressure (5 kPa) at a temperature of about 20 ° C and then in an oven at a reduced pressure (10 Pa) at a temperature of about 60 ° C. 0.46 g of methyl (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3- dihydrochloride is obtained. acetate as a light pink solid, m.p. 80 DEG C. with softening.

^X H-NMR (400 MHz, _d6 - _{(CD3) 2} SO to 110 ° C, δ in ppm). The presence of two diastereoisomers was found: 1.20-2.05 and 2.30-2.65 (mts, 20H overall), 2.82 (mt, 1H), 2.85-3, 50 (broad unresolved peak, 4H ), 2.96 (mt, 2H), 3.19 (mt, 2H), 3.62 and 3.63 (2 s, 3H overall), 4.00 (s, 3H), 5.37 (mt, 1H), 7.50-7.65 (mt,

2H), 7.73 (unresolved peak, 1H), 8.15 (broad d, J = 9 Hz, 1H),

8.83 (d, J = 4.5Hz, 1H).

Methyl (3R, 4R) -1- [2- (cyclohexylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate

2.06 g of 2-chloroethylcyclohexylsulfide in 50 cm @ ^{3 of} acetonitrile and then 1.78 g of potassium iodide and 7.25 g of potassium carbonate are added to a solution of 3.9 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate in 50 cm ^{3 of} acetonitrile. The mixture was heated to about 80 ° C for 18 hours. After cooling to approximately 20 ° C, a mixture of 100 cm ^{3 of} water and 100 cm ^{3 of} ethyl acetate is added. The organic phase is separated by settling and the aqueous phase is extracted with 200 cm ^{3 of} ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature of about 45 ° C. The oil obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 pm, diameter 3.5 cm, height 46 cm), eluting with a 95/5 by volume mixture of dichloromethane and methanol and collecting 50 cm. ³ fractions. Fractions 18 to 37 are combined and concentrated in vacuo. The product obtained is purified by a second chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 pm, diameter 4 cm, height 40 cm), eluting with a mixture of ethyl acetate and hexane (7/3 by volume) and collecting 100 cm. ³ fractions. Fractions 24 to 54 are combined and then concentrated under the same conditions as above. It will be obtained

3.7 g of methyl (3 R, 4 R) -1- [2- (cyclohexylthio) ethyl] -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate as of brown oil.

Infrared (CH2 Cl2): 2933, 2855, 1732, 1693, 1620,

1505, 1244, 1029 and 853 cm ^-1 .

Methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate was obtained as described in Example 48.

Example 53

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine acid -3-acetic acid, diastereoisomer A, and (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) acid] (Prop-2-ynyl) piperidine-3-acetic acid, diastereoisomer B

1.2 g of (-32 R, 4 R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) -propyl] -1- [3- (thien-2-yl) prop- The 2-ynyl] piperidine-3-acetic acid is chromatographed on a 35 cm long, 6 cm diameter column packed with 700 g Kromasil® silica gel (10 µm particle size). Elution is carried out using a mixture of dichloromethane, acetonitrile, methanol and triethylamine (70/15/15 / 0.05 by volume). The flow rate is 90 cm ³ per minute. Detection was by ultraviolet radiation at 265 nm. Two preparative injections lead to separation of the two diastereoisomers. The fractions corresponding to the first, diastereoisomer A, are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The crystalline material obtained is dried in an oven under reduced pressure (10 Pa) at a temperature of about 20 ° C. 0.408 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-] was obtained. inyl] piperidine-3-acetic acid, diastereoisomer A, as a yellow solid ([.alpha.] _D @ ²⁰ = -62.9)

326 ± 1.3, in methanol at 0.5%). The fractions corresponding to the other, diastereoisomer B, are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The crystalline material obtained is dried in an oven under reduced pressure (10 Pa) at a temperature of about 20 ° C. 0.376 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] acid is obtained. piperidine-3-acetic acid, diastereoisomer B, as a yellow solid ([α] D ²⁰ = + 46.9 ° ± 1.1, in methanol at 0.5%).

Diastereomer A: ^X H-NMR (300 MHz, _d6 - _{(CD3) 2} SO with the unit

several drops d ₄ -CD ₃ COOD, δ v ppm) : 1.20-2.00 and 2.05-2.50 (2 mts, 12H total), 2.60-2, 85 (mt, 2H) ), 3.55 (limit AB, J = 17 Hz, 2H) 3.90 (s, 3H), 5.27 (Dd, J = 8 and 3 Hz, 1H), 7.04 (mt, 1H); 26 (broad d, J = 4 Hz, 1H), 7.30-7.45 (mt, 2H), 7.52 (d, J =  5.5 Hz, 1H), 7.56 ( d, J = 4.5 Hz, 1H), 7.93 (d, J = 10Hz, 1 H) 8.70 (d, J = 4.5Hz) 1H). Diastereoisomer B: ¹ H-NMR spectrum (300 MHz , d ₆ - (CD ₃ ) ₂ SO with several drops d ₄ -CD ₃ COOD, δ v ppm) : 1.20-1.90 and 2.00-2.45 (2 mts, . 12H overall), 2.60-z 85 (Mt. 2H), 3.50 (AB,

J = 17 Hz, 2H), 3.91 (s, 3H), 5.27 (dd, J = 8 and 3.5 Hz, 1H),

7.05 (dd, J = 5.5 and 4 Hz, 1H), 7.26 (broad d, J = 4 Hz, 2H),

7.35-7.45 (mt, 2H), 7.50-7.60 (mt, 2H), 7.95 (d, J = 10Hz, 1H), 8.71 (d, J = 4, 5 Hz, 1 H).

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [3- (thien-2-yl) -prop-2-ynyl] -piperidin-3 acid acetic acid

A solution of 3 g of methyl (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine Of 3-acetate in 50 cm ^{3 of} dioxane, to which 5 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added, was stirred at about 60 ° C for 17 hours under an inert atmosphere. After cooling to about 20 ° C, the mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C and then the residue is taken up in 100 cm ^{3 of} dichloromethane and 5 cm ^{3 of} water. The mixture is acidified with such an amount

327 of citric acid to reach a pH of 4-5 and then dried over magnesium sulfate, filtered and concentrated as previously described. The residual water was removed by azeotropic evaporation with chloroform. After concentration under the conditions outlined above, the residue is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-45 μm, diameter 3.5 cm, silica gel volume 200 cm ³ ), eluting with a mixture of chloroform, methanol and methanol. % ammonia (12/2 / 0.5 by volume) and about 60 cm ³ fractions are collected. The fractions containing the expected product are combined and then concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is taken up in 40 cm ^{3 of} diethyl ether, filtered, washed with 2 x 5 cm ^{3 of} ether and dried under reduced pressure (5 kPa) at a temperature of about 20 ° C and then in an oven under reduced pressure (10 Pa) at a temperature of about 40. C. 1.9 g of (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-] are obtained. inyl] piperidine-3-acetic acid as a white solid.

^X H-NMR (300 MHz, C 6 (CD 3) 2 SO, δ in ppm). The presence of two diastereoisomers was found: 1.20-2.45 (mts, 12H), 2.60-2.85 (mt, 2H), 3.48 (mt, 2H), 3.92 (s, 3H), 5.28 '(mt, 1H), 7.06 (dd, J = 5.5 and 3.5 Hz, 1H), 7.27 (dd, J = 3.5 and 1 Hz, 1H), 7, 30-7.45 (mt, 2H), 7.50-7.60 (mt, 2H), 7.94 (d, J = 9Hz, 1H), 8.70 (d,

J = 4.5Hz, 1H).

Example 53A

Methyl (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3- acetate

0.317 g of sodium borohydride is added to a solution of 4.0 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl)] under stirring in an inert atmosphere over approximately 40 minutes at a temperature below 30 ° C. 3-Oxopropyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-acetate in 65 cm ^{3 of} methanol to which 1 drop of 5 N sodium hydroxide solution was added. The mixture is stirred at a temperature of about 20 ° C for

328 hours and then 100 cm ^{3 of} water are added and the mixture is extracted with x 50 cm ^{3 of} dichloromethane. The extracts are washed with 3 x 50 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The oil product obtained is purified by atmospheric pressure chromatography on a silica gel column (20-45 µm particle size, 3.2 cm diameter, 300 cm ³ silica gel volume), eluting with ethyl acetate and collecting approximately 100 cm ^{3 of} fraction. Fractions corresponding to the desired product are combined. These fractions are concentrated as described above. 3.5 g of methyl (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2] are obtained. -inyl] piperidine-3-acetate as a yellow oil.

Infrared (CCIJ): 2939, 1739, 1622, 1509, 1434, 1241, 850 and 696 cm ^-1 .

The hydrochloride is prepared as follows: a solution of 0.5 g of methyl (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) 1-Prop-2-ynyl] piperidine-3-acetate in 20 cm @ ^{3 of} dichloromethane is added, with stirring, to 30 cm @ ^{3 of} diethyl ether, to which 4 cm @ ^{3 of a} 1 N solution of hydrogen chloride in ether are added. After 2 hours the resulting solid is filtered off, washed with 2 x 5 cm ^{3 of} diethyl ether and dried under reduced pressure (5 kPa) and then in a vacuum oven (10 Pa) at a temperature of about 40 ° C to constant weight. 0.35 g of methyl (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (thien-2-yl) prop-2] dihydrochloride is obtained. -inyl] piperidine-3-acetate as a white solid.

Infrared (KBr): 3278, 2932, 2524, 1730, 1619, 1601, 1427, 1248, 1021, .849 and 714 cm ^{@ -1} .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine-3-acetate

0.263 g of triphenylphosphine and then 0.85 g of tetrakis (triphenylphosphine) palladium, 0.4 g of copper (I) iodide and 1.75 g of 2-iodothiophene are added under stirring at about 20 ° C under an inert atmosphere to

329 solution of 4.3 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-acetate in 100 cm ³ acetonitrile. The mixture is stirred for 10 minutes and then 2.95 cm @ ^{3 of} triethylamine are added. After stirring at about 20 ° C for 48 hours, the mixture is filtered through diatomaceous earth and the insoluble material is washed with 2 x 50 cm ^{3 of} acetonitrile. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C and the residue is purified by atmospheric pressure chromatography on a silica gel column (20-45 µm particle size, 4.5 cm diameter, 500 cm ³ silica gel volume). eluting with pure ethyl acetate and collecting approximately 60 cm ^{3 of} fraction. Fractions corresponding to the desired product are combined. These fractions are concentrated under the conditions outlined above. 4 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [3- (thien-2-yl) prop-2-ynyl] piperidine are obtained. -3-acetate as a yellow oil.

IR (CC1 _4): 2935, 1740, 1692, 1431, 1242, 1032, 849 and 698 cm ^1st

Methyl. (3 R, 4 R) -4- [3- (6-méthoxyquinolin-4-yl) -3-oxo-propyl] -1- (prop-2-ynyl) piperidine-3-acetate

4.8 cm &lt; ^{3 &gt; of} triethylamine is added under stirring under an inert atmosphere at about 20 [deg.] C. to a solution of 5 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine -3-acetate in 60 cm ^{3 of} dimethylformamide. The mixture is stirred for 15 minutes at this temperature, then 1.5 cm ^{3 of} propargyl bromide are added over about 15 minutes and after 15 minutes the mixture is heated to about 45 ° C for 14 hours. After cooling to about 20 ° C, the reaction mixture is poured into about 700 cm ^{3 of} water and then extracted with 4 x 80 cm ^{3 of} diethyl ether. The combined extracts are washed with 3 x 80 cm ^{3 of} water, dried, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μη, diameter 4 cm, silica gel volume 500 cm ³ ), eluting with pure ethyl acetate and collected.

330 with 60 cm ³ fractions. Fractions 9 to 20 are combined and then concentrated under the conditions outlined above. 4.3 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- (prop-2-ynyl) piperidine-3-acetate are obtained in the form of a yellow solid. oil.

IR (CC1 _4): 3311, 2936, 1739, 1692, 1620, 1431, 1242, 1932, 49, 654 and 627 cm ^'first

Methyl • (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate was prepared as described in Example 48.

Example 54

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid, diastereoisomer A, and acid dihydrochloride (3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid, diastereoisomer B

Following the procedure described in Example 52, the two diastereoisomers of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- ( cyclopentylthio) ethyl] piperidine-3-acetic acid. (3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid, diastereoisomer B, is isolated in a white solid, which was prepared from the dihydrochloride ([a] _D ²⁰ = -89, 6 ° ± 1.6 in methanol at 0.5%), and (3R, 4R) -4- [3-hydroxy -3- (6-methoxyquinol-4-yl) -propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetic acid, diastereoisomer A, isolated as a yellow viscous oil ([a] _D ²⁰ = +57.4 ° ± 0.9, in methanol at 0.5%).

Diastereoisomer ppm): 1.15-2.10 3.11 (mt, 1H), 7.35-7.45 (mt,

J = 10Hz, 1H)

A: ³ H-NMR spectrum (300 MHz, and 2.25-2.60 (mts, 24H total) 3.92 (s, 3H), 5.26 (dd, J =

2H), 7.54 (d, J = 4.5Hz,

8.71 (d, J = 4.5Hz, 1H).

d ₆ - (CD ₃ ) ₂ SO, 2.70 (mt, a 4 Hz, δ in 2H), 1H), (d,

1H),

7, 94

331

Diastereoisomer B: ¹ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.30-2.10, 2.15-2.40 and 2.65-3.50 (mts, 27H total),

4.00-4.01 (2 s, 3H total), 5.50 (mt, 1H), 7.54 and 7.58 (2 d,

J = 2.5 Hz, IH overall), 7.71 (very broad d, J = 9 Hz, IH), 7.96 (mt, IH), 8.23 (very broad d, J = 9 Hz, IH 9.00 (very broad d, J = 4.5 Hz, IH), 9.70-9.85 and 10.15-10.35 (2 unresolved peaks, IH overall).

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (cyclopentylthio) -ethyl] -piperidine-3-acetic acid

A solution of 1.6 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] dihydrochloride -piperidine-3-acetate in 30 cm ^{3 of} dioxane, to which 2.6 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added, was stirred for 6 hours at a temperature of about 65 ° C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature of about 40 ° C, the residue obtained is taken up twice in 30 cm ^{3 of} chloroform and evaporated under the conditions already mentioned. The residue is purified by silica gel column chromatography (20-45 μπι particle size, 3 cm diameter, 100 cm ³ silica gel volume), eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (12/3 / 0.5 by volume). ) and 30 cm ³ fractions are collected. Fractions containing the desired product were combined and concentrated under the conditions outlined above. 1.5 g of a colorless lacquer are obtained, which is taken up in 20 cm ^{3 of} diethyl ether, filtered and washed with 2 x 10 cm ^{3 of} diethyl ether. The product is dried under reduced pressure (5 kPa) and then in a drying oven under reduced pressure (10 Pa) at a temperature of about 40 ° C to constant weight. 1.35 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] acid are obtained. piperidine-3-acetic acid as a white solid.

^X H-NMR (300 MHz, _d6 - _{(CD3) 2} SO, δ in ppm). The presence of two diastereoisomers was found: 1.00-2.20 and 2.25-2.80 (mts, 25H overall), 3.10 (mt, 2H), 3.92 (broad s, 3H), 5.26 (unresolved

332 peak, 1H), 7.20-7.60 (mt, 3H), 7.93 (broad d, J = 9 Hz, 1H),

8.71 (mt, 1H).

Example 54A

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetate dihydrochloride

0.227 g of sodium borohydride is added portionwise over approximately 30 minutes at a temperature below 30 ° C while stirring under an inert atmosphere to a mixture of 2.5 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-). yl) -3-oxopropyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetate in 40 cm ^{3 of} methanol to which 1 drop of 5 N aqueous sodium hydroxide solution was added. The reaction mixture is stirred at about 20 DEG C. for 3 hours, 100 cm @ ^{3 of} water are added and the mixture is extracted with 4.times.50 cm @ ^{3 of} ethyl acetate. The combined extracts are washed with 3 x 50 cm ^{3 of} water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The oil obtained is purified by column chromatography at atmospheric pressure on a silica gel column (particle size 20-40 μτη, diameter 3.2 cm, silica gel volume 100 cm ³ ), eluting with pure ethyl acetate and collecting 25 cm ^{3 of} fractions. The fractions containing the desired product were combined and then concentrated as described above. 2.1 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl] are obtained. piperidine-3-acetate as a light yellow oil. The hydrochloride is prepared as follows: a solution of 0.5 g of the obtained oil in 15 cm @ ^{3 of} dichloromethane is poured into 4 cm @ ^{3 of a} 1 N hydrochloric acid solution in diethyl ether with stirring. The product precipitates and then crystallizes by adding 25 cm ^{3 of} diethyl ether. The solid is filtered off, washed with 2 x 10 cm ^{3 of} ether and dried under vacuum (5 kPa) over sodium hydroxide and then in an oven under reduced pressure (10 Pa) at a temperature of about 40 ° C. 0.35 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (cyclopentylthio) ethyl dihydrochloride is obtained. ] piperidine-3-acetate as an off-white solid.

333

Infrared (KBr): 3355, 2950, 2560, 2051, 1982, 1731, 1619, 1601, 1428, 1248, 1206, 1020, 849, and 714 cm ^-1 .

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetate

A mixture of 4.9 g of methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate, 2.9 g of 2-chloroethylcyclopentylsulfide, 9 g of carbonate potassium iodide and 2.7 g of potassium iodide in 130 cm ^{3 of} acetonitrile are stirred for 17 hours at a temperature of about 65 ° C. After cooling to about 20 ° C, 150 cm ^{3 of} water are added to the reaction mixture and the mixture is extracted with 3 x 60 cm ^{3 of} ethyl acetate. The organic extracts are combined, washed with 2 x 50 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at about 40 ° C. The oil obtained is purified by atmospheric pressure chromatography on a silica gel column (particle size 20-45 μπι, diameter 4 cm, silica gel volume 300 cm ³ ), eluting with pure ethyl acetate and collecting approximately 70 cm ^{3 of} fraction. The fractions containing the expected product are concentrated under the conditions outlined above. 2.6 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] -1- [2- (cyclopentylthio) ethyl] piperidine-3-acetate is obtained. in the form of an orange oil.

IR (CC1 _4): 2952, 2802, 1738, 1692, 1620, 1504, 1242, 1165, 1032 and 850 ^cm-first

Methyl (3 R, 4 R) -4- [3- (6-methoxyquinol-4-yl) -3-oxopropyl] piperidine-3-acetate was obtained as described in Example 48.

2-Chloroethylcyclopentylsulfide is prepared according to the procedure described in patent application FR 2,395,260.

Example 55

(3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,6-difluorophenyl) prop] 2-ynyl] piperidine-3-carboxylic acid

A solution of 0.531 g of methyl (3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxy-334 quinol-4-yl) propyl] -1- (3- (2,6) -difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 5.3 cm ^{3 of} dioxane, to which 0.84 cm ^{3 of} aqueous sodium hydroxide solution was added, was stirred for 15 hours at a temperature of about 60 ° C. at about 20 ° C, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue is purified by chromatography under 50 kPa nitrogen pressure on a silica gel column (particle size 20-45 µm, diameter 3 cm, 20 g) eluting with dichloromethane / methanol (90/10 by volume), collecting a first fraction of 100 cm ³ and then collecting 25 cm ^{3 of} fractions, fractions 1 to 12 are pooled and concentrated as above. The foam obtained is stirred in 15 cm ^{3 of} diisopropyl ether for 15 minutes, after addition of 15 cm ^{3 of} pentane and stirring for a further 10 minutes, the resulting crystalline product is filtered off, washed with 2 x 10 cm ^3. of a mixture of diisopropyl ether and pentane (50/50 by volume) and then 3 x 20 cm ^{3 of} pentane and air dried. 0.293 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,6-difluorophenyl)) is obtained. -prop-2-ynyl] piperidine-3-carboxylic acid in the form of a cream-colored solid, m.p.

^X H-NMR (300 MHz, _d6 - _(CD3) 2 SO, δ in ppm). Two diastereoisomers were found: 1.40-1.95 and 2.30-3.00 (mts, 12H total), 3.67 and 3.68 (2 s, 2H total), 3.88 and 3.92 (2 s, 3H total), 5.24 (mt, 1H), 5.55 (unresolved peak, 1H), 7.22 (mt,

2H), 7.30-7.60 (mt, 4H), 7.39 (d, J = 9Hz, 1H), 8.70 (mt, 1H),

12.20-12.80 (broad unresolved peak, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,6-difluorophenyl) prop-2- ynyl] piperidine-3-carboxylate

A mixture of 1.07 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine- The 3-carboxylate in 10 cm ^{3 of} triethylamine is stirred under an inert atmosphere at a temperature of about 20 ° C. 0.156 g of tetrakis (triphenylphosphine) palladium, 0.051 g of copper (I) iodide and 0.78 g of 1-bromo-2,6-difluorobenzene are then added. The mixture is stirred for 3.5 hours at a temperature of about 80 ° C. After cooling to

At about 20 DEG C., 30 cm @ ^{3 of} ethyl acetate and 30 cm @ ^{3 of} water are added. The mixture was stirred for 10 minutes and then separated by settling. After separation of the organic phase, the aqueous phase is extracted with 2 x 30 cm ^{3 of} ethyl acetate. The organic extracts are combined, washed with 3 x 30 cm ^{3 of} water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 µm, diameter 3 cm, 50 g), eluting with pure ethyl acetate and first collecting a first 300 cm ³ fraction and then collecting 38 ° C. cm ³ fraction. Fractions 6 to 16 are combined and concentrated as described above. 0.55 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,6- difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate as a light yellow foam.

IR (CC1 _4): 3615, 2950, 1738, 1622, 1470, 1241, 1007, 854 and 719 ^cm-first

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate may be prepared as described in Example 32.

Example 56

(3R, 4R) -4- [3- (6-Methoxyquinol-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop-2-ynyl] piperidine-3-acetic acid

0.83 cm ^{3 of a} 5 N aqueous sodium hydroxide solution is added to a solution of 0.525 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1 with stirring at about 20 ° C. - [3- (3,5-difluorophenyl) prop-2-ynyl] piperidine-3-acetate in 5 cm ^{3 of} dioxane, and then the mixture is heated at a temperature of about 60 ° C for 3 hours. After cooling to about 20 ° C, the mixture is stirred for 3 days and then concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue is taken up in 15 cm @ ^{3 of} water and then the solution is extracted with 5 cm @ ^{3 of} ethyl acetate. The pH of the aqueous layer is then adjusted to pH 3

336 value 5-6 by addition of 4.1 cm ^{3 of} aqueous hydrochloric acid and the mixture is extracted first with 30 cm ³ and then with 10 cm ^{3 of} dichloromethane. The organic extracts are combined, washed with 2 x 5 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue obtained is taken up in diethyl ether and then concentrated under the same conditions as described above to constant weight. There was obtained 0.45 g of (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop-2-ynyl] piperidine- 3-acetic as a light beige solid.

¹ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm). 1.20-1.80 (mt, 7H), 2.10-2.35 (mt, 4H), 2.43 (dd, J = 16.5 and 10.5 Hz, 1H), 2.75 ( mt, 2H), 3.05 (mt, 2H), 3.47 (s, 2H), 3.93 (s, 3H), 7.18 (mt, 2H), 7.25-7.35 (mt) (1H), 7.33 (d, J = 4Hz, 1H), 7.35-7.45 (mt, 2H), 7.92 (d, J = 9Hz, 1H), 8.62 (d) , J = 4 Hz, 1 H).

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop-2-ynyl] piperidine-3-acetate

0.35 cm @ ^{3 of} 1-bromo-3,5-difluorobenzene and then 0.112 g of tetrakis (triphenylphosphine) palladium and 0.37 g of copper (I) iodide are added at about 20 DEG C. under an inert atmosphere to a stirred mixture of 0.77 g of methyl ( 3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) -piperidine-3-acetate in 7.7 cm ^{3 of} triethylamine. The resulting suspension is heated to about 80 ° C for 3 hours and then concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue is taken up in 50 cm ^{3 of} ethyl acetate and 20 cm ^{3 of} water. The mixture was stirred for 15 minutes, the insoluble material was filtered off and the filtrate was separated by settling. The organic phase is separated, washed with 3 x 3 cm ^{3 of} water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The oily residue obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 40-63 pm, diameter 3 cm, 45 g), eluting with a mixture of dichloromethane and methanol.

337 (97/3 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 0.345 g of methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- [3- (3,5-difluorophenyl) prop-2-ynyl] piperidine-3- is obtained. acetate as a light yellow oil.

Mass spectrum (EI): m / z = 506 (M) &lt; ^{+ &gt};.

Methyl (3R, 4R) -4- [3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-acetate was prepared according to the procedure described in Example 39.

Example 57

(3R, 4R) -1- [2- (3,5-Difluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine acid dihydrochloride 3-carboxylic acid

1.6 cm ^{3 of} 5 N aqueous sodium hydroxide solution are added under stirring under an inert atmosphere at about 20 ° C to a solution of 0.42 g of methyl (3R, 4R) -1- [2- (3,5-difluorophenylthio) ethyl 4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate in 5.5 cm ^{3 of} methanol. The mixture is heated to about 60 ° C for 16 hours. The solution obtained is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C and then 5 cm ^{3 of} distilled water and 2.66 cm ^{3 of} 6 N aqueous hydrochloric acid are added to the residue. The mixture is heated to a temperature of about 60 ° C until a homogeneous solution is obtained, which is then evaporated under the conditions outlined above. The residue is triturated in 10 cm @ ^{3 of a} mixture of dichloromethane and methanol (90/10 by volume) and the resulting insoluble material is filtered off and washed with 2.times.5 cm @ ^{3 of the} same mixture. The filtrate is concentrated under the same conditions as above. 0.465 g of (3R, 4R) -1- [2- (3,5-difluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) -hydrochloride is obtained. 1-propyl] -piperidine-3-carboxylic acid in the form of a yellow foam, m.p. 160 DEG C. with decomposition.

338 H-NMR spectrum (300 MHz, _d6 - _{(CD3) 2} SO, δ in ppm). The presence of two diastereoisomers was found: .1.35-2.35 and 2.60-4.00 (mts, 16H total), 5.45-5, 65 (mt, 1H), 7.10 (mt, 1H). 7.21 (mt, 2H), 7.50-7.70 (mt, 1H), 7.76 (mt, 1H), 8.00 (mt, 1H), 8.33 (mt, 1H), 9.04 (d, J = 5.5 Hz, 1H), 11.10-11.55 (2 unresolved peaks, 1H overall).

Methyl (3R, 4R) -1- [2- (3,5-difluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine- 3-carboxylate

0.332 g of potassium carbonate and then 0.4 g of potassium iodide and finally 0.675 g of 1- (2-bromomethylthio) -3,5-difluorobenzene dissolved previously in 5 cm ^{3 of} acetonitrile are stirred under an inert atmosphere at about 20 ° C to the solution 0.717 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] piperidine-3-carboxylate in 15 cm ^{3 of} acetonitrile and 1 cm ^{3 of} methanol. The mixture is heated to about 80 ° C for 3 hours. After cooling to about 20 ° C, the reaction mixture is filtered and the filter cake is washed with 2 x 5 cm ^{3 of} acetonitrile. The filtrate is evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 50 kPa of nitrogen on a silica gel column (particle size 40-63 gm, diameter 3.5 cm, height 35 cm), eluting with a mixture of dichloromethane and methanol (5/5 by volume) and collected at 35 cm. ³ fractions. Fractions 18 to 21 were combined and then evaporated as described above. 0.47 g of methyl (3R, 4R) -1- [2- (3,5-difluorophenylthio) ethyl] -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-one) are obtained. yl) propyl] piperidine-3-carboxylate as an orange-yellow viscous oil.

Infrared (CH ₂ Cl ² ): 3597, 2951, 2814, 1733, 1611,

1586, 1242, 1119, 985, 877, 840, and 667 cm ^-1 .

1- (2-bromoethylthio) -3,5-difluorobenzene

A solution of 2.59 g of sodium hydroxide pellets in 27 cm ^{3 of} distilled water and then 0.27 cm ^{3 of} Aliquat 336 (tricaprylmethylammonium chloride) is added to a mixture of 7.5 g under stirring under an inert atmosphere.

339

Of 3,5-difluorothiophenol in 9.01 cm ^{3 of} 1,2-dibromoethane while maintaining the temperature at about 23 ° C. The mixture is stirred for 15 minutes at about 20 DEG C., then 50 cm @ ^{3 of} dichloromethane are added to the mixture and after a few minutes the organic phase is separated by settling, washed with 25 cm @ ^{3 of} water and 25 cm @ ^{3 of} saturated sodium chloride solution. magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at about 40 ° C. The evaporation residue is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 40-63 µm, diameter 5 cm, height 30 cm), eluting with cyclohexane and collecting a 500 cm ³ fraction first and then collecting 50 g of the product. cm ³ fraction. Fractions 9 to 26 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 5.9 g of 1- (2-bromomethylthio) -3,5-difluorobenzene are obtained in the form of a colorless liquid.

IR (CC1 _4): 3094, 1607, 1587, 1492, 1192, 1122, 988, 876, 841 and 667 cm ^1st

3,5-Difluorothiophenol can be prepared according to the procedure described by Dae-Kee Kim et al., J. Med. Chem., 1997, 2371.

Example 58

(3 R, 4 R) -4- [3- (2 R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3-difluorophenyl) prop] 2-ynyl] piperidine-3-carboxylic acid

A mixture of 0.810 g of methyl (3β, 4β) -4 - [[(S, S) -hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [3- (2,3-difluorophenyl)] prop-2-ynyl] piperidine-3-carboxylate in 8 cm ^{3 of} dioxane, to which 1.3 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added, was stirred for 17 hours at a temperature of about 60 ° C. After cooling to about 20 ° C, the reaction mixture is evaporated under reduced pressure (5 kPa) at about 50 ° C. The residue obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 [mu] m, diameter 3 cm, weight 45 g), eluting with a dichloromethane mixture of 340 methane and methanol (92/8 by volume). First, a 275 cm ³ fraction is collected and then 20 cm ³ fractions are collected. Fractions 12 to 46 are combined and concentrated under reduced pressure (5 kPa) at a temperature of about 35 ° C. The residue is taken up in dichloromethane and filtered. The filtrate is evaporated as above and the new residue is triturated in 10 cm @ ^{3 of} diisopropyl ether. The mixture was stirred for 1 hour at about 20 ° C and then allowed to stand for 16 hours. The solid precipitate is collected by filtration and washed with 2 x 10 cm ^{3 of the} same solvent and then 2 x 10 cm ^{3 of} pentane. 0.47 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3- difluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid as a white solid, m.p.

¹ H-NMR spectrum (300 MHz, d 6 - (CD 3) 2 SO, δ in ppm). Two diastereoisomers were found: 1.40-1.95 and 2.30-3.00 (2 mts,

12H overall, 3.64 and 3.65 (2 s, 2H overall), 3.90 and 3.92 (2 s, 3H overall), 5.25 (mt, 1H), 5.52 (unresolved peak, 1H), 7.15-7.30 (mt, 1H), 7.30-7.60 (mt, 5H), 7.93 (d, J = 10Hz, 1H), 8.70 (d, J) = 4.5 Hz, 1H), 11.90-12.80 (very broad unresolved peak, IH).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3-difluorophenyl) prop-2- ynyl] piperidine-3-carboxylate

0.16 g of tetrakis (triphenylphosphine) palladium, 0.053 g of copper (I) iodide and 0.47 cm @ ^{3 of} 1-bromo-2,3-difluorobenzene are added to a mixture of 1.1 g of methyl (1) under stirring under an inert atmosphere. 3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate in 11 cm ³ triethylamine. The mixture is heated to about 80 ° C for 3.5 hours. After cooling to approximately 20 DEG C., the reaction mixture is taken up in 30 cm @ ^{3 of} ethyl acetate and 30 cm @ ^{3 of} water and stirred for 15 minutes. The organic phase is separated by settling and the aqueous phase is extracted with 3 x 30 cm ^{3 of} ethyl acetate. Combine the organic extracts, wash with 3 x 30 cm ^{3 of} water, dry over sodium sulfate, filter and concentrate

341 under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 50 psi of nitrogen on a silica gel column (particle size 20-45 µm, diameter 3 cm, 50 g), eluting with pure ethyl acetate. A 300 cm ³ fraction was collected first and then 30 cm ³ fractions were collected. Fractions 10 to 30 are combined and evaporated under the conditions outlined above. 0.94 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3- difluorophenyl) prop-2-ynyl] piperidine-3-carboxylate as an orange foam.

Infrared (CH ₂ Cl ₂ ): 3598, 2951, 1733, 1622, 1489,

1475, 1243, 1227, 1031, 856 and 831 cm ^-1 .

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate can be prepared as described in Example 32.

Example 59

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3,5-trifluorophenyl) prop- 2-iny1] piperidine-3-carboxylic acid

A solution of 1.7 g of methyl (3R, 4R) -4- (3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3,5) -trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylate in 17 cm ^{3 of} dioxane, to which 2.58 cm ^{3 of a} 5 N aqueous sodium hydroxide solution was added, was stirred for 15 hours at a temperature of about 60 ° C. to about 20 ° C, the reaction mixture is concentrated under reduced pressure (5 kPa) at about 40 ° C. The residue obtained is purified by chromatography under 50 kPa nitrogen pressure on a silica gel column (particle size 20-45 μη, diameter 3 cm, 50 g), eluting with a mixture of dichloromethane and methanol (90/10 by volume), first collecting a 200 cm ³ fraction and then collecting 23 cm ³ fractions. Fractions 3 to 21 are pooled and concentrated as above. The product is obtained in the form of a foam which is subjected to a second product

Purification by chromatography under 50 psi of nitrogen on a silica gel column (20-45 µm particle size, 3 cm diameter, 70 g), eluting with a 95/5 by volume mixture of dichloromethane and methanol. First, 250 cm ³ fractions were collected, then 100 cm ³ fractions, and finally 20 cm ³ fractions were collected. Fractions 1 to 17 are combined and concentrated as described above. The foam obtained is taken up in dichloromethane and then in 20 cm ^{3 of a} mixture of diisopropyl ether and pentane (50/50 by volume). The resulting crystalline product is filtered off, washed with 2 x 10 cm ^{3 of a} mixture of diisopropyl ether and pentane (50/50 by volume) and then with 2 x 10 cm ^{3 of} pentane and air-dried. 0.524 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3, 5-) is obtained. trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid as a cream colored solid, m.p.

¹ H-NMR spectrum (300 MHz, d 6 - (CD 3) ₂ SO, δ in ppm). The presence of two diastereoisomers in the ratio 50/50: 1.40-2.00 (mt,

7H), 2.35-3.00 (mt, 5H), 3.65 and 3.66 (2 s, 2H overall), 3.90 and 3.92 (2 s, 3H overall), 5.24 ( mt, 1H), 5.54 (unresolved peak, 1H), 7.25-7.45 (mt, 3H), 7.50-7.70 (mt, 2H), 7.94 (d,

J = 9.5 Hz, 1H), 8.71 (d, J = 4.5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop- 2-ynyl] piperidine-3-carboxylate

A mixture of 1.95 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine- The 3-carboxylate in 20 cm ^{3 of} triethylamine is stirred under an inert atmosphere at a temperature of about 20 ° C for 5 minutes. Then 0.284 g of tetrakis (triphenylphosphine) palladium, 0.094 g of copper iodide and 1.56 g of 1-bromo-2,3,5-trifluorobenzene are added. The mixture is stirred for 2.5 hours at about 80 ° C. After cooling to approximately 20 ° C, 60 cm ^{3 of} ethyl acetate and 60 cm ^{3 of} water are added to the reaction mixture. After stirring for 30 minutes, the mixture was separated by settling. After separation of the organic phase, the aqueous layer is extracted with 3 x 30 cm ^{3 of} ethyl acetate. Combine the organic extracts, wash with 3 x 30 cm ^{3 of} water, dry over sodium sulfate,

The 343 are filtered and concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The residue obtained is purified by chromatography under 50 kPa of nitrogen pressure on a silica gel column (particle size 20-45 µm, diameter 4 cm, 80 g), eluting with pure ethyl acetate and first collecting a 100 cm ³ fraction and then collecting 20 cm ³ fractions. Fractions 23 to 27 are combined and concentrated as described above. There were obtained 1.3 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [3- (2,3, 5-trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylate as a foam.

IR (CC1 _4): 2950, 1740, 1624, 1496, 1231, 1133, 861 and 845 ^cm-first

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (prop-2-ynyl) piperidine-3-carboxylate may be prepared as described in Example 32.

Example 60

(3R, 4R) -4- [3- (R, S) -Fluoro-3- (6-methoxy-quinol-4-yl) -propyl] -1- [2- (thien-2-yl-thio) -ethyl] -piperidine -3-acetic acid

A mixture of 1.28 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-2-ylthio) Ethyl] piperidine-3-acetate in 25 cm ^{3 of} dioxane, to which 2 cm ^{3 of} 5 N aqueous sodium hydroxide solution was added, was stirred for 18 hours at a temperature of about 60 ° C. After evaporation under reduced pressure (5 kPa), at a temperature of about 50 ° C, the residue is taken up in 50 cm ^{3 of} acetone. The acetone is evaporated under reduced pressure (5 kPa) at a temperature of about 50 ° C. The residue is taken up in 75 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane. The organic phase was separated. The aqueous phase is extracted with 2 x 100 cm ^{3 of} dichloromethane and then the organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. The solid obtained is taken up in 50 cm ^{3 of} diethyl ether and the suspension obtained is stirred for 48 hours at a temperature in the region of 20 ° C.

344

The solid is filtered off, washed with a total of 75 cm ^{3 of} diethyl ether and dried under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1 g of solid is obtained, which is purified by chromatography under 100 kPa of nitrogen pressure on a silica gel column (60-200 µm particle size, 2 cm diameter, 15 cm silica gel height), eluting with a mixture of chloroform, methanol and aqueous ammonia (24/24). 6/1 by volume) and 20 cm ³ fractions are collected. Product containing fractions were combined and evaporated under reduced pressure (5 kPa) at about 40 ° C. 0.97 g of (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-) acid is obtained. ylthio) ethyl] piperidine-3-octyl, as a white foam which is a mixture of two diastereoisomers.

¹ H-NMR spectrum (400 MHz, d 6 - (CD ₃ ) ₂ SO with the addition of a few drops d ₄ -CD ₃ COOD, δ in ppm). The presence of two diastereo-

and visual straight in porn rt 50/50: 1.15-1.65 (mt, 5H); , 90-2.60 (Mt. 7H), 2, 61 (mt, 2H). 2.78 (mt, 2H), 2.93 (broad t, J = 7 Hz, 2H), 3, 92 and 3.93 (2 s, 3H total), 6.36 (mt, J _H F = = 48 Hz, 1H), 7.04 (Dd, J = 5.5 and 3.5 Hz (1H), 7.18 (dd, J = 3.5) a 1 Hz, 1H), 7.29 (Mt. 1H), 7.44 (mt, 1H), 7.49 (broad d, J = 4.5 Hz, 1H), 7.59 (Dd, J = 5.5 and 1 Hz, 1H), 7.98 (broad d, J) = 9 Hz, 1H), 8.77 (d, J = 4.5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine 3-acetate

0.62 cm &lt; ^{3 &gt; of} diethylaminosulfurtrifluoride is added over approximately 15 minutes in an inert atmosphere at about 20 [deg.] C. to a stirred solution of 1.96 g of methyl (3R, 4R) -4- [3- (R, S) -hydroxy 3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate in 15 cm ^{3 of} dichloromethane. Stirring was continued for 18 hours. 30 cm @ ^{3 of a} saturated aqueous solution of sodium hydrogen carbonate are then added and the organic phase is separated by settling. The aqueous phase is extracted with 2 x 50 cm ^{3 of} dichloromethane and then the organic extracts are combined, washed with 2 x 50 cm ^{3 of} distilled water, dried over sodium sulfate, filtered and evaporated under reduced pressure (5 kPa) at about 40 °. C. 1.95 g are obtained

345 yellow oil which was purified by chromatography under 100 kPa of nitrogen pressure on a silica gel column (particle size 20-45 µm, diameter 3 cm, height silica gel 40 cm) eluting with a mixture of cyclohexane and ethyl acetate (3/2 by volume) and collected 80 cm ³ fractions. Fractions 32 to 64 are combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.28 g of methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2- ylthio) ethyl] piperidine-3-acetate as a colorless oil.

¹ H-NMR spectrum (300 MHz, d ₆ - (CD 3) 2 SO, δ in ppm). The presence of two diastereoisomers in the ratio 60/40: 1.10-1.60 (mt,

5H), 1.85-2.15 (mt, 6H), 2.20-2.80 m (mt, 5H), 2.88 (br t, J = 7 Hz, 2H), 3.53 and 3.55 (2 s, 3H total), 3 , 93 a 3.94 (2 with, 3H overall), 6.40 (mt, J _H + = 48 Hz, 1H), 7.03 (Dd, J = 5.5 and 3.5 Hz, 1H), 7.15 (broad d, J = 3.5 Hz, 1H) 7.30 (br 'D. J = 1.5 Hz, 1H), 7.46 (dd, J = 9 and 1.5 Hz, 1H), 7.49 (br d. J = 4.5 Hz, 1H), 7.60 (dd, J = 5, 5 and 1 Hz, 1H), 7.99 (br d.

J = 9 Hz, 1H), 8.79 (d, J = 4.5 Hz, 1H).

Methyl (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine -3-Acetate was prepared as described in Example 48.

Example 61

(3R, 4R) -4- [3-Fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetic acid, diastereoisomer A ₍ I

0.5 g methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidin-3- acetate, diastereoisomer A ([α] D ²⁰ = -48 ° ± 3, in methanol) in 10 cm ^{3 of} dioxane, to which 0.77 cm ^{3 of} 5 N aqueous potassium hydroxide solution was added, was stirred for 18 hours at a temperature of about 60 ° C. After evaporation under reduced pressure (5 kPa) at a temperature of about 50 ° C, 0.6 g of solid is obtained, which is purified by chromatography under a nitrogen pressure of 100 kPa on a silica gel column (particle size 20-45 μιη, diameter

346 cm, silica gel height 30 cm), eluting with a mixture of chloroform, methanol and aqueous ammonia (24/6/1 by volume) and collecting 20 cm ^{3 of the} fraction. The fractions containing the product were combined and evaporated under reduced pressure (5 kPa) at a temperature of about 40 ° C. There was obtained 0.27 g of (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-yltip) ethyl] acid. piperidine-3-acetic acid, diastereoisomer A, as a white foam ([.alpha.] _D @ ²⁰ = -66 DEG. + -. 1.2, in methanol).

³ H-NMR spectrum (300 MHz, d 6 - (CD ₃ ) ₂ SO, δ in ppm): 1.20-1.55 (mt, 5H), 1.85-2.20 and 2.35-2, 60 (2 mts, 9H total), 2.68 (mt, 2H),

2.89 (broad t, J = 7 Hz, 2H), 3.94 (s, 3H), 6.38 (mt, JH-48 Hz, 1H), 7.05 (dd, J = 5.5) and 3.5 Hz, 1Ή), 7.17 (dd, J = 3.5 and 1 Hz, IH), 7.32 (d, J = 2.5 Hz, IH), 7.45 (dd, J = 9 and 2.5 Hz, IH), 7.51 (d, J = 4.5 Hz, IH), 7.60 (dd, J = 5.5 and 1 Hz, IH), 7.99 (broad) d, J = 9 Hz, 1H), 8.78 (d, J = 4.5 Hz, 1H).

Methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetate, diastereoisomer A, and methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2-

- (Thien-2-ylthio) ethyl] piperidine-3-acetate, diastereoisomer B

3.2 g of methyl (3R, 4R) -4- [3- (7R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2) -ylthio) ethyl] piperidine-3-acetate is chromatographed on a 30 cm long column 8 cm in diameter filled with 1200 g of Chiracel OD silica gel. Elution is carried out using a mixture of heptane and isopropanol (90/10 by volume). The flow rate is 140 cm ³ per minute. Detection is by ultraviolet radiation at 265 nm. After several preparative injections, fractions corresponding to diastereoisomers A and B are collected. Fractions containing diastereoisomer A are concentrated under reduced pressure (5 kPa) at a temperature of about 40 ° C. 1.6 g of methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] was obtained. ] piperidine-3-acetate, diastereoisomer A, in the form of a viscous oil ([α] _D ²⁰ = -48 ° ± 3, in methanol at 0.1%). The fractions containing diastereoisomer B are concentrated under the same conditions as above. 1.7 g of methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine are obtained. -3-acetate, diastereomer B, in the form of a viscous oil ([.alpha.] _D @ ²⁰ = +82 DEG. + -. 3, in methanol at 0.1%).

Diastereoisomer A: Infrared (KBr): 2936, 2861,

2805, 2768, 1731, 1623, 1594, 1508, 1475, 1435, 1359, 1229,

1217, 1167, 1108, 1084, 1030, 855, 847 and 830 cm ^{@ -1} .

Diastereoisomer B: Infrared (KBr): 2932, 2861,

2805, 2768, 1731, 1623, 1594, 1509, 1475, 1435, 1359, 1229,

1217, 1168, 1108, 1083, 1030, 855, 847, and 830 cm ^-1 .

Methyl (3R, 4R) -4- [3- (R, S) -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine -3-Acetate was prepared as described in Example 60.

Example 62

(3R, 4R) -4- [3-Fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetic acid, diastereoisomer B

The preparation is carried out as described in Example 60, but starting from 0.5 g of methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- Of [2- (thien-2-ylthio) -ethyl] piperidine-3-acetate, diastereoisomer B ([.alpha.] D @ ²⁰ = +82 DEG) gives 0.29 g of (3R, 4R) -4- [3] acid. -fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] piperidine-3-acetic acid, diastereoisomer B, in the form of a white foam ([ct] _D ²⁰ = +66, 3 ± 1.1 °).

¹ H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1.20-1.60 (mt, 5H), 1.90-2.15 and 2.30-2 60 (2 mts, 9H overall), 2.68 (mt, 2H),

2.89 (broad t, J = 7 Hz, 2H), 3.95 (s, 3H), 6.38 (mt,

J _hf = 48 Hz, 1H), 7.05 (dd, J = 5.5 and 3.5 Hz, 1H), 7.18 (dd,

J = 3.5 and 1 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 9 and

2.5 Hz, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 5.5 and 1 Hz,

1H), 7.99 (broad d, J = 9 Hz, 1H), 8.78 (d, J = 4.5 Hz, 1H).

348

Methyl (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- (2- (thien-2-ylthio) ethyl) piperidine-3-acetate, diastereoisomer B, was prepared as described in Example 61.

Example 63

(3R, 4R) -4- [3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3,5-trifluorophenyl) prop-2-ynyl) piperidine- 3-carboxylic acid, diastereoisomer A, and (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3,5-trifluorophenyl) acid) prop-2-ynyl] piperidine-3-carboxylic acid diastereoisomer B

1.50 g of (3R, 4R) -4- [3- (R, S) -hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- (3- (2,3, 5-) Trifluorophenyl) prop-2-ynyl] piperidine-3-carboxylic acid dissolved in 200 cm ^{3 of} dichloromethane is chromatographed on a 30 cm column packed with 700 g of Kromasil® silica gel (10 µm particle size) eluting using a mixture of dichloromethane, acetonitrile and methanol (90 The flow rate is 130 cm ³ per minute and detection is performed by ultraviolet radiation at 265 nm, which after 4 preparative injections yields two diastereoisomers. The fractions corresponding to the first one are concentrated to dryness under reduced pressure (5). 5 kPa) at a temperature of about 40 ° C and the residue obtained is dried in an oven under reduced pressure (13 Pa) at a temperature of about 40 ° C. 1.9 g of (3R, 4R) -4- (3-hydroxy-) are obtained. 3- (6-Methoxyquinol-4-yl) -propyl] -1- (3- (2,3,5-trifluorophenyl) prop-2-ynyl) piperidine-3-carboxylic acid diastereoisomer A as a foam ([a] d ²⁰ = -50.9 ° ± 1.4 , in methanol at 0.5%).

1 H-NMR spectrum (300 MHz, d ₆ - (CD ₃ ) ₂ SO, δ in ppm): 1,40- -2.00 (Mt. 7H), 2.35-3.00 (Mt. 5H), 3.66 (s, 2H), 3.92 (s, 3H) overall), 5.24 (mt, 1H), 5.54 (unresolved peak, 1H), 7.25-7.45 (Mt. 3H), 7, 50-7.70 (mt, 2H) 7.94 (d, J = 9.5 Hz, 1H), 8.71 (D,

J = 4.5 Hz, 1H).

Fractions corresponding to the second diastereoisomer are processed

349 as mentioned above. 2.17 g of (3R, 4R) -4- [3-hydroxy-3- (β-methoxyquinol-4-yl) propyl] -1- [3- (2,3,5-trifluorophenyl) prop- 2-ynyl] piperidine-3-carboxylic acid diastereoisomer B vo

foam ([a] _D ²⁰ = +67.8 ° ± 1,2, in methanol at 0,5%) • 1 H-NMR spectrum (300 MHz D6 _(CD3) 2 SO, δ in ppm): 1,40- 2.00 (Mt. 7H), 2.35-3.00 (Mt. 5H), 3.65 (s, 2H); 3.90 ( s, 3H overall), 5.24 (mt, 1 H), 5, 54 (unresolved peak, 1H), 7.25-7.45 (Mt. 3H), 7.50-7.70 (mt, 2H) , 7, 94 (d, J = 9.5Hz) 1H), 8.71 (D,

J = 4.5Hz, 1H).

(3R, 4R) -4- [3- (R, S) -Hydroxy-3- (6-methoxy-quinol-4-yl) -propyl] -1- (3- (2,3,5-trifluorophenyl) -prop) The 2-ynyl] piperidine-3-carboxylic acid may be prepared as described in Example 59.

The present invention also relates to pharmaceutical compositions comprising at least one quinolylpropylpiperidine derivative of the invention, if desired in salt form, in pure form or in combination with one or more compatible pharmaceutically acceptable diluents or adjuvants.

The composition of the present invention may be used orally, parenterally, topically, rectally or in the form of aerosols.

As solid compositions for oral administration, tablets, pills, hard gelatin capsules, powders or granules may be used. In these compositions, the active ingredients of the present invention are mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch. These compositions may also contain other diluents, for example lubricants, such as magnesium stearate, or controlled release coatings.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups or elixirs containing inert diluents such as water or

350 liquid paraffin. These compositions may contain substances other than diluents, for example humectants, sweeteners or flavors.

Compositions for parenteral administration may be emulsions or sterile solutions. Water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters, for example ethyl oleate, may be used as a solvent or vehicle. These compositions may also contain adjuvants, in particular humectants, isotonizing agents, emulsifiers, dispersing and stabilizing agents.

Sterilization can be carried out in several ways, for example by using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved just before use in sterile water or any injectable sterile medium.

Compositions for topical administration may be, for example, creams, ointments, lotions or aerosols.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, ingredients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions may also be in the form of an aerosol. For use in the form of a liquid aerosol, the compositions may be in the form of stable sterile solutions or in the form of solid solutions dissolved just prior to use in pyrogen-free sterile water, in ^{1 L of} saline, or in any pharmaceutically acceptable vehicle. When used in the form of dry aerosols to be inhaled directly, the active compound is formulated into fine particles of 30 to 80 μπι which are combined with a water-soluble diluent or vehicle such as dextran, mannitol or lactose.

The novel quinolylpropylpiperidine derivatives of the present invention are used in medicine in particular for the treatment of infections

351 of bacterial origin. The doses depend on the desired effect and the duration of treatment. The physician will determine the most appropriate dosages based on age, weight, condition of infection and other factors specific to the subject being treated. Dosages in adult patients are usually between 750 mg and 3 g of the active compound when administered orally, the dose being taken 2-3 times a day, or between 400 mg and 1.2 g when administered intravenously.

The following examples illustrate the compositions of the invention.

Example 1

A liquid composition for parenteral use is prepared using a conventional procedure and the composition comprises:

(3R, 4R) -4- [3- (R, S) -3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] acid piperidine-3-carboxylic acid 125 mg

glucose Sodium hydroxide q. q. with. with. to to 2.5% pH 4-4.5 Water for injections . . . to 20 ml

Example 2

A liquid composition for parenteral use is prepared using a conventional procedure and the composition comprises:

(3R, 4R) -4- [3- (R, S) -3-Hydroxy-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (thien-2-ylthio) ethyl] acid -piperidin

-3-acetic ... 125 mg Glucose ... ... d. with. up to 2,5% Sodium hydroxide q. with. to pH 4-4.5 Water for injections ... . . . to 20 ml

352

Claims (11)

A quinolylpropylpiperidine derivative of the formula I R ⁴ —0 N-R ³ (I) wherein R ¹ R ¹ ' R R ¹ R ¹ 'is either R ² R ³ where R ¹ R ¹ ' R R ¹ R ¹ 'is either R ² R ³ is a hydrogen atom or a halogen atom or a hydroxyl group; a hydrogen atom or may represent a halogen atom, when R ¹ is also a halogen atom, and is a hydrogen atom or and R 0 together form a bond, and is a hydrogen atom, and represents a carboxyl group, a carboxymethyl group, or 2-carboxyethyl; represents an alkyl group (1 to 6 carbon atoms) substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, oxo, carboxyl, alkoxycarbonyl, alkyloxy or alkylthio or phenyl, phenylthio or phenylalkylthio; may carry 1 to 4 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkyloxy, 353 trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido (C 1 -C 4) or amino] or cycloalkyl or cycloalkylthio group, wherein the cyclic moiety contains 3 to 7 members, or a 5- to 6-membered aromatic heterocyclyl or a heterocyclylthio group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted with [halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, amino or cyano] or R ³ represents a propargyl group substituted by a phenyl group which may itself carry 1 to 3 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethyl toxo, carboxyl, alkoxycarbonyl, cyano or amino] or substituted with 3 to 7 membered cycloalkyl or substituted with 5 to 6 membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone [ halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano or amino] or R ³ is cinamyl or 4-phenylbuten-3-yl, and R ⁴ represents an alkenyl-CH ₂ - or alkynyl-CH ₂ - group wherein the alkenyl or alkynyl moiety contains 2 to 6 carbon atoms, or R is a carboxyl, carboxymethyl or carboxyethyl group, and 354 R ³ represents an alkyl group (containing 1 to 6 carbon atoms) substituted with 1 to 3 substituents selected from the group consisting of halogen, oxo, carboxyl, alkoxycarbonyl or alkylthio or phenylthio or phenylalkylthio which may carry 1 to 4 substituents [selected a halogen atom, a hydroxyl group, an alkyl group, an alkyloxy group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, an alkyloxycarbonyl group, a cyano group, a C 1 -C 4 acetamido group or an amino group or a cycloalkylthio group; or a 5- to 6-membered aromatic heterocyclylthio group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur, and optionally alone substituted by a halogen atom, a hydroxyl group, an alkyl group, an alkyloxy group, a trifluoromethyl group, a trifluoromethoxy group or oxo, carboxyl, alkoxycarbonyl, cyano, or amino], or R ³ represents a phenyl-substituted propargyl group which may itself carry 1 to 4 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy , trifluoromethyl, trifluoromethoxy, carboxyl, alkoxycarbonyl, cyano or amino] or substituted with 3 to 7 membered cycloalkyl or substituted with 5 to 6 membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano, or amino], and R ⁴ represents an alkyl group (containing 1 to 6 carbon atoms), or 355 R ² is hydroxymethyl, alkyloxycarbonyl, alkyloxykarbonylmetylovú or 2- (alkyloxycarbonyl) ethyl, (wherein the alkyl group contains 1 to 6 carbon atoms), and R ³ represents an alkyl group (containing 1 to 6 carbon atoms) substituted by a phenylthio group which itself carries 1 to 4 substituents [selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkoxycarbonyl cyano or amino], a cycloalkylthio group wherein the cyclic moiety contains 3 to 7 members, or a 5- to β-membered aromatic heterocyclyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone with [halogen, hydroxyl , alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkoxycarbonyl, cyano, or amino] or R ³ represents a phenyl-substituted propargyl group which may itself have 1 to 4 substituents [select is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkoxycarbonyl, cyano or amino] or substituted with 3 to 7 membered cycloalkyl, or substituted with 5 to 6 membered members an aromatic heterocyclyl group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted alone by [halogen atom, hydroxyl group, alkyl group, alkyloxy group, trifluoromethyl group, trifluoromethoxy group, oxo group, carboxyl group, alkoxycarbonyl group, amino group or cyano group] and R ⁴ represents an alkyl group (containing 1 to 6 carbon atoms), 356 is an alkenyl-CH ₂ - or alkynyl-CH ₂ - group wherein the alkenyl or alkynyl moiety contains 2 to 6 carbon atoms, it being understood that the alkyl groups and moieties are straight or branched and contain, if any, not otherwise specified, 1 to 4 carbon atoms, i in its diastereoisomeric forms or in mixtures thereof and also as salts. A quinolylpropylpiperidine derivative according to claim 1 wherein R ¹ is an atom pina, hydrogen or halogen or hydroxyl R ¹ ' is an atom hydrogen, and R is an atom or R ¹ and R c together form a bond, and R ¹ ' is an atom H, R ² means a carboxyl or carboxymethyl group, and R ³ means halosubstituted (C 1 -C 6) alkyl 1 to 3 substituents selected from the group consisting of a halogen atom, an oxo group or an alkylthio group or a phenylthio group which may carry 1 to 4 halogen atoms, or a cycloalkylthio group wherein the cyclic moiety contains 3 to 7 members, or a 5- to 6-membered aromatic heterocyclythio group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur, and optionally substituted with a halogen atom, or R ³ represents a phenyl-substituted propargyl group which may itself carry 1 to 3 halogen atoms or a 5- to propargyl group A 6-membered aromatic heterocyclyl group containing 357 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; or R ² represents a hydroxymethyl, alkyloxycarbonyl or alkyloxykarbonylmetylovú group (wherein the alkyl portion contains 1 to 6 carbon atoms), and R ³ represents an alkyl group (containing 1 to 6 carbon atoms) substituted with a 5- to β-membered aromatic heterocyclylthio group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or R ³ represents a propargyl group substituted with a 5- to β-membered aromatic heterocyclyl a group containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; and R ⁴ represents an alkyl group (having 1 to 6 carbon atoms), wherein the alkyl groups and moieties are straight or branched chain, as well as diastereomeric forms or mixtures thereof, as well as salts thereof. The quinolylpropylpiperidine derivative according to any one of claims 1 and 2, which is (3R, 4R) -4- [3-hydroxy-3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (shadow- 2-ylthio) ethyl] piperidine-3-acetic acid in their diastereomeric forms or mixtures thereof and salts thereof. A quinolylpropylpiperidine derivative according to any one of claims 1 and 2 which is (3R, 4R) -4- [3- (6-methoxyquinolin-4-yl) propyl] -1- [2- (thien-2-ylthio) acid]. ethyl] piperidine-3-acetic acid and salts thereof. The quinolylpropylpiperidine derivative according to any one of claims 1 and 2 which is (3R, 4R) -4- [3-fluoro-3- (6-methoxyquinol-4-yl) propyl] -1- [2- (shadow- 2-ylthio) ethyl] piperidine-3-acetic acid in their diastereomeric forms or mixtures thereof and salts thereof. 358 The quinolylpropylpiperidine derivative according to any one of claims 1 and 2 which is (3P, 4P) -1- [2- (3-fluorophenylthio) ethyl] -4- [3-hydroxy-3- (6-methoxyquinol-4-yl) -acid). yl) propyl] piperidine-3-acetic acid in their diastereomeric forms or mixtures thereof and salts thereof. The quinolylpropylpiperidine derivative according to any one of claims 1 and 2, which is (3β, 4F) -4- [3-hydroxy-3- (o-methoxyquinolin-4-yl) propyl] -1- [3- (2, 2, 3, 4H)]. 3,5-Trifluorophenyl) prop-2-ynyl] -piperidine-3-carboxylic acid in its diastereomeric forms or mixtures thereof, and salts thereof. A process for the preparation of a quinolyl-propyl-piperidine derivative according to claim 1, characterized in that the R ³ chain defined in claim 1 is condensed with a quinolyl-propyl- ^piperidine derivative of the formula II wherein R ⁴ is as defined in claim 1, R ¹ and R ¹ are hydrogen atoms or together form an oxo group and R ² represents a protected carboxyl, carboxymethyl or 2-carboxyethyl radical or an alkyloxycarbonyl group, an alkyloxycarbonyl group or a alkyloxykarbonylmetylovú-2-ethyl, to obtain a quinolylpropylpiperidine derivative of general formula III 359 wherein R ¹ , R ¹ , R ² and R ⁴ are as defined above, and R ³ is as defined in claim 1, and then, if appropriate, removal of the acid protecting group and then, if appropriate, td is appropriate followed by reduction of the oxo group represented by R ^{@ 1} or R ^{@ 1} to an alcohol wherein R ^{@ 1} is hydroxyl and, if appropriate, optionally halogenated to give a quinolylpropyl piperidine derivative wherein R ^{@ 1} is a halogen atom and optionally dehydrohalogenated the corresponding halogenated derivative a quinolylpropylpiperidine derivative wherein R ¹ and R 0 together form a bond, or even by dihalogenation of a product of formula III wherein R ¹ and R ¹ together form an oxo group to give a quinolylpropylpiperidine derivative wherein R ¹ and R ¹ are halogen atoms, and / or, where appropriate, acid protected in the form of R ² at position 3 of the piperidine is reduced to a hydroxymethyl radical, or optionally followed by conversion of the carboxymethyl or 2-carboxyethyl radical according to the usual methods, '· optionally followed by deprotection of the acid, and optionally the diastereoisomers are separated and the product obtained is optionally converted into salt. The process according to claim 2, characterized in that the condensation of the R ³ chain with the piperidine group is carried out by the action of a derivative of the general formula IV 360 wherein R ³ is as previously defined and X represents a halogen atom, a methylsulfonyl group, a trifluoromethylsulfonyl group or a p-toluenesulfonyl group. A process according to any one of claims 2 and 3, characterized in that R ³ represents a propargyl group substituted by a phenyl group, a cycloalkyl group or a heterocyclyl group, wherein the reaction is preferably carried out by condensation of the propargyl halide and then chain substitution by phenyl, cycloalkyl or heterocyclyl. A pharmaceutical composition comprising at least one derivative according to claim 1 in pure form or in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.