MXPA01006569A - Piperidines as ccr5 modulators - Google Patents

Abstract

Compounds of formula 1:[Region&agr;]- [Region&bgr;]- [Region&ggr;]- [Region&dgr;]which are useful as modulators of chemokine activity. The invention also provides pharmaceutical formulations and methods of treatment using these compounds.

Description

PIPERIDINS AS MODIFIERS OF CCR5 This invention relates to new chemical compounds. These compounds find a particular use, although not exclusive, as pharmaceutical compounds, especially as modulators of CCR5. This invention also relates to formulations or dosage forms including these compounds, to the use of these compounds in the manufacture of pharmaceutical formulations or dosage forms and to methods of treatment, especially the treatment of anti-inflammatory diseases and conditions and the treatment and prevention of infections caused by HIV-1 and by genetically related retroviruses. The compounds of the present invention can be modulators, especially antagonists, of the activity of the CCR5 receptors of chemokines, particularly those that exist on the surfaces of certain cells within the human body. Modulators of the CCR5 receptor can be useful in the treatment and prevention of various inflammatory diseases and conditions, and in the treatment and prevention of HIV-1 infection and genetically related retroviruses. The name "chemokine" is a contraction of "chemoattractant cytokines". Chemokines are a large family of proteins that have important structural features in common and that have the ability to attract leukocytes. As chemoattractants of leukocytes, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process that is essential both for inflammation and for the body's response to an infection. Since chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents that are active in modulation, preferably antagonizing the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases. . The CCR5 chemokine receptor is of particular importance in the context of the treatment of inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for macrophage inflammatory proteins (MIPs) called MIP-1a and MIP-1β, and for a protein that is regulated after activation and that is expressed and secreted in normal T cells ( RANTES). The relationship between modulators, especially between antagonists of CCR5 activity, and the therapeutic utility in the treatment of inflammation and HIV infection, and the way in which such a relationship can be demonstrated are explained in more detail below. Substantial research of different classes of modulators of chemokine receptor activity, especially that of the CCR5 chemokine receptor, is underway in the art. A representative description is Mills et al., WO 98/25617, which references substituted arylpiperazines as modulators of chemokine receptor activity. However, the compositions described in said document are not the same nor suggest those of the present invention. Other descriptions are WO 98/025605; WO 98/025604; WO 98/002151; WO 98/004554; and WO 97/024325. The present invention relates to compounds which can be conveniently considered to have four independent variable regions, which are read from the left side to the right side of said compounds: Region a, Region β, Region? and Region d, of Formula (I): [Region a] - [Region ß] - [Region?] - [Region d] (I) and pharmaceutically acceptable salts and prodrug derivatives thereof. The compounds of the present invention can be selective antagonists of CCR5 receptors and are non-peptidic in nature. The compounds illustrated by the formula (I) may contain one or more stereogenic centers and the present invention includes the mentioned compounds both in their separate forms and in their non-separated forms. Separate forms can be obtained by conventional means, for example, by asymmetric synthesis, by the use of high performance liquid chromatography using a chiral stationary phase, or by chemical resolution by the formation of suitable salts or derivatives. It will be understood that the separate optically active forms of the compositions of the present invention, as well as the racemic mixtures thereof, will usually vary with respect to their biological properties because of the chirality-dependent conformation of the active site of an enzyme, receptor. , etc.

The description that follows provides details of the particular remains that comprise each of said Regions. To present details in order and in a way that saves space, each main group of each Region is indicated with a single dash ("-") and each successive subdivision within each of said groups is indicated with two, three , etc. scripts, as required. In this specification and claims, a reference to a range or class of groups, for example, alkyl (CrC3), should be understood as an explicit description and reference of each member of this range or class, including the isomers. According to the present invention, a compound of formula (I) is provided: [Region a] - [Region ß] - [Region?] - [Region d] (I) in which [Region a] is selected from among group consisting of: A. Substituent components arylheterocyclyls comprising: 1. Remains hetero-phenylmethylene partial formula (1.0.0): (1.0.0) where: the symbol "*" indicates the point of attachment of the rest of the partial formula (1.0.0) to the Region ß, as defined below; R5 is a member selected from the group consisting of a direct link; -OR-; -C (= O) -; -NR4- and -S (= O) p-; wherein: R4 is hydrogen or alkyl (C2); R6 is a member selected from the group consisting of hydrogen; alkyl (C C2); alkoxy (CrC2); -CN; -OH; and -C (= O) NH2; j is an integer selected from 0, 1 and 2; m is an integer selected from 0, 1 and 2; each of R7 and R8 is a member selected from the group consisting of -F; -Cl; -CO2R4; -OH; -CN; -CONR4aR b; -NR4aR4b-; -NR4aC (= O) R4b; -NR4aC (= O) OR4; -NR4S (= O) pR4b; -S (= O) pNR4aR4b; alkyl (C C) and (C 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (CrC2); alkylcarbonyl (C -? - C2); and alkylcarbonyloxy (C? -C2); wherein: p is an integer selected from 0, 1 and 2; each of R4a and R4b is independently selected from hydrogen and alkyl (CrC2). the rest represented by the partial formula (1.0.1): (1.0.1) in the formula (1.0.0) represents a monocyclic heterocyclic group, or a benzo-fused bicyclic ring system containing said heterocyclic group, wherein said heterocyclic group contains a total of 5 or 6 members of the heterocyclic group. which one or two of said members is nitrogen, the presence of the second optional nitrogen atom being represented by: "[N]"; wherein said heterocyclic group or ring system is selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperazinyl; indolyl; indazolinyl; benzoimidazolyl; quinolinyl; iso-quinolinyl; and quinazolinyl; wherein: R12a is a member selected from the group consisting of hydrogen; F; Cl; -CO2R4; oxo; -OH; CN; NH2; NH-alkyl (C C2); N-dialkyl (C -? - C2) 2; -CF3; alkyl (CrC); alkenyl (C2-C4); alkoxy (C -? - C); cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with from 0 to 2 substituents R9 in which: R9 is a member independently selected from the group consisting of F; Cl; -CO2R4; -OH; cyano; -CONR4aR4; -NR4aR4b-; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR4aS (= O) pR4b; -S (= O) pNR4aR4; (d-C4) alkyl including dimethyl, and (C 1 -C 4) alkoxy, wherein said alkyl and alkoxy are independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C -? - C2); alkylcarbonyl (Cr C2); and alkylcarbonyloxy (C-1-C2); and R12b is absent or is a member selected from the group consisting of hydrogen; (C 1 -C 4) alkyl; alkenyl (C2-C4); (C 1 -C 2) alkoxy; cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R9, wherein R9 has the same meanings as above, with the exception that it is independently selected from them: and 2. hetero moieties -phenylmethylene of partial formula (1.1.0): where: the symbol "*"; R5; R6; R7; R8; j and m are as defined in detail above, with the exception that all the aforementioned substituents are independently selected from their previous selection; the rest represented by the partial formula (1.1.1): in the partial formula (1.1.0) it represents: a. a monocyclic heterocyclic group containing a total of 5 or 6 members of which one of said members is nitrogen and Q is selected from O and S, wherein S may optionally be in the sulfonate form, -S (= O) 2; wherein said heterocyclic group is selected from the group consisting of oxazolyl; oxazolidinyl; isoxazolyl; thiazolyl; thiazolidinyl; iso-thiazolyl; morpholinyl; and thiomorpholinyl; or b. a monocyclic heterocyclic group containing a total of 5 or 6 members of which two of said members are nitrogen and a third or fourth of said members is independently selected from N, O and S, wherein said S may optionally be in the sulfonate form, -S (= O) 2; wherein said heterocyclic group is selected from the group consisting of triazolyl, triazinyl; tetrazolyl; Oxadiazolyl; thiadiazolyl; and R13a is selected from the group consisting of hydrogen; F, Cl; -CO2R4; oxo; -OH; -CN; NH2; NH-alkyl (C C2); N-dialkyl (C C2) 2; -CF3; (C 1 -C 4) alkyl; alkenyl (C2-C4); alkoxy (C? -C2); cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein: R11 is a member selected from the group consisting of F; Cl; -CO2R4; -OH; -CN; -CONR4aR4b; -NR4aR4b; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR4aS (= O) pR4b; -S (= O) pNR4aR4b; (C 4 C) alkyl including dimethyl, and (G 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C1-C2); alkylcarbonyl (Cr C2); and (C1-C2) alkylcarbonyloxy; And R 3b is a member selected from the group consisting of hydrogen; alkyl (C C4); alkenyl (C2-C4); alkoxy (C? -C2); cycloalkyl (C3-C7); C (= O) alkyl (CrC4); S (= O) 2 (C 1 -C 4) alkyl and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein R11 has the same meaning as above, with the exception that it is independently selected; B. an amido-aryl or -heterocyclyl moiety (substituted) selected from the group consisting of 1. amido-aryl alkyl-, alkenyl- and alkynyl-substituted moieties of partial formula (2.0.0): where: the symbol "*"; R4; R6 are as defined above, with the exception that all the substituents mentioned above are selected independently from their previous selection; A is a member selected from the group consisting of: 1. The rest of the partial formula (2.0.3) (2.0.3) wherein: the symbols R7; R8 and m are as defined above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and the symbol "*" indicates the point of union of residue A to the remaining portions of partial formula (2.0.0); 2. the rest of the partial formula (2.0.4) which represents a monocyclic heterocyclic group, selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; or pyrimidinyl; wherein: the symbols R12a and R12b are as defined above, with the exception that all the substituents mentioned above are selected independently of their previous selection; and the symbol "*" indicates the point of union of residue A to the other remaining portions of partial formula (2.0.0); , - 3. the rest of the partial formula (2.0.5) which represents a. a monocyclic heteroaromatic group containing a total of 5 members, of which one of said members is nitrogen and Q is selected from O and S, wherein said S may optionally be in the sulfonate form, -S (= O) 2; selected from the group consisting of oxazolyl; isoxazolyl; thiazolyl; and iso-thiazolyl; or b. a monocyclic heterocyclic group containing a total of 5 or 6 members, of which two of said members are nitrogen and a third or fourth of said members is independently selected from N, O and S, wherein said S may be optionally the sulfonate form, -S (= O) 2; selected from the group consisting of triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl; and wherein: R13a, R13b and j are as defined above, with the exception that all mentioned substituents are independently selected from their previous selection; and the symbol "*" indicates the point of attachment of residue A to the other remaining portions of partial formula (2.0.2); R5a is a member selected from the group consisting of a direct link; -C (= O) -; and -S (= O) 2-; W1 is (1.) a direct link; (2.) in the case where R5a is -C (= O) - or -S (= O) 2, W1 is a direct bond or - (C1-C3) alkylene-, in which any carbon atom simple theris substituted with 0 to 2 substituents R23, wherein R23 is a member selected from the group consisting of -F; -Cl; -CO2R4; -OH; -CN; alkoxy (C C4); cycloalkyl (C3-C); and phenyl; wherein said alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein said R11 is as defined above, with the exception that all the substituents mentioned above are selected independently from their previous selection; or (3.) is a member selected independently from the group consisting of the remnants of partial formulas (2.0.6) to (2.0.16), including: (2.0.6) (2.0.7) (2.0.8) (2.0.9) (2.0.10) (2.0.11) (2.0.12) (2.0.13) (2.0.14) (2.0.15) (2.0.16) in which: the symbol "?" indicates the point of attachment of residue W1 to the nitrogen atom in the partial formula (2.0.0), and the symbol "*" indicates the point of attachment of residue W1 to the other remaining portions of partial formula (2.0.0); and R4 is as defined in detail above, but selected in an independent manner; R24 is selected from the group consisting of hydrogen and (C1-C4) alkyl, and R25 and R2d are each selected from the group consisting of -OH; (C -? - C2) alkyl substituted with 0 to 3 substituents selected from F; and OH; and alkoxy (C C2); and R27 is selected from the group consisting of alkyl (CrC6); alkenyl (C2-Cß); and (C2-C6) alkynyl; wherein said alkyl, alkenyl and alkynyl group comprising R27 are substituted with 0 to 3 substituents R28, wherein: R28 is selected from the group consisting of phenyl; F or Cl; oxo; hydroxy; alkyl (C C2); alkoxy (C C3); C (= O) OR29; -C (= O) (C 1 -C 4) alkyl; -S (= O) 2alkyl (d-C4); C (= O) NR29R30; -NR29R30; -NR29C (= O) R30; -NR29C (= O) OR30; NR29S (= O) pR30; and -S (= O) 2NR29R30, wherein: each of R29 and R30 is a member independently selected from the group consisting of hydrogen and (C-1-C4) alkyl substituted with 0 to 3 substituents selected from the group consisting by F and CI; 2. cycloalkyl-substituted amido-aryl radicals of partial formula (2.1.0): in which: a; W1; the symbol "*"; R4 R5a and R6 have the same meaning as indicated above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and R32 is a member selected from the group consisting of - (CH2) n-cycloalkyl (C3-C7), wherein n is an integer selected from 0, 1 and 2; in case n is 0, then the carbon atom a of said cycloalkyl (C3-C) is substituted with 0 or 1 alkyl groups (C? -C) or phenyl, wherein said alkyl or phenyl is substituted with 0, 1 or 2 groups CH3, OCH3, OH or NH2; and in case n is 1 or 2, the resulting methylene or ethylene is substituted with 0 or 1 f groups; NH2; N (CH3) 2; OH; OCH3; (C 1 -C 4) alkyl; or phenyl; wherein said alkyl and phenyl are substituted with 0, 1 or 2 CH3, OCH3, OH and NH2 groups; and wherein said cycloalkyl (C3-C7) is further substituted with 0 to 3 substituents R28, wherein R28 is as defined above, but independently selected. 3. aryl and heterocyclyl-substituted amido-aryl residues of partial formula (2.2.0): wherein: A; W1; the symbol "*"; R4; R5a; and R6 have the same meanings indicated above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and R35 is selected from the group consisting of phenyl; Furyl tetrahydrofuranyl; tetrahydropyranyl; oxetanyl; thienyl; pyrrolyl; pyrrolidinyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; imidazolyl; pyrocollo; Oxadiazolyl; thiadiazolyl; triazolyl; pyridyl; pyrazinyl; pyridazinyl; piperazinyl; pyrimidinyl; pyranyl; azetidinyl; morpholinyl; parathiazinyl; Nolyl; indolinyl; benzo [bjfuranyl; 2,3-dihydrobenzofuranyl; benzothienyl; 1 H-indazolyl; benzoimidazolyl; benzoxazolyl; benzoisoxazolyl; benzothiazolyl; quinolinyl; Soquinolinyl; phthalazinyl; quinazolinyl; and quinoxalinyl; wherein (1.) said R35 group can be substituted on any one or more carbon atoms with 0 to 3 substituents R28, wherein R28 is as defined above, with the exception that it is independently selected; (2.) said R35 group is substituted with respect to any one or more nitrogen atoms that are not a point of attachment of said aryl or heterocyclic moiety, with 0 to 3 substituents R13b, wherein R13b is as defined above , with the exception that it is selected independently; and (3.) said R35 group with respect to any sulfur atom thereof which is not a point of attachment of said heterocyclic moiety, is substituted with 0 to 2 oxygen atoms; [Region ß] is an alkyl linking element of partial formula (3.0.0): where: "*" is a symbol that represents the point of union of the rest of partial formula (3.0.0) to Region a; "?" is a symbol that represents the point of union of the rest of partial formula (3.0.0) to the Region?; R 540 and R. 41 are independently selected from the group consisting of hydrogen; alkyl (C? -C2), including dimethyl; hydroxy; and alkoxy (CrC3); [Region?] is an aza-monocyclic residue of partial formula (4.0.0): wherein: "*" is a symbol representing the point of attachment of the remainder of partial formula (4.0.0) to the Region β of the compound of formula (I); "?" is a symbol representing a covalent bond joining any carbon atom of said aza-monocyclic moiety of partial formula (4.0.0) to Region d; the rest of the partial formula (4.0.1): in the partial formula (4.0.0) represents a monocyclic heterocyclic group containing a total of 4 to 7 members, of which one of said members is nitrogen, wherein said heterocyclic group is a member independently selected from the group consisting essentially of by azetidinyl; pyrrolidinyl; piperidinyl; and azepinílo; R45 is absent or is a member independently selected from the group consisting essentially of alkyl (dC4) including dimethyl; cycloalkyl (C3-C6); alkoxy (CrC4); alkoxy (dC2) alkyl (C1-C2); CF3; -C02R4 in which R4 is as defined in detail above; oxo; -OH; cyano; -C (= O) NR4aR4b; -NR4aR4b; - NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR4aS (= O) pR4b; -S (= O) pNR4aR4b; alkoxycarbonyl (d-C2); alkylcarbonyl (C? -C2); alkylcarbonyloxy (C C2); and alkoxy (d-C) alkyl (C C2); understanding that in the rest of the partial formula (4.0.0) R45 is a substituent attached to a single carbon atom thereof; in which: Each of R 4a and R b is independently selected from hydrogen and (C 1 -C 2) alkyl; R46 is absent or is a member independently selected from the group consisting essentially of hydrogen; and (C? -C4) alkyl substituted with 0 or 1 substituents independently selected from (C1-C2) alkoxy and -CO2R4, wherein R4 is as defined in detail above; I or; it being understood that in the case that it is chosen that the substituent R46 is not absent, it results that said nitrogen atom and said partial formula residue (4.0.0) are in quaternary form; [Region d] is a heterocyclyl radical (substituted) selected from the group consisting of: 1. a heterocyclyl residue of partial formula (5.3.0): where: the symbol: "*" indicates the point of union of the partial formula (5.3.0) to the Region?; Q is N, O or S and the partial formula (5.3.0) represents: a. a monocyclic heterocyclic group containing a total of 5 members, of which one of said members is nitrogen and a second member is selected from O and S, wherein said S may optionally be in the sulfonate form, wherein said group heterocyclic is selected from the group consisting of oxazolyl; isoxazolyl; thiazolyl; and isothiazolyl; or b. a monocyclic heterocyclic group containing a total of 5 members, of which two of said members are nitrogen and a third or fourth of said members is independently selected from N; O and S, wherein said S may optionally be in the sulfonate form, S (= O) 2; wherein said heterocyclic group is independently selected from the group consisting of triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl; and each of R90a and R90b is a member independently selected from the group consisting of hydrogen, -alkylcarbonyl (d-C2); -alkyl (C1-C4); - (CH2) n-cycloalkyl (C3-C7); -alkenyl (C2-C3); - (CH2) n- (phenyl); and - (CH2) n- (HET?), wherein n is an integer independently selected from 0, 1 and 2; wherein said (C1-C4) alkyl, alkenyl, cycloalkyl, phenyl and HET-i groups are independently substituted with 0 to 3 substituents R91, wherein: j has the same meanings as indicated above, but is selected from an independent form among them; HETi is a heterocyclyl group selected from the group consisting of thienyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl; Oxadiazolyl; thiadiazolyl; triazolyl; pyridyl; pyrazinyl; pyridazinyl; pyrimidinyl; parathiazinyl; and morpholinyl; in which: R91 is selected from the group consisting of -F; -Cl; -CO2R4; oxo; -OH; -CN; -CONR ^ R ^ -NR ^ R94; C (= 0) alkyl (C C); -NR C ^ OJR94; -NR93C (= O) OR94; -NR93S (= O) R94; -S (= O) NR93R94; alkyl (d-C4) and alkoxy (d-C4) wherein each of said alkyl and alkoxy are independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C1-C2); alkylcarbonyl (d-C2) and alkylcarbonyloxy (C1-C2); wherein: R93 and R94 are each a member independently selected from the group consisting of hydrogen; and alkyl (d-C2); and 2. a heterocyclyl moiety of partial formula (5.4.0): wherein: R90a; R90b; and j have the same meanings indicated above, but are independently selected. See the patent applications of the present applicants, being processed together with the present, Nos. P60162WO and P60191WO. An important aspect of the present invention is the limitation to the Region? The pending case relates to alternative limitations of formula (I) - This invention also provides pharmaceutical formulations and dosage forms including as active ingredient a compound of formula I. The use of a compound of formula I in the manufacture is also provided of a formulation or a dosage form and methods of treatment. The [Region a is at the far left of the modulator of the CCR5 receiver of the present invention, the region called Region a can comprise a residue selected from various different classes of substituent components, all of which, however, are contemplated to be, and preferably they are, isosteros to each other. The first class of substituent components of the Region a (in A.) are heterocyclyl phenylmethylene moieties as additionally described below. A preferred group of heterocyclic phenylmethylene moieties (in A. 1.) comprises the group consisting of heterophenylmethylene radicals of partial formula (1.0.0), (1.1.0) The substituent R5 is a member selected independently from the group consisting of a direct bond; -OR; -C (= 0) -; -NR4-; and -S (= O) p-; wherein R4 is hydrogen or alkyl (d-C2). The substituent R6 is a member selected independently from the group consisting of hydrogen; (C1-C2) alkyl; (C 1 -C 2) alkoxy; -C (= O) NH2; -CN; and -OH. More preferably, R6 is hydrogen and there is no substituent in this position. Isomers are not included in the partial formula (1.0.0), but appear when the substituents R7 and R8 are different. The substituents R7 and R8 are present once or twice or are not present, as indicated by their representation as: "(R7) m" and "(R8) m", wherein m is defined as an integer selected from 0, 1 and 2. In the most preferred embodiments of the present invention, m is 0, although in alternative embodiments m is 1. Substituents R7 and R8 comprise -F; -Cl; -CO2R4; -OH; -CN; -CONR4aR4b; -NR4aR4b-; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; NR4aS (= O) pR4b; -S (= O) pNR4aR4; (C 1 -C 4) alkyl including dimethyl, and (C 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is independently substituted with 0 to 3 substituents independently selected from -F and -Cl; alkoxycarbonyl (CrC2); alkylcarbonyl (C C2); and alkylcarbonyloxy (d-C2). The substituents R4a and R4b, in turn, are selected from hydrogen and alkyl (CrC2). With respect to the substituent groups R7 and R8, it is preferred that they be absent (m = 0); or, if present, that are methyl; cyclopropyl; cyclobutyl; methoxy; -COOH; -OH; -F; -Cl; -COO-alkyl (CrC2); or -CF3. Of these options, the most preferred substituent options for R7 and R8 are those in which they are absent or are -F or Cl. R5, as defined by the formula (1.0.0), is preferably a direct link. Alternatively, the radical R5 can be selected from -O-; -C (= O) -; -NR4- wherein R4 is hydrogen or alkyl (d-C2); and -S (= O) p-. In the partial formula (1.0.0), the presence of the substituent R12a is determined by the subscript "j". which is an integer independently selected between 0, 1 and 2. When j is 0, therefore, the substituent R12a will be absent. When j is 1 or 2, there may be one or two R12a substituents present, and these may be attached to any available carbon atom in the partial formula (1.0.0). R12a is a member selected independently from the group consisting of hydrogen; -F; -Cl; -CO2R4 wherein R4 is hydrogen or alkyl (CrC2) as defined above; -oxo; -OH; -CN; -NH2; -NH-(C1-C2) alkyl; -N-dialkyl (C? -C2) 2; -CF3; (C 1 -C 4) alkyl; alkenyl (C2-C4); (C 1 -C 4) alkoxy; cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl groups are substituted with 0 to 2 substituents R9, wherein R9 is a member independently selected from the group consisting of -F; -Cl; -CO2R4 wherein R4 is hydrogen or alkyl (d-C2); -OH; cyano; -CONR4aR4b; -NR4aR4b; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; - NR4aS (= O) pR4b; -S (= O) pNR4aR4b; (C 4 C) alkyl including dimemethyl, and (C 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (d-C2); alkylcarbonyl (d-C2); and (C 1 -C 2) alkylcarbonyloxy. When a R 2a substituent is present and consists of an alkyl, alkenyl, alkoxy, cycloalkyl or phenyl group, it may be optionally mono- or di-substituted in turn by an additional substituent R 9, which is independently selected from the groups mentioned above. This includes, in particular, (C1-C4) alkyl substituted with 1 to 3 substituents independently selected from F and Cl. Accordingly, the substituent -CF3 is a preferred definition of R9 in the compounds of partial formula (1.0.0). Substituent R12 is directly bonded to the nitrogen atom of the heterocyclic group represented in the partial formula (1.0.0), and its presence is determined by the subscript "j", which is an integer independently selected between 0, 1 and 2. When j is 0, therefore, the substituent R12b is absent. In this case, the nitrogen atom is linked by a covalent double bond to an adjacent atom in the heterocyclic group represented in the partial formula (1.0.0). When j is 1 or 2, there will be one or two R12 substituents attached to the nitrogen atom of the heterocyclic group represented in the partial formula (1.0.0). When two of said substituents R12 are attached, the nitrogen atom is in quaternary form. The substituent R 2b is independently selected from the group consisting of hydrogen; alkyl (d-d); alkenyl (C2-C4); alkoxy (Cr C2); cycloalkyl (C3-C); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl groups are substituted with 0 to 2 substituents R9, wherein R9 has the same meanings as the R9 defined above, with the exception that it is independently selected from them. The group represented by the partial formula (1.0.1): represents a monocyclic heterocyclic group or a benzo-fused bicyclic ring system containing said heterocyclic group, wherein said heterocyclic group contains a total of 5 or 6 members of which one or two of said members is nitrogen, the presence being represented of the second optional nitrogen atom by: "[N]"; wherein said heterocyclic group or ring system is selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperazinyl; indolyl; indazolinyl; benzoimidazolyl; quinolinyl; isoquinolinyl and quinazolinyl. Heterocyclic residues containing N of partial formula (1.0.0) result in some of the preferred modalities of Region a, represented by the partial formulas (1.0.4) to (1.0.10) inclusive: (1.0.4) (1.0.5) (1 0.6) (1.0.7) (1.0.8) (1.0.9) (1.0.10) Another group of heterocyclic phenylmethylene residues containing N (in A. 2), comprise several subgeneric groups within of the partial formula (1.1.0): wherein the symbols "*" and R5; R6; R7; R8; j and m are as defined above; and R13a is a member selected from the group consisting of hydrogen; F; Cl, -CO2R4-; oxo; -OH; CN; NH2; NH-alkyl (C C2); N-dialkyl (C? -C2) 2; -CF3; (C 1 -C 4) alkyl; alkenyl (C2-C4); alkoxy (d-C2); cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein R11 is a member independently selected from the group consisting of F; Cl; -CO2R4; -OH; -CN; -CONR4aR4b; -NR4aR4b; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR aS (= O) pR4b; -S (= O) pNR4aR4b; alkyl (C? -C4) including dimethyl and (C1-C4) alkoxy, wherein each of said alkyl and alkoxy is independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C1-C2); alkylcarbonyl (C? -C2); and alkylcarbonyloxy (C? -C2); and R13 is selected from the group consisting of hydrogen, (C1-C4) alkyl; alkenyl (C2-d); alkoxy (d-C2), cycloalkyl (C3-C7); C (= O) alkyl (C C4); S (= O) 2-(C 1 -C 4) alkyl; and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein R11 have the same meaning as indicated above, with the exception that they are independently selected from each other. The rest of the partial formula (1.1.1): (1.1.1) represents, among others, a monocyclic heterocyclic group containing a total of 5 members of which one of said members is nitrogen and Q is selected from O and S. The heterocyclic group may be selected from the group consisting of oxazolyl; oxazolidinyl, isoxazolyl; thiazolyl; thiazolidinyl; iso-thiazolyl: morpholinyl and thiamorpholinyl. The remains of partial formula (1.1.0) containing the partial formula group (1.1.1) result in the following preferred modalities of Region a, represented by the partial formulas (1.1.3) to (1.1.9) ): (1.1.8) (1.1.9) In preferred alternative embodiments, the heterocyclic group may be selected from the group consisting of triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl. Other preferred modalities of Region a are represented by the partial formulas (1.1.20) to (1.1.24) inclusive: (1.1.20) (1.1.21) (1.1.22) (1.1.23) (1.1.24) Another class of Region a residues (in B) are amido-aryl or -heterocyclic (substituted) moieties that can be independently selected from various groups, as described in more detail below. The first class of amido-aryl or -heterocyclic (substituted) moieties of Region a are those in which the amido-aryl or -heterocyclyl portion of the group is substituted by alkyl, alkenyl or alkynyl, as represented in the partial formula ( 2.0.0) (2.0.0) in which the symbols "*" and R4 and R6; and m, R7 and R8 in the detailed definition of A; they are as defined in the above partial formulas, with the exception that all the substituents mentioned above are independently selected. Remainder A of the partial formula (2.0.0) is a member independently selected from the group consisting of several different kinds of residues, as described below. The first class represented by the partial formula (2.0.3) is a preferred embodiment of this invention wherein the symbols R7; R8 and m are as defined in the above additional partial formulas, with the exception that all the aforementioned substituents are selected ietly of their selection in said above additional partial formulas; and the symbol: "*" indicates the point of union of residue A to the other remaining portions of partial formula (2.0.0). Other modalities of the rest A are represented by the partial formulas (2.0.4) and (2.0.5). The partial formula (2.0.4) is: representing a monocyclic heterocyclic group, selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; and pyrimidinyl. Note that in the rest of the partial formula (2.0.3), the symbols R12a and R12b. and the subscript "j" which determines its presence, are as defined in the above additional partial formulas, with the exception that "j" is 0 or 1 and all the aforementioned substituents are ietly selected from their further prior selection; and the symbol: "*" indicates the point of union of residue A to the other remaining portions of partial formula (2.0.0). Other modalities of the remai A are represented by the partial formula (2.0.5) which represents a monocyclic heteroaromatic group containing a total of 5 members, of which one of said members is nitrogen and Q is selected from O and S, wherein said S may be optionally in the sulfonate form, -S (= O )2. Said heterocyclic group may be selected from the group consisting of oxazolyl; isoxazolyl; thiazolyl and iso-thiazolyl; triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl. Note that the symbols R13a and R13b and the subscript "j". which determines its presence, are as defined in the above additional partial formulas, with the exception that "j" is 0 or 1 and all the aforementioned substituents are selected ietly of their selection in said above additional partial formulas; and the symbol "*" indicates the point of union of rest A to the other remaining portions of partial formula (2.0.0). The group R5a is selected from a direct link; -C (= O) -; and -S (= O) 2. In preferred embodiments of the present invention, R5a is a direct bond. However, when R5a is -CO- or -SO2-, the divalent moiety W1 is further defined to include the meaning of being a direct link. In the partial formula (2.0.0), R27 is a member selected from the group consisting of alkyl (d-Cß); alkenyl (C2-C6); and (C2-C6) alkynyl; wherein said alkyl, alkenyl and alkynyl groups comprising R27 may be substituted with 0 to 3 substituents R28, wherein R28 is selected from the group consisting of F; Cl; oxo; hydroxy; (C1-C2) alkyl; alkoxy (C C3); -C (= O) OR29; C (= O) alkyl (d-C4); -S (= O) 2alkyl (d-C4); -C (= O) NR29R30; -NR29R30; -NR29C (= O) R30; -NR29C (= O) OR30; -NR29S (= 0) 2R3 °; and -S (= O) 2NR29R30, wherein R29 and R30 are ietly selected from hydrogen and (C1-C4) alkyl.

The residue W1 is a member ietly selected from the group consisting of divalent residues of partial formulas (2.0.6) to (2.0.16), inclusive: (2.0.6) (2.0.7) (2.0.8) (2.0.19) (2.0.10) (2.0.11) (2.0.12) (2.0.13) (2.0.14) (2.0.15) (2.0.16) where the symbol: "- >" indicates the point of attachment of the remai W1 to the nitrogen atom in the partial formula (2.0.0), and the symbol "*" indicates the point of union of the remai W1 to the rest R27, which represents the remaining portions of the partial formula (2.0.0); and each of R25 and R26 is ietly a member selected from the group consisting of hydrogen; (C 1 -C 2) alkyl substituted with 0 or 1 substituents ietly selected from F and OH; and alkoxy (d-C2). As an alternative, the linking element -N (R4) -W1- can constitute or contain several different functionalities. The first and most preferred of these is an amide functionality, which may be represented as: -NR4-C (= O) -. Other types of functionality include sulfonamide and ureido moieties within the scope of the partial formulas (2.0.6) to (2.0.16). Preferred alkyl and alkenyl R27 groups include: methyl; ethyl; iso-propyl; t-butyl; and propenyl (allyl). These alkyl and alkenyl groups may be substituted with 0 to 3 substituents R28. It is preferred that when a substituent is present, it is a simple substituent independently selected from F; Cl; OH; CF3; CH3; OCH3; CN; NHCH3; N (CH3) 2; NHCOCH3; NCH3 (COCH3) and NH2. Accordingly, the partial formula groups (2.0.0) which are preferred embodiments of the present invention and which constitute Region a include the following partial formula residues (2.0.30) to (2.0.36), inclusive: .0.30) .0.31) .0.32) (2.0.33) (2.0.36) The second class of amido-aryl (substituted) moieties comprising Region a are those in which the amido-aryl portion of the group is substituted by - (cycloalkyl) or -alkyl (cycloalkyl), as depicted in the partial formula (2.1.0). in which; TO; W1; the symbol "*" and R4; R5a; R6; and m, R7 and R8 in the additional definition of A; they have the same meanings indicated in the above additional partial formulas, with the exception that all the aforementioned substituents are independently selected from their previous additional selection. R 32 is a member independently selected from the group consisting of - (CH 2) n-cycloalkyl (C 3 -C 7), wherein n is an integer selected from 0, 1 and 2; in the case that n is 0, then the carbon atom of said cycloalkyl (C3-C) may be substituted by (C1-C4) alkyl or phenyl, wherein said alkyl or phenyl may be substituted with 1 or 2 groups CH3, OCH3, OH or NH2; and in case n is 1 or 2, the resulting methylene or ethylene group can be substituted by F; Cl; CN; NH2; N (CH3) 2; OH; OCH3; alkyl (d-d); or phenyl. Also note additionally that the basic (C3-C) cycloalkyl group comprising R32 may also be substituted with 0 to 3 substituents R28, wherein R28 has the same meanings as defined above with respect to the substituents for the R27 group of the partial formula (2.0.0), but independently selected among them. Representative cycloalkyl and alkylcycloalkyl groups within the scope of R 32 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; cyclopropylmethyl; cyclobutylethyl; cyclopentylpropylmethyl; and cyclopentylmethyl. The most preferred single substituents for these cycloalkyl and alkylcycloalkyl groups include F, Cl and CN, especially OH; OCH3; and NH2. Therefore, the partial formula groups (2.1.0) which are preferred modalities of the Region a include the partial formulas (2.1.3) to (2.1.10). (2.1.3) (2.1.4) (2.1.5) (2.1.6) (2.1.7) (2.1.8) (2.1.9) (2.1.10) The third class of amido-aryl (substituted) moieties of Region a are those in which the amido-aryl portion of the group is substituted by aryl- and heterocyclyl-substituted amido-aryl residues of partial formula (2.2.0) wherein A, W1; the symbol "*" and R4; R5a; R6; and m, R7 and R8 in the definition of A; they have the same meaning as indicated above, with the exception that all the aforementioned substituents are independently selected. The R35 moiety can be selected from the group consisting of phenyl; Furyl tetrahydropyranyl; tetrahydrofuranyl; oxetanyl; thienyl; pyrrolyl; pyrrolidinyl; oxazolyl; Soxazolyl; thiazoliol; isothiazolyl; imidazolyl; imidazolinyl; pyrazolyl; pyrazolinyl; Oxadiazolyl; thiadiazolyl; triazolyl; pyridyl; pyrazinyl; pyridazinyl; piperazinyl; pyrimidinyl; pyranyl; azetidinyl; morpholinyl; parathiazinyl; indolyl; isoindolyl; 3H-indolyl; indolinyl; benzo [b] furanyl; 2,3-dihydrobenzofuranyl; benzothienyl; 1 H-indazolyl; benzoimidazolyl; benzoxazolyl; benzoisoxazolyl; benzothiazole; benzoxadiazolyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; and quinoxalinyl. Preferred meanings of R 35 are phenyl, pyrrolyl; oxazolyl; imidazolyl; pyridinyl; pyrimidinyl; triazolyl; indolyl; benzoimidazolyl; benzotriazolyl; quinolinyl; thienyl; furfuril; benzofuranyl; thiazolyl; oxazolyl; isoxazolyl; Oxadiazolyl; benzoxazolyl; and benzoxadiazolyl. Most preferred are tetrahydropyranyl, oxetanyl; azetadinyl and tetrahydrofuranyl. The R35 group may be substituted with 3 substituents R28, wherein R28 has the same meaning defined above but independently selected. Alternative aryl and heterocyclyl groups included within the scope of R 35 include phenyl; pyrrolyl; imidazolyl; pyridyl; oxazolyl; Furyl and benzofuranyl. Preferred single or double substituents for these groups include -CN; -F; -Cl; -CONH2; -CH3; -CF3; and -OCH3. Therefore, the partial formula groups (2.2.0) that are preferred modalities of the Region a include the partial formulas (2.2.3) to (2.2.14). (227) (2 28) (229) (22 10) 11) 12) 13) (22 14) Does the lRequest include a link between the Region described above and the Region? described later. The alkyl bonding element of Region ß comprises a partial formula residue (3.0.0): wherein the symbol "*" represents the point of attachment of the remainder of the alkyl linking element of partial formula (3.0.0) to Region a of the modulator compound of formula (I); and the symbol "->" represents the point of attachment of the remainder of the alkyl linking element of partial formula (3.0.0) to the Region? of the modulator compound of formula (I). Both the substituent R40 and R41 are independently selected from the group consisting of hydrogen, alkyl (CrC2) including dimethyl; hydroxy; and alkoxy (CrC3); with the proviso that only one of R40 and R41 may be alkoxy (CrC3) or hydroxy, the other of R40 or R41 being selected from hydrogen and alkyl (C2), including dimethyl. Accordingly, R40 and R41 may be hydrogen; methyl, ethyl, dimethyl, that is, two methyl groups attached to the single carbon atom to which R40 or R41 is attached; hydroxy; methoxy; ethoxy; or propoxy. Some representative embodiments of the alkyl linking element of partial formula (3.0.0) include the following residues of partial formulas (3.0.1) to (3.0.7) inclusive: 3.0.1) (3.0.2) (3.0.3) ) (3.0.4) (3.0.5) (3.0.6) (3.0.7) In the most preferred embodiments of the modulator compounds of the present invention, both R40 and R41 are hydrogen and the alkyl linking element of partial formula (3.0.0) is unsubstituted ethylene. In the preferred embodiments, a single methyl, hydroxy or methoxy substituent may be present, resulting in alkyl linking elements such as those of the partial formulas (3.0.8) to (3.0.10): (3.0.8) (3.0.9) (3.0.10) The [Region? L comprises a member selected from the group consisting of a partial formula residue (4.0.0): wherein "*" is a symbol representing the point of attachment of the aza-monocyclic moiety of partial formula (4.0.0) to the β region; and "-» "is a symbol representing the point of attachment to region d. It will be appreciated that in the partial formula residues (4.0.0), the nitrogen atom covalently binds said heterocyclic moieties to the β region. The heterocyclic radical of partial formula (4.0.1): which constitutes a part of the partial formula (4.0.0), represents a monocyclic heterocyclic group containing a total of 4 to 7 members, of which one of said members is nitrogen, wherein said heterocyclic group is a independently selected member between the group consisting essentially of azetidinyl; pyrrolidinyl; piperidinyl; and azepinyl, which may also be referred to as homopiperidinyl. With respect to the remains of partial formula (4.0.0) that defines the region?, The following groups represented by the partial formulas (4.0.2) to (4.0.5) are included: (4.0.2) (4.0.3) (4.0.4) (4.0.5) The above-defined residues of partial formula (4.0.0) are optionally mono-substituted with R45, wherein R45 is absent or is a member independently selected from the group consisting essentially of alkyl (C? -C4) including dimethyl; cycloalkyl (C3-Cß); alkoxy (d-C4); alkoxy (d-C2) alkyl (d-C2); -CF3; -CO2R4 wherein R4 is as defined in detail above; oxo; -OH; -CN; -C (= O) NR4aR4b; -NR4aR4b; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR4aS (= O) pR4b; -S (= O) pR4aR4b in which each of R4a and R4b is independently selected from hydrogen; (C1-C2) alkyl; (C 1 -C 2) alkoxycarbonyl; alkylcarbonyl (C1-C2); alkylcarbonyloxy (C1-C2); and (C1-C2) alkoxy alkyl (d-C2). It will be understood that in the partial formula residues (4.0.0), the R45 substituent is attached to a single carbon atom of the heterocyclic group described above. It will be further understood that when R 45 is defined as (C 1) alkyl, the methyl substituent may appear twice at a single carbon atom of the heterocyclic group, ie, it may be a dimethyl substituent. Substituent group R46 is absent or is a member independently selected from the group consisting essentially of hydrogen; alkyl (C? -C) substituted with 0 or 1 substituent independently selected from (C1-C2) alkoxy and -CO2R4 wherein R4 is as defined in detail above; I. It will be appreciated that in the case that it is chosen that the substituent R46 is not absent, it will be obtained as a result that said nitrogen atom and said partial formula residue (4.0.0) are in quaternary form. However, generally the quaternary forms of the compounds of the present invention are less preferred than their non-quaternary equivalents, although those skilled in the art can easily foresee that some particular embodiment may have more advantageous properties in its quaternary form than in its non-quaternary form. Quaternary Although it is preferred that the partial formula moieties (4.0.0) remain unsubstituted, ie, that R45 is absent, some examples of substituted moieties that fall within the scope of preferred embodiments of the present invention are those depicted in FIGS. partial formulas (4.0.6) to (4.0.13), inclusive: (4.0.10) (4.0.11) (4.0.12) (4.0.13) [Region dl constitutes the left end of the compounds of formula (I) and is directly linked to the region? described above. The region d of the compounds of formula (I) comprises two subclasses of substituted heterocyclyl radicals. The first subclass of such heterocyclyl radicals is selected from those of partial formula (5.3.0): wherein the symbol "*" indicates the point of attachment of partial formula (5.3.0) to the region?; Q is N, O or S; and R90a and R90b are independently selected from the group consisting of hydrogen; -alkylcarbonyl (C1-C2); -alkyl (d-C4); - (CH2) n-cycloalkyl (C3-C7); -alkenyl (C2-C3); - (CH2) n- (venyl); and - (CH2) n (HET1), wherein n is an integer selected from 0, 1 and 2. In addition, j has the same meaning as above, but is independently selected. It is especially preferred that j is 0, in which case the R90b substituent is absent. However, preferred embodiments of the present invention also include those in which j is 1 and R90b is methyl. The heterocyclyl group HETi can be selected from the group consisting of thienyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl; Oxadiazolyl; thiadiazole; triazolyl; pyridyl; pyrazinyl; pyridazinyl; pyrimidinyl; parathiazinyl; and morpholinyl. The alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups mentioned above are optionally substituted with up to 3 R91 substituents independently selected from the group consisting of F; Cl; -C (= O) OR93; oxo, -OH, -CN; C (= O) alkyl (C c4); S (= O) 2alkyl (d-C4); -CONR93R94; -NR8-R9-, -NR93C (= O) R94; -NR93C (= O) OR94; -NR93S (= O) 2R94; -S (= O) 2NR93R94; alkyl (d-d) including dimethyl and (C 1 -C 4) alkoxy, each substituted with 1 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C1-C2); alkylcarbonyl (C1-C2); and (C1-C2) alkylcarbonyloxy, wherein each of R93 and R94 is a member independently selected from the group consisting of hydrogen; and (C1-C2) alkyl. The heterocyclic group that constitutes a part of the partial formula moiety (5.3.0), can be a 5-membered monocyclic group containing two or more N, O or S atoms, for example, oxazolyl; / 'soxazolyl; thiazolyl; / so-thiazolyl; triazolyl; triazinílo; tetrazolyl; Oxadiazolyl and thiadiazolyl. Preferred embodiments include the formulas (5.3.5) to (5.3.9): (5.3.5) (5.3.6) (5.3.7) (5.3.8) (5.3.9) Accordingly, preferred embodiments of the compounds of the present invention comprising residues that define region d according to the partial formula (5.3.0), as represented by the partial formulas (5.3.15) a ( 5.3.26): (5.3.15) (5.3.16) (5.3.17) (5.3.18) (5.3.19) (5.3.20) (5.3.21) (5.3.22) (5.3.23) (5.3.24) (5.3.25) (5.3.26) The second subclass of residues (in C.2.) That define region d can be selected from those of partial formula (5.4.0): wherein Q, R90a and R90b have the same meaning as defined above, but independently selected.

The heterocyclic group may be the same as in formula 5.3.0, with the exception that the nitrogen atom is the point of attachment. Therefore, the formulas (5.4.5) to (5.4.8) result: (5.4.5) (5.4.6) (5.4.7) (5.4.8) The following preferred modalities of region d are represented by the partial formulas (5.4.10) to (5.4.17): (5.4.10) (5.4.11) (5.4.12) (5.4.13) (5.4.14) (5.4.15) (5.4.16) (5.4.17) The compounds of the present invention can be used in the form of acids, esters or other chemical derivatives. Also within the scope of this invention is the use of these compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases, according to methods well known in the art. The term "pharmaceutically acceptable salt", as used herein, is intended to mean an active ingredient comprising a compound of formula (I) used in the form of a salt thereof, especially when said salt form confers said active ingredient. pharmacokinetic properties compared to the free form of said active ingredient or other salt form previously described. A pharmaceutically acceptable salt form of said active ingredient may also initially confer a pharmacokinetic property of said active ingredient with respect to its therapeutic activity in the body. The pharmacokinetic properties of said active ingredient that can be favorably affected include, for example, the way in which said active ingredient is transported across the cell membranes which, in turn, can directly and positively affect the absorption, distribution , biotransformation or excretion of said active ingredient, although the route of administration of the pharmaceutical composition is important and various anatomical, physiological and pathological factors can critically affect the bioavailability, the solubility of said active ingredient is normally dependent on the character of the form of particular salt of the same one that is used. In addition, an aqueous solution can provide the fastest absorption of an active ingredient in the body of a patient to be treated, while lipid solutions and suspensions, as well as solid dosage forms, can produce a less rapid absorption. Oral ingestion of said active ingredient is the most preferred route of administration for reasons of safety, convenience and economy, but the absorption of such oral dosage form can be adversely affected by physical characteristics such as polarity, emesis caused by irritation of the gastrointestinal mucosa, destruction by digestive enzymes and low pH values, irregular absorption or propulsion in the presence of food or other drugs, and metabolism by enzymes of the mucosa, the intestinal flora or the liver. The formulation of said active ingredient in different forms of pharmaceutically acceptable salts can be effective in solving or alleviating one or more of the aforementioned problems encountered with the absorption of oral dosage forms. Well known pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, aspatate, benzoate, benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisuccinate, hemysulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxyethanesulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, salicylate, sodium phosphate, stearate, succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate, p-toluenesulfonate and undecanoate. Base salts of the compounds of the present invention include, but are not limited to, ammonium salts; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris- (hydroxymethyl) -methylamine (tromethamine) and salts with amino acids such as arginine, lysine, etc. The compounds of the present invention comprising basic groups containing nitrogen can be quatemized with agents such as (C1-C4) alkyl halides, for example, methyl, ethyl, / so-propyl and tert-butyl chlorides, bromides and iodides; dialkyl sulfate (C 1 -C 4), for example, dimethyl, diethyl and diamyl sulfates; alkyl halides (CIO-CIB), for example, decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and arylalkyl (C1-C4) halides, for example benzyl chloride and phenethyl bromide. Such salts allow the preparation of water-soluble and oil-soluble compounds of the present invention. Among the pharmaceutical salts mentioned above, those which are preferred include, but are not limited to, acetate, besylate, citrate fumarate, gluconate, hemisuccinate, hipurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate. , stearate, sulfate, sulfosalicylate, tartrate, thiomalate, p-toluenesulfonate and tromethamine.

Within the scope of the present invention multiple salt forms are included in which a compound of the present invention contains one or more groups capable of forming such pharmaceutically acceptable salts. Examples of typical multiple salt forms include, but are not limited to, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trichlorhydrate. The compounds of this invention can be administered alone, but will generally be administered in admixture with one or more suitable excipients, diluents or pharmaceutical carriers selected with respect to the desired route of administration and conventional pharmaceutical practice. For example, the compounds of formula (I) can be administered orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate or controlled release applications. Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch (preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, and granulation aids such such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be included. Solid compositions of a similar type can also be used as gelatin capsule fillers. Preferred excipients in this regard include lactose or milk sugar, as well as high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of formula (I) may be combined with various sweetening or flavoring agents, coloring materials or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin , and combinations thereof. The compounds of formula (I) can also be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrastaneously, intracranially, intramuscularly or subcutaneously, or they can be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with the blood. The aqueous solutions should be buffered conveniently (preferably at a pH of 3 to 9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art. For oral and parenteral administration to human patients, the daily dosage level of the compounds of formula (I) will normally be from 1 microgram / kg to 25 mg / kg (in a single dose or in divided doses). Thus, the tablets or capsules of the compound of formula (I) may contain from 0.05 mg to 1.0 g of active compound for single administration or two or more at a time, as appropriate. In any case, the doctor will determine the actual dose that is most suitable for any individual patient, and this will vary with the age, weight and response of the particular patient. The above doses are examples of the middle case. Of course, there may be individual cases where larger or smaller dosage intervals are required, and such cases are within the scope of this invention. The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or in an aerosol spray presentation from a pressure vessel or a nebulizer with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2-tetrafluoroethane (HFA134a), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by equipping it with a valve to release a metered amount. The pressure vessel or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol and the propellant as solvent, which may further contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) can be formulated for use in an inhaler or insufflator, such that they contain a powder mixture of a compound of formula (I) and a suitable powder base such as lactose or starch.

The aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 20 μg to 20 mg of a compound of formula (I) to be administered to the patient. The total daily dose with an aerosol will be in the range of 20 μg to 20 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day. Alternatively, the compounds of formula (I) can be administered in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or fine powder. The compounds of formula (I) can also be administered transdermally, for example, by the use of a skin patch. They can also be administered by the ocular route, particularly for the treatment of neurological disorders of the eye. For ophthalmic use, the compounds can be formulated as mechronized suspensions in sterile saline solution, pH adjusted or, preferably, as solutions in sterile saline solution, pH adjusted, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they can be formulated in an ointment such as petrolatum. For topical application to the skin, the compounds of formula (I) may be formulated in the form of a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil; liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated in the form of a suitable, suspended or loose lotion or cream in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, wax cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of formula (I) are described herein as compounds possessing such a biological activity that they can modulate the activity of the CCR5 receptor of chemokines and the consequent or associated pathogenic processes mediated by the CCR5 receptor and its ligands. The term "modulate the activity of the chemokine CCR5 receptor", as used herein, is intended to refer to the manipulation of the basic physiological processes and the means involving CCR5 receptors of chemokines and their ligands. Within the scope of this desired meaning are included all types and subtypes of CCR5 receptors present in any tissue of a particular patient and in any component of the cells constituting those tissues. Most commonly, CCR5 receptors are located in the cell membranes of particular cell types such as monocytes. The CCR5 receptors participate and define, along with various endogenous ligands to which they naturally bind, signaling pathways that control important cellular and tissue functions through the influence they exert on the movement of agents such as chemokines, to the interior and outside of those cells and tissues.

The basic functioning of CCR5 receptors and their ligands can be modulated in various ways, and the scope of the present invention is not limited in this respect to any particular or existing hypothetical path or process. Thus, within the intended meaning of modulation of the CCR5 chemokine receptor activity is the use of modulators obtained by synthesis introduced in a patient to be treated, such as the compounds of formula (I) described herein. These exogenous agents can modulate the activity of the CCR5 receptor by well known mechanisms such as competitive binding, in which the natural ligands are displaced and their intrinsic functions are interrupted. However, the present invention is not limited to any of such specific mechanisms or modes of action. So that"Modulation", as used herein, is intended to preferably include antagonism, but also agonism, partial antagonism and / or partial agonism. Correspondingly, the term "therapeutically effective amount" means the amount of the subject compound that will induce the biological or medical response that is being sought from a tissue, system, animal or human being. The term "patient" in this specification refers particularly to humans. However, the compounds, methods and pharmaceutical compositions of the present invention can be used in the treatment of animals.

Also included within the scope of the present invention are metabolites or residues of the compounds of formula (I) which possess biological activities such that they are capable of modulating the activity of the CCR5 chemokine receptor and the consequent or associated pathogenic processes subsequently mediated by the receptor. CCR5 and its ligands. Once synthesized, the modulating activities of the chemokine CCR5 receptor and the specificities of the compounds of formula (I) according to the present invention can be determined using in vitro and in vivo assays which are described in more detail below. The desirable biological activity of the compounds of formula (I) can also be improved by adding appropriate functionalities that improve the existing biological properties of the compound, improve the selectivity of the compound by the existing biological activities or add other desirable biological activities to existing biological activities. Such modifications are known in the art and include those that increase biological penetration in a given biological system, for example, the blood, the lymphatic system and the central nervous system; those that increase oral availability; those that increase the solubility to allow administration by injection; those that alter the metabolism; and those that alter the rate of excretion of the compound of formula (I). The dosage and dose ratio of the compounds of formula (I) effective for the treatment or prevention of diseases or conditions in a patient that are mediated or associated with the modulation of chemokine CCR5 receptor activity, as described in this document, as well as to favorably affect the result in said patient, according to the treatment methods of the present invention comprising administering to said patient a therapeutically effective amount of a compound of formula (I), will depend on a variety of factors such as the nature of the active ingredient, the size of the patient, the purpose of the treatment, the nature of the pathology being treated, the specific pharmaceutical composition used, the joint treatments to which the patient may be subjected and the observations and conclusions of the patient. corresponding doctor. However, in general, the effective therapeutic dose of a compound of formula (I) to be administered to a patient will be between about 10 μg (0.01 mg) / kg and about 60.0 mg / kg of body weight and per day, preferably between about 100 μg (0.1 mg) / kg and about 10 mg / kg of body weight and per day, more preferably between about 1.0 mg / kg and about 6.0 mg / kg of body weight and per day, and even more preferably between about 2.0 mg / kg and approximately 4.0 mg / kg of body weight and per day of the active ingredient of formula (I). Within the scope of the present invention are included modalities comprising the co-administration of compositions containing, in addition to a compound of the present invention as an active ingredient, other therapeutic agents and active ingredients. Such multiple drug regimens, often referred to as combination therapy, can be used in the treatment and prevention of any of the diseases or conditions mediated or associated with the modulation of the chemokine CCR5 receptor, particularly infection by the human immunodeficiency virus, HIV The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment and prevention of infection and multiplication, in a patient in need of treatment or in a patient at risk of being such a patient, of the human immunodeficiency virus, HIV, and of related pathogenic retroviruses. The ability of such retroviral pathogens to develop within a relatively short period of time in strains resistant to any monotherapy that has been administered to said patient is well known in the technical literature. In addition to the therapeutic efficacy requirement that the use of active agents in addition to the modulators of the chemokine CCR5 receptor of formula (I) may require, there may be additional logical bases that greatly oblige or recommend the use of combinations of drugs that include active ingredients that represent adjuvant therapy, that is, that complement and supplement the function performed by the modulators of the CCR5 receptor of chemokines of the present invention. Such supplementary therapeutic agents used as auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition mediated or associated with the modulation of chemokine CCR5 receptors, treat diseases or conditions directly or indirectly accompanying the disease or condition. modulated by the CCR5 receptor of basic or underlying chemokines. For example, when the basic disease or condition modulated by the CCR5 chemokine receptor is infection and multiplication of HIV, it may be necessary or at least desirable to treat opportunistic infections, neoplasms and other conditions that appear as a result of the immunocompromised state of the patient. try. With the compounds of formula (I) other active agents can be used, for example, to provide an immune stimulation or to treat the pain and inflammation that accompany the initial and fundamental HIV infection. Thus, the methods of treatment and the pharmaceutical compositions of the present invention can employ the compounds of formula (I) in the form of monotherapy, but such methods and compositions can also be used in the form of a multiple therapy in which one or more compounds of formula (I) in combination with one or more known therapeutic agents such as those described in more detail herein. The present invention also provides methods of treatment wherein said pharmaceutical compositions are administered to a patient. Such methods relate to the treatment or prevention of a disease or condition by modulating the activity of the CCR5 receptor of chemokines and the consequent or associated pathogenic processes subsequently mediated by the CCR5 receptor and the active ligands with which it interacts or binds. CCR5 and the other chemotactic cytokine receptors, ie chemokines, play a role in the control of various processes that take place in the bodies of animals. The chemokine receptors, of which it is currently known that there are more than forty different species divided into four families, are proteins that have several structural characteristics in common, which act through chemical signaling. In the a family of chemokines, an amino acid (X) separates the first two cysteine residues, whereas in β chemokines the first two cysteine residues are adjacent to each other (C-C). Therefore, these two families are identified as CXC and CC chemokines, respectively. Chemokines bind to specific receptors on the surface of cells belonging to the family of proteins with seven transmembrane domains coupled to G proteins, called "chemokine receptors", which are named according to the class of chemokines to which they are assigned. join, followed by "R" and a number. Thus, "CCR5" is a C-C chemokine receptor. See Horuk, Trends Pharm. Sci., 15, 159-165 (1994) for more detail. Thus, CCR5 belongs to the ß-chemokine receptor family, which, as is now known, contains eight members, CCR1 to CCR8. The CC type of chemokine receptors interacts with various signaling proteins, including monocyte chemoattractant proteins, MCP-1, -2, -3, -4 and -5; eotaxin-1; inflammatory proteins of macrophages MIP-1a and MIP-1β; and those regulated after activation, which are expressed and secreted in normal T cells, RANTES. It is known that the CCR5 type of chemokine receptor in particular interacts with MIP-1a and MIP-1β and RANTES in monocytes, activated T cells, dendritic cells and natural killer cells. These β-chemokines do not act on neutrophils, but rather attract monocytes, eosinophils, basophils and lymphocytes with varying degrees of selectivity. The present invention relates to compounds of formula (I) which are useful in the treatment or prevention of HIV infection, and to methods of treatment and to pharmaceutical compositions containing such compounds as an active ingredient. It will be understood that the term "HIV", as used herein, refers to the human immunodeficiency virus (HIV), which is the etiological agent of AIDS (acquired immunodeficiency syndrome), a disease that causes progressive destruction of the human immunodeficiency virus (HIV). immune system and the degeneration of the central and peripheral nervous system. Several inhibitors of HIV replication are currently used as therapeutic or prophylactic agents against AIDS, and many others are currently under investigation. In addition to cell surface CD4, it has recently been shown that in order to enter target cells, human immunodeficiency viruses require a receptor for chemokines, CCR5 and CXCR-4 among others, as well as the primary receptor for CD4 virus. The main cofactor for the entry mediated by envelope glycoproteins of strains of HIV-1 that present primary tropism for macrophages is CCR5, which, as already mentioned, is a receptor for the β-chemokines RANTES, MIP-1a and MIP-1 ß. See Deng, et al., Nature, 381, 661-666 (1996) for an additional description of HIV entry mediated by CCR5. HIV binds to the CD4 molecule present on the cells through a region of its envelope protein, gp120, with gp120 being a part of a complex of multiple subunits, most likely a trimer of gp160, ie, gp120 + gp41 . It is believed that the CD4 binding site in HIV gp120 interacts with the CD4 molecule present on the cell surface, activating conformational changes through the trimer, which allow it to bind to another cell surface receptor, such as CCR5 . This in turn allows gp41 to induce fusion with the cell membrane and the entry of the viral nucleus into the cell. In addition, it has been shown that envelope proteins from HIV and SIV, which exhibit tropism for macrophages, induce a signal through CCR5 on CD4 + cells, which can improve the replication of the virus. See Weissman, et al., Nature, 389, 981-985 (1997) for a description of this phenomenon. In addition, it has been shown that a soluble gp120 and CD4 complex interacts specifically with CCR5 and inhibits the binding of natural CCR5 ligands, as described in Wu, et al., Nature, 384, 179-183 (1996); and Trkola, et al., Nature, 384, 184-187 (1996). It has also been shown that β-chemioxins and related molecules, eg, (AOP) -RANTES, prevent fusion of HIV to the cell membrane and subsequent infection, both in vitro and described in Dragic, et al., Nature , 381, 667-673 (1996), as in animal models. Finally, the absence of CCR5 seems to confer protection against HIV-1 infection, as described in Nature, 382, 668-669 (1996). In particular, it has been shown that an inherited mutation of phase shift in the CCR5 gene,? 32, overrides the functional expression of the gene in vitro, and individual homozygotes for the mutation apparently are not susceptible to HIV infection, whereas at the same time they do not seem to be immunocompromised by this variant. In addition, heterozygous individuals who have been infected with HIV progress more slowly to fully established clinical AIDS. In addition to the validation of the role of CCR5 in the HIV infectious cycle, the previous observations suggest CCR5 is essential in the adult organism. Although most of the HIV-1 isolates studied to date use CCR5 or CXCR-4, at least nine other chemokine receptors or structurally related molecules have also been described as molecules that support membrane fusion mediated by the envelope of HIV-1 or viral entry in vitro. These include CCR2b, CCR3, BOB / GPR15, Bonzo / STRL33TYMSTR, GPR1, CCR8, US28, V28 / CX3CR1, LTB-4 and APJ. There is good evidence that CCR3 can be used effectively by a significant fraction of HIV-1 isolates in vitro, provided that this protein is overexpressed in transfected cells. However, consistent evidence indicates that anti-HIV drugs directed against chemokine receptors may not be compromised by this variability. In fact, it has been shown that the chemokines RANTES, MIP-1a, MIP-1β and SDF-1 suppress the replication of primary HIV isolates. A derivative of RANTES, (AOP) -RANTES, is a subnanomolar antagonist of the function of CCR5 in monocytes. Monoclonal antibodies against CCR5 have been reported to block infection of cells by HIV in vitro. It has been reported that a small CXCR4 antagonist molecule, identified as AMD3100, inhibits the infection of susceptible cultures by HIV virus adapted to the laboratory and CXCR4-dependent primary, while another small molecule called TAK 779 blocks the entry of strains that have tropism to it. CCR5 (Baba, et al., PNAS, 96 (10), 5698-5703 (1999); In addition, most of the primary strains from the early and late stages of the disease use CCR5 exclusively or in addition to other chemokine receptors, indicating that CCR5-dependent infection can play an essential role in the initiation and maintenance of the infection. of productive HIV in a host. Accordingly, an agent that blocks CCR5 in patients, including mammals, and especially in humans possessing normal chemokine receptors, can reasonably be expected to prevent infection in healthy individuals and to slow or stop viral progression in infected patients. Accordingly, the present invention relates to compounds of formula (I) which inhibit the entry of the human immunodeficiency virus into target cells and which, therefore, are valuable in the prevention and / or treatment of HIV infection, as well as in the prevention and / or treatment of the resulting acquired immunodeficiency syndrome (AIDS). Evidence can be produced that demonstrates that the compounds of formula (I) described herein inhibit viral entry through selective blocking of CCR5-dependent fusion. Accordingly, the present invention also relates to pharmaceutical compositions containing the compounds of formula (I) as an active ingredient, as well as to the corresponding method of using the compounds of formula (I) as individual agents, or in conjunction with other agents for the prevention and treatment of HIV infection and AIDS resulting. The utility of the compounds of formula (I) of the present invention as inhibitors of HIV infection can be demonstrated by one or more methodologies known in the art, such as the HIV microculture assays described in Dimitrov et al., J. Clin, Microbiol. 28, 734-737 (1990)) and the pseudotyped HIV reporter assay described in Connor et al., Virology 206 (2) 935-44 (1995). In particular, it is demonstrated that the specific compounds of formula (I) described herein as preferred embodiments inhibit the production of p24 after the replication of strains of HIV adapted to the laboratory and primary in primary blood lymphocytes (PBL) and cell lines. clones that support the replication of viruses that exhibit tropism for CCR5 and CXCR-4, for example, PM-1 and MOLT4-clone 8. It is also observed that only viral strains known to use CCR5 are inhibited, while that the replication of viruses that exhibit tropism for CXCR-4 is not affected, indicating that the compounds of formula (I) described herein are capable of preventing viral entry through selective blockade of CCR5-dependent fusion. . In addition, it is demonstrated that the compounds of formula (I) inhibit the entry of chimeric HIV reporter viruses pseudotyped with the envelope of a CCR5-dependent strain (ADA). Finally, it is demonstrated that the compounds of formula (I) inhibit the infection of primary cells by HIV isolated from the blood of an infected patient. Another confirmation of this anti-VI H mechanism is provided by the experiments indicated below. The ability of the compounds of formula (I) to modulate chemokine receptor activity is demonstrated by the methodology known in the art, such as the CCR5 binding assay following procedures described in Combadiere et al., J. Leukoc. Biol. 60, 147-52 (1996); and / or intracellular calcium mobilization assays as described by the same authors. Cell lines that express the receptor of interest include those that naturally express the receptor, such as peripheral blood lymphocytes (PBL) stimulated by PM-1 or IL-2, or a cell engineered to express a recombinant receptor such as CHO, 300.19, L1.2 or HEK-293. In particular, it is demonstrated that the compounds of formula (I) described herein have activity in preventing the binding of all known ligands of chemokines to CCR5 in the aforementioned binding assays. further, it is demonstrated that the compounds of formula (I) described herein prevent the mobilization of intracellular calcium in response to endogenous agonists, which is consistent with their function as CCR5 antagonists. For the treatment of HIV infection and the prevention and / or treatment of the resulting acquired immunodeficiency syndrome (AIDS), compounds of formula (I) which have been shown to be antagonists are preferred to compounds of formula (I) which have proven to be agonists. The present invention, in one of its preferred embodiments, refers to the use of the compounds of formula (I) described herein for the prevention or treatment of infection caused by a retrovirus, in particular, the human immunodeficiency virus ( HIV) and the treatment and / or delay of the onset of the following pathological conditions, including but not limited to AIDS. The terms "treatment or prevention of AIDS" and "prevention or treatment of HIV infection" as used herein, are intended to mean the treatment of a wide range of HIV infection states: AIDS, ARC (complex related to HIV infection). AIDS), both symptomatic and asymptomatic, and the actual or potential exposure to HIV. However, the cited terms are not intended to be limited to the treatments mentioned, but rather include the inclusion of all the beneficial uses related to the conditions attributable to an agent causing AIDS. For example, the compounds of formula (I) are useful in the treatment of HIV infection after the last suspected exposure to HIV, for example, by blood transfusion, organ transplantation, exchange of body fluids, sexual intercourse, bites. , prick with a needle or exposure to the blood of a patient. In addition, a compound of formula (I) can be used for the prevention of HIV infection and the prevention of AIDS, such as in pre- or post-coital prophylaxis or in the prevention of maternal transmission of the HIV virus to a fetus. or child, at the time of birth, during the breastfeeding period, or in any other way as described above. In a preferred embodiment of the present invention, a compound of formula (I) can be used in a method of inhibiting the binding of human immunodeficiency virus to a chemokine receptor, such as CCR5, which comprises contacting the target cell with a therapeutically effective amount of a compound of formula (I) which is effective to inhibit the binding of the virus to the chemokine receptor. The subject treated by these preferred methods of the present invention is a mammal, preferably a human being, male or female, wherein the modulation of chemokine receptor activity is desired and considered effective. As already indicated, the term "modulation" as used herein is preferably intended to include antagonism, but also agonism, partial antagonism and / or partial agonism. In addition, the term "therapeutically effective amount" as used herein, is intended to mean the amount of a compound of formula (I) as described herein that will induce the biological or medical response sought from a tissue, system or animal, especially the human being. In another preferred embodiment of the present invention, a compound of formula (I) can be used to evaluate putative mutants of retroviruses, especially HIV considered resistant to therapeutic agents against HIV, including the compounds of formula (I) described herein. Mutant viruses can be isolated from in vitro cultures by methods known in the art, but can also be isolated from in vivo animal infection models that have been described in the art. More significantly, mutant viruses can be isolated from samples of patients undergoing treatment, optimal or sub-optimal, comprising the administration of a compound of formula (I) or any combination thereof with other known or undiscovered therapeutic agents. Such mutant viruses or their components, particularly their envelope proteins, can be used for several advantageous purposes, including but not limited to the following: (i) the evaluation and / or development of new modulators of chemokines or other agents that have better activity against such mutant viruses; and (ii) the development of diagnostics capable of helping physicians or other clinical specialists in the choice of a therapeutic regimen and / or in the prediction of results for a patient. In another preferred embodiment of the present invention, the compounds of formula (I) described herein are used as tools to determine the affinity for co-receptors of retroviruses, including HIV and SIV, or their components, especially their envelope proteins. . These affinity data can be used for several advantageous purposes, including, but not limited to, the phenotyping of a given viral population, for example, prior to the administration of antiretroviral therapy. Affinity data can also be used to predict the progression and results of infection by the population of viruses involved. In another preferred embodiment of the present invention, a compound of formula (I) is used in the preparation and execution of screening tests for compounds that modulate the activity of chemokines, especially CCR5 receptors. For example, the compounds of formula (I) described herein are useful for isolating receptor mutants, which can then be transformed into screening tools for the discovery of even more potent compounds, following procedures well known in the art. In addition, the compounds of formula (I) are useful for establishing or characterizing the binding sites of other ligands, including compounds other than those of formula (I) and viral envelope proteins, to chemokine receptors, for example, by inhibition. competitive The compounds of formula (I) are also useful for the evaluation of specific modulator assumptions of various chemokine receptors. As the skilled person will appreciate, the complete evaluation of specific agonists and antagonists of the chemokine receptors described above has been hampered by the absence of non-peptide compounds, ie, metabolically resistant compounds with high binding affinity for these receptors. Thus, the compounds of formula (I) are useful as products that can be commercially exploited for these and other beneficial purposes. Within the scope of the present invention are combinations of the compounds of formula (I) with one or more therapeutic agents useful in the prevention or treatment of AIDS. For example, the compounds of the present invention can be administered effectively, in periods of pre-exposure and / or post-exposure to HIV, in combination with therapeutically effective amounts of known AIDS antivirals, immunomodulators, anti-infectives or vaccines familiar to the specialists in the technique. It will be understood that the scope of such combinations including the compounds of formula (I) is not limited to the aforementioned list but also includes any combination with another pharmaceutically active agent that is useful for the prevention or treatment of HIV and AIDS. Preferred combinations of the present invention include simultaneous or sequential treatments with a compound of formula (I) and one or more HIV protease inhibitors and / or HIV reverse transcriptase inhibitors, preferably selected from the class of reverse transcriptase inhibitors. non-nucleosidic (NNRTI), including, but not limited to, nevirapine, delavirdine and efavirenz; among the nucleoside / nucleotide inhibitors, including, but not limited to, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and adefovir dipivoxil; and among protease inhibitors, including but not limited to indinavir, ritonavir, saquinavir, nelfinavir and amprenavir. Other agents useful in the combinations of preferred embodiments described above of the present invention include current and undiscovered research drugs of any of the above classes of inhibitors., including, but not limited to, FTC, PMPA, fozivudine tidoxil, talviraline, S-1153, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378 and KNI-764. Also included within the scope of the preferred embodiments of the present invention are combinations of a compound of formula (I) together with a supplemental therapeutic agent used as an auxiliary treatment, wherein said supplementary therapeutic agent comprises one or more members independently selected from the group consisting of by inhibitors of proliferation, for example, hydroxycarbamide; immunomodulators, for example, sargramostim, and various forms of interferon or interferon derivatives; fusion inhibitors, for example, AMD3100, T-20, PRO-542, AD-349, BB-10010 and other chemokine receptor agonists / antagonists; integrase inhibitors, for example, AR177; RNaseH inhibitors; inhibitors of viral transcription and RNA replication; and other agents that inhibit viral infection or improve the condition or consequences of individuals infected with HIV through different mechanisms. Preferred methods of treatment of the present invention for the prevention of HIV infection or the treatment of avirhemic and asymptomatic subjects potentially or effectively infected with HIV include, but are not limited to, the administration of a member selected independently from the group consisting of: (i) a compound within the scope of formula (I) as described herein; (ii) an NNRTI in addition to a compound of (i); (iii) two NRTIs in addition to a compound of (i) (iv) an NRTI in addition to the combination of (ii); and (v) a compound selected from the class of protease inhibitors used in place of an NRTI in combinations (iii) and (iv). Preferred methods of the present invention for therapy of HIV infected individuals with detectable viremia or with abnormally low CD4 numbers, further include, as a member to be selected: (vi) treatment according to (i) above in addition to the initial regimens conventionally recommended for the therapy of established HIV infections, for example, as described in Bartlett, JG, "1998 Medical Management of HIV infection," Johns Hopkins University publishers, ISBN 0-9244-2809-0. Such conventional regimens include, but are not limited to, an agent of the class of protease inhibitors in combination with two NRTIs; and (vii) a conventional recommended initial regimen for the therapy of established HIV infections, for example, as described in Bartlett, JG, "1998 Medical Management of HIV infection," Johns Hopkins Univ. publishers, ISBN 0-9244-2809- 0), wherein the protease inhibitor component or one or both of the NRTIs are replaced by a compound within the scope of formula (I) as described herein. Preferred methods of the present invention for therapy of HIV-infected individuals who have not responded acceptably to antiviral therapy further include as a member to select: (viii) the treatment in accordance with (i) above, in addition to the conventional recommended regimens for the therapy of such patients, for example, as described in Bartlett, JG, "1998 Medical Management of HIV infection," Johns Hopkins University publishers, ISBN 0-9244-2809-0); and (ix) a conventional recommended initial regimen for the therapy of patients who have not responded acceptably to antiretroviral therapy, for example, as described in Bartlet, JG "1998 Medical management of HIV infection", Johns Hopkins University publishers, ISBN 0-9244-2809-0), wherein one of the protease inhibitor components, or one or both of the NRTIs are replaced by a compound within the scope of formula (I) as described herein. In the combinations of the preferred embodiments described above of the present invention, the compound of formula (I) and other active therapeutic agents can be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration , either in series or simultaneously. Thus, the administration of a component can be done before, jointly or after the administration of the other component agents. The compounds of formula (I) can be administered according to a regimen of 1 to 4 times a day, preferably once or twice a day. The specific dosage level and frequency of dosing for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound used, the metabolic stability and the period of action of that compound, age, body weight, general health status, sex, diet, mode and time of administration, the rate of excretion, the combination of drugs, the severity of the particular condition and the therapy to which the host is subjected. However, in particular, the treatment of infections caused by retroviruses and, more particularly, by HIV, can be guided by the genotyping and phenotyping of the virus in the course of or prior to the initiation of administration of the therapeutic agent. In this way, it is possible to optimize dosage regimens and efficacy when administering a compound of formula (I) for the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV). The compounds of this invention can be used for the treatment of respiratory disorders that include; respiratory distress syndrome in adults (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis. The invention is further described by way of examples, but are not in any way limiting. The following general synthesis routes were used.

PROCEDURES FOR THE PREPARATION OF THE COMPOUNDS OF THE PRESENT INVENTION SYNTHESIS I n is 0 or 1 The compounds of formula III can be prepared by coupling the amino acid derivative of formula I with an acid chloride of formula II, in the presence of a tertiary amine, such as triethylamine, in a suitable solvent, such as dichloromethane , at a temperature between 0 ° C and room temperature. The compounds of formula IV can be prepared by reducing compounds of formula III, using a suitable reducing agent, preferably diisobutylaluminum hydride in dichloromethane at -78 ° C. Removal of the nitrogen protecting group (when P is a protecting group, typically benzyl, Boc, CBz or trifluoroacetate), of the amine of formula VI, can be achieved using a conventional methodology, to provide the amine of formula V. For example , Boc can be removed under protonolysis conditions using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as dichloromethane, methanol or tetrahydrofuran, at room temperature, for a period between 2 and 15 hours. Removal of a benzyl group or CBz can be achieved under conditions of catalytic transfer hydrogenation, using a catalyst such as the Pearlman catalyst, in the presence of excess ammonium formate, in a suitable solvent such as ethanol, under reflux conditions. Alternatively, a benzyl group can be removed by treatment with 1-chloroethyl chloroformate in a suitable solvent, such as dichloromethane, at a temperature between 0 ° C and room temperature. A protecting group of trifluoroacetate can be removed under basic hydrolysis conditions, using an excess of a suitable base, such as sodium hydroxide, in an alcoholic solvent, typically methanol or ethanol, at room temperature.

The compounds of general formula VII can be prepared by reductive alkylation of an appropriate amine of formula V, with an aldehyde of formula IV. The reaction can be carried out in the presence of an excess of suitable reducing agent (for example, sodium triacetoxyborohydride), in a protic solvent system (acetic acid in dichloromethane or 1,1-trichloroethane), at room temperature, for a period between 30 minutes and 18 hours. Alternatively, a compound of formula VII can be prepared in a "one step" process, by deprotection of the nitrogen protecting group of the compound of formula VI, and by the reaction of the intermediate amine V, with the aldehyde of formula IV , under reductive alkylation conditions, using the procedures described above. When a compound of formula I is required as a single enantiomer, it can be obtained according to the procedure of Davies et al., (J. Chem. Soc. Perk. Trans. I; 9; 1994; 1129).

SYNTHESIS II VIII The preparation of the compounds of formula VIII from the amino acid derivative I in which P is a suitable protective group (preferably BOC), can be achieved, for example, by reaction with di-tert-butyl dicarbonate in the presence of a base, such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran. The compounds of formula IX can be prepared by the reduction of compounds of formula VIII, according to the process described in synthesis I. The reductive alkylation of the amine of formula V, with the aldehyde of formula IX, according to the procedure described in synthesis I, it can provide the compounds of formula X. Subsequent removal of the nitrogen protecting group can be achieved, for example, using trifluoroacetic acid or hydrochloric acid in a solvent such as methanol or dichloromethane, at room temperature, over a period of 1 to 60 hours, to provide the compound of formula XI. The compounds of general formula VII can be prepared by coupling the amine of formula XI with an acid (R1CO2H), using conventional techniques of amide bond formation. For example, the acid can be activated using a carbodiimide such as 3- (3-dimethylamino-1-propyl) -1-ethylcarbodiimide, optionally in the presence of 1-hydroxybenzotriazole hydrate. These reactions can be carried out in a suitable solvent such as dichloromethane, optionally in the presence of a tertiary amine, such as triethylamine or N-ethyldiisopropylamine, at about room temperature.

SYNTHESIS lll XIV XV Compounds of the general formula XIII can be prepared by coupling the amine of formula XI with the protected amino acid of formula XII (P is a protecting group, typically BOC), using the procedures previously described in synthesis II. Removal of the nitrogen protecting group, using a conventional methodology such as protonolysis using trifluoroacetic acid, according to the procedures previously described, provides the compound of formula XIV. Alternatively, the amine of general formula XIV can be formed in a "one step" process, by coupling the amine of formula XI with the acid of formula XII, followed by deprotection of the resulting intermediate, using the procedures previously described . The compounds of formula XV can be prepared by coupling the amine of formula XIV with an acid (R3CO2H), according to the procedures described in synthesis II.

SYNTHESIS IV XVIII ix The compounds of general formula XVII can be prepared by reductive alkylation of the protected amine XVI (wherein P2 is preferably benzyl), with the aldehyde of general formula IX (wherein P1 is preferably Boc), according to the procedures previously described . Removal of the nitrogen protecting group, P1, using the conditions previously described, provides the amine of general formula XVIII. The compounds of formula XIX can be prepared by coupling the amine of formula XVIII with an acid chloride (R1COCI), in the presence of a tertiary amine, such as N-ethyldiisopropylamine, in a suitable solvent, such as dichloromethane, at room temperature . Removal of the oxygen protecting group from the compound of formula XIX using the conventional methodology provides the acid of formula XX.

Typically, removal of the benzyl group can be carried out under conditions of catalytic hydrogenation using a catalyst such as palladium on carbon, in an alcohol solvent, preferably ethanol, at a hydrogen pressure of about 1 atmosphere and at room temperature. The compounds of formula XXII can be prepared from compounds of formula XXI using conventional techniques. For example, treatment of nitrile of formula XXI, with a 5-fold excess of hydroxylamine hydrochloride, in the presence of a 5-fold excess of base, typically sodium carbonate or sodium methoxide, in a suitable solvent such as aqueous methanol, at room temperature environment, can provide compounds of formula XXII. The compounds of formula VII can be prepared by coupling the acid of formula XX with an appropriate amidoxime of formula XXII, using conventional techniques of amide bond formation, followed by in situ cyclocondensation of the intermediate product. For example, the acid can be activated using a carbodiimide, such as 3- (3-dimethylamino-1-propyl) -1-ethylcarbodiimide, optionally in the presence of N-dimethylaminopyridine. These reactions can be carried out in a solvent such as dichloromethane, optionally in the presence of a tertiary amine, such as N-methylmorpholine or N-ethyldiisopropylamine, at about room temperature. Alternatively, the acid can be activated using a fluorinating agent, such as N, N, N ', N'-bis (tetramethylene) fluoroformamydine hexafluorophosphate (JACS 1995; 117 (19); 5401) in the presence of a base such as N-ethyldiisopropylamine, in a suitable solvent such as dichloromethane at room temperature. The cyclocondensation of the resulting intermediate can be subsequently achieved by heating in an appropriate solvent, such as dioxane or toluene, at an elevated temperature (eg, 130 ° C), for a period of between 4 and 15 hours. Alternatively, a compound of formula VII can be formed in a "one-step process", by preparing the amidoxime of formula XXII from the nitrile of formula XXI, and then by coupling and cyclizing the resulting intermediate with the acid of formula XX according to the procedures described above.

SYNTHESIS V XXV XXII XXVI VI n is independently 0 or 1.

Compounds of formula VI can be prepared by coupling the protected amino acid of formula XXV (wherein P is a protective group, preferably trifluoroacetate) with an amyloxime of formula XXII, followed by cyclization of the resulting intermediate. The amino acid coupling can be achieved using procedures previously described in synthesis IV. Cyclization of the resulting O-acylamidoxylamine intermediate of formula XXVI to produce the compound of formula VI can be achieved by heating in an appropriate solvent, such as dioxane or toluene, at an elevated temperature (111 ° C) for about 18 hours. hours. Alternatively, in a variation of this "one step" procedure, the O-acylamidoxime can be isolated and then cyclized using the procedures described above.

SYNTHESIS VI XXVII XXVIII VI n is independently 0 or 1. The compound of formula XXVIII can be prepared from the protected nitrile of formula XXVII (wherein P is typically Boc), using conventional methodology. Typically, the nitrile is treated with an excess of hydroxylamine hydrochloride in the presence of a suitable excess base, such as sodium bicarbonate, in an appropriate solvent, (for example, aqueous methanol) at the reflux temperature, for about 5 hours. The compounds of formula VI can be prepared by coupling the amidoxime of formula XXVIII with the acid (R4CO2H), and the cyclization of the resulting intermediate, according to the procedures described in synthesis V.

SYNTHESIS Vil VI Ralk = d-Cß alkyl, preferably CrC2. N = independently 0 or 1. The preparation of the compounds of the formula XXX from the amine XXIX, in which P is a suitable protective group (preferably BOC), can be achieved, for example, by the reaction with di-carbonate dicarbonate. tert-butyl in the presence of a base, such as aqueous sodium hydroxide, in a suitable solvent such as dioxane or tetrahydrofuran. The hydrazide of formula XXXI can be prepared from the compound of formula XXX, using conventional methodology. For example, the alkyl ester of formula XXIX can be treated with excess hydroxylamine, in an alcohol solvent such as methanol, at the reflux temperature of the mixture. The compound of formula VI can be prepared by condensation of this hydrazide of formula XXXI with an excess of imino ether (RalkOC (NH) R4), in a suitable solvent such as ethanol, at the reflux temperature, for about 18 hours.

SYNTHESIS HIV XXXII XXXIII XXXVII The compounds of general formula XXXIII can be prepared by coupling the hydroxylamine of formula XXII with an acid (Z = OH) or acid derivative (for example, Z = Cl) of formula XXXII (Y is a functional group derived from carboxylic acid , for example, CO2Et, CN) using conventional amide bond formation techniques, as described above. Alternatively, an acyl chloride of formula XXXII can be reacted with the hydroxylamine of formula XXII in the presence of a tertiary amine, such as triethylamine or N-ethyldiisopropylamine, in a suitable solvent such as dichloromethane, at a temperature of about 10 ° C. at about room temperature. The cyclocondensation of the compounds of formula XXXIII, according to the procedures described in synthesis V, can provide the compound of formula XXXIV. In another variation, the compound of formula XXXIV can be formed in a "one-step" process, by coupling the hydroxylamine of formula XXII with the acid derivative of formula XXXII, and cyclizing the resulting intermediate, according to procedures described above. The compounds of formula XXXVI can be prepared by the reaction of the compounds of formula XXXIV, with an alkylating agent of formula XXXV (wherein P is a protective group, preferably benzyl, and L is a leaving group, such as halo and preferably chloro). This reaction can be carried out in a suitable solvent such as 2-methylpyrrolidine, in the presence of an excess of base, such as sodium hydride, additionally in the presence of a catalyst, such as tetra-n-butylammonium bromide, at an elevated temperature (for example, example, 60 ° C). The compounds of formula gXXXVII can be prepared by transformations of functional groups, from the compounds of formula XXXVI, using conventional methodology. For example, methylamide (Y '= CONHMe) can be prepared from the corresponding ethyl ester of formula XXXVI, by treatment with methylamine in a solvent such as tetrahydrofuran, in an airtight container, at elevated temperature (eg, 100 ° C) .

SYNTHESIS IX XXXVIII The preparation of the compound of formula XXXIX from the protected amino acid of formula XXXVIII (in which P is a suitable protecting group, preferably Boc), can be carried out, for example, by reaction with ethyl chloroformate, in the presence of a tertiary amine , such as triethylamine, in a suitable solvent such as dichloromethane, followed by the addition of aqueous ammonia at room temperature. Compounds of formula XXXX can be prepared by alkylation of compounds of formula XXXIX, using an excess of suitable alkylating agent, such as triethyloxonium hexafluorophosphate, in a solvent such as dichloromethane at room temperature. Compounds of formula VI can be prepared by reacting the compounds of formula XXXX with an acylating agent, typically acyl chloride (R COCL), in the presence of a tertiary amine, such as triethylamine, in a suitable solvent such as toluene, room temperature, for about an hour.

Reaction of the intermediate with an appropriate hydrazine (R5NHNH2) for a period between 5 and 18 hours at room temperature, can provide the compound of formula VI.

SYNTHESIS X XXXXI XXXXII XXXXIII VI Compounds of formula XXXXII can be prepared by the reductive alkylation of the protected carbonyl compound of formula XXXXI (P is typically benzyl), with a protected hydrazine (P2NHNH2), wherein P2 is preferably Boc, according to the procedures described above. The subsequent removal of the nitrogen protecting group using a conventional methodology, such as protonolysis using trifluoroacetic acid in dichloromethane, according to the procedures previously described, can provide the compound of formula XXXXIII. The compounds of formula XXXXIV can be prepared from the nitrile compound of formula XXI, by initial protonolisis using hydrochloric acid, in a suitable solvent such as diethyl ether, and treatment of the resulting intermediate with an alcohol, preferably methanol, at room temperature. Alternatively, the imidate of formula XXXXIV can be prepared from the corresponding bromine compound, by treatment, for example, with an excess of 1,1-tetramethylguanidine and cyanohydrin acetone in a solvent such as acetonitrile, at room temperature . The compounds of formula VI, can be prepared by coupling the hydrazine of formula XXXXIII, with the imidate of formula XXXXIV, in a suitable solvent such as dichloromethane or methanol, and cyclizing the resulting intermediate in the presence of an appropriate orthoester, typically orthoacetate of triethyl or triethyl orthoformate, at the reflux temperature. Alternatively, the compounds of formula VI can be prepared from the compounds of formula XXXXIII in a "one step" process, by deprotection of the nitrogen group, P2, coupling the product with the imidate of formula XXXXIV, and then cyclizing the intermediate according to the procedures described above. The compounds of formula VI can also be prepared according to the plethora of currently available methods. For example, the procedure of Lin et al (J. Org. Chem. 44; 23; 1979; 4160), provides 1,4-triazoles from the compounds of formula XXXIX by reaction with the N-dimethyl acetal. N-dimethylformamide and the appropriate hydrazine. Alternatively, the treatment of the compound of formula XXXIX with Lawesson's reagent, followed by the reaction of the resulting thioamide intermediate with an appropriate hydrazide according to the procedure of Bull et al. (WO 9732873) can also provide compounds of formula VI. In a further variation, the 4-piperidinamines with the protected nitrogen (eg, 1-benzyl-4-piperidinamine), can be treated with N, N-dimethylformamide azine (JACS 1995; 117; 5951), to provide compounds of formula VI . The reaction can be carried out in a suitable solvent, such as toluene, in the presence of an acid catalyst, such as p-toluenesulfonic acid, at room temperature for about 24 hours.

PREPARATION 1 Methyl 3-amino-3-phenylpropanoate hydrochloride 4 3-phenyl-α-alanine (13.0 g, 78.8 mmol) was dissolved in methanolic hydrochloric acid (200 ml, 2.25 M). The reaction was heated to reflux for 18 hours and then the cooled mixture was concentrated under reduced pressure to obtain the title compound as a yellow oil, 16.9g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 3.00-3.19 (2H, m), 3.72 (3H, s), 4.74 (1 H, t), 7.48 (5H, s).

PREPARATION 2 3-f.Ciclobutilcarbor.il) amipol-3-phenylpropanoate methyl Cyclobutanecarbonyl chloride (6.91ml, 86.7mmol) was added dropwise to a solution of the title compound of preparation 1 (16.9g, 78.8mmol) and triethylamine (24.2ml, 173.4mmol) in dichloromethane (200ml). ml) at 0 ° C. The reaction mixture was stirred for 56 hours at room temperature, after which the mixture was washed with water and then with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure to obtain the title compound in the reaction mixture. shape of a yellow oil, 20.8 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 2.00-2.10 (2H, m), 2.10-2.35 (4H, m), 2.80-3.00 (2H, m), 3.03 (1H, m), 3.62 ( 3H, s), 5.42 (1H, m), 6.50 (1H, d), 7.25-7.35 (5H, m). LRMS (low resolution mass spectroscopy) m / z 262 (MH +).

PREPARATION 3? / - (3-Oxo-1-phenylpropyl) cyclobutanecarboxamide Diisobutylaluminum hydride (42.1 ml of a 1.0 M solution in dichloromethane, 42.1 mmol) was added dropwise to a solution of the title compound of preparation 2 (5.0 g, 19.1 mmol) in dichloromethane (100 ml) at -78 ° C. C. The reaction mixture was stirred at this temperature for one hour, then methanol (5 ml) was added, pre-cooled to -78 ° C. The mixture was warmed to room temperature and washed with 2M hydrochloric acid, water and brine, dried (MgSO4) filtered and the solvent was evaporated under reduced pressure to obtain the title compound as a yellow oil, 3.3 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.81-2.35 (6H, m), 2.90-3.10 (3H, m), 5.50 (1H, m), 6.00 (1H, da), 7.23-7.39 ( 5H, m), 9.75 (1H, m). LRMS: m / z 232 (MH +).

PREPARATION Methyl 4 (3S) -3-Amino-3-phenylpropanoate A solution of tere-butyl (3S) -3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrochloric acid (100 ml) was heated to reflux for 2 hours. The mixture was cooled to room temperature, basified with a saturated sodium carbonate solution to pH 8 and the phases were separated. The aqueous layer was extracted with dichloromethane (4x), the combined organic solutions were washed with brine, dried (MgSO 4), filtered and evaporated under reduced pressure to obtain the title compound, 3.97 g. 1 H-NMR (400 MHz, CDCl 3): d [ppm] 1.70 (2H, s), 2.66 (2H, d), 3.68 (3H, s), 4.43 (1H, t), 7.25-7.40 (5H, m ). LRMS: m / z 180.3 (MH +).

PREPARATION 5 (3S) -3-r (tert-Butoxycarbonyl) amino-1-methyl-3-phenylpropanoate The title compound of preparation 4 (5.38 g, 30 mmol) and di-fer-butyl dicarbonate (8.72 g, 40 mmol) in tetrahydrofuran (50 ml) and a 2N sodium hydroxide solution (25 ml) were stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, the layers were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic solutions were washed with water and brine, dried (MgSO), filtered and evaporated under reduced pressure to obtain the title compound as a white solid, 8.39 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9H, s), 2.84 (2H, m), 3.61 (3H, s), 5.10 (1H, sa), 5.41 (1H, sa), 7.22-7.36 (5H, m). LRMS: m / z 279.7 (MH +).

PREPARATION 6 (3s) -3-r (Cyclobutylcarbonyl) amino-3-phenylpropanoate methyl Obtained from the title compound of preparation 4 and cyclobutanecarbonyl chloride as a brown solid, with a yield of 82%, using a procedure similar to that of preparation 2. 1 H-NMR (300 MHz, CDCl 3): d [ppm] 1.81-2.06 (2H, m), 2.10-2.40 (5H, m), 2.82-3.08 (2H, m), 3.62 (3H, s), 5.42 (1H, m), 6.42 (1H, d) , 7.22-7.38 (5H, m).

PREPARATION 7 (1S) -3-Oxo-1-phenylpropylcarbamate tere-butyl The diisobutylaluminium hydride (1 M in dichloromethane, 60 ml, 60 mmol) was cooled to -78 ° C and added dropwise to a solution of the title compound of preparation 5 (8.39 g, 30 mmol) in dichloromethane (150 ml) at -78 ° C. The reaction was stirred for 90 minutes, then methanol (pre-cooled to -78 ° C) (40 ml) was added. The mixture was allowed to warm to room temperature and poured into 2 M hydrochloric acid (200 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a white solid, 6.72 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.42 (9H, s), 2.86-3.00 (2H, m), 5.06 (1H, sa), 5.20 (1H, sa), 7.22-7.38 ( 5H, m), 9.75 (1 H, s). LRMS: m / z 250.1 (MH +).

PREPARATION 8? / - r (1 S) -3-Oxo-1-phenylpropylcyclobutanecarboxamide Obtained from the title compound of preparation 6 in the form of a brown oil, with a yield of 82%, using a procedure similar to that of preparation 7. 1 H-NMR (300 MHz, CDCl 3): d [ppm] 1.81 -2.35 (6H, m), 2.90-3.10 (3H, m), 5.53 (1H, m), 5.98 (1H, da), 7.23-7.39 (5H, m), 9.78 (1H, m).

PREPARATION Tere-Butyl 9 (E) -3- (3-fluorophenyl) -2-propenoate To a solution of 3-fluorobenzaldehyde (10.0 g, 80 mmol) in tetrahydrofuran (350 ml) was added 2- (triphenylphosphoranylidene) -ebutyl acetate (27.6 g, 73 mmol) in 1 g portions over 30 minutes. After the final addition, the mixture was heated to reflux for 10 minutes. The solvent was removed under reduced pressure and the solid residue was triturated with pentane (x2). The pentane extracts were combined and evaporated under reduced pressure. The residue was purified by filtration through a short pad of silica gel, using diethyl ether: hexane (1: 2) as eluent, obtaining the title compound as a colorless oil, 16.2 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.52 (9H, s), 6.32-6.39 (1 H, d), 7.00-7.06 (1 H, m), 7.16-7.21 (1 H, m), 7.26-7.29 (1 H, m), 7.29-7.37 (1H, m), 7.48-7.55 (1 H, d).

PREPARATION 10 (3S) -3-. { Benzir (1 R) -1-phenylethyl-1-amino) -3- (tert-butyl 3-fluorophenpropanoate) To a solution of (1 R) -? / - benzyl-1-phenyl-1-ethanamine (23.1 g, 109 mmol) in tetrahydrofuran (100 ml) at -10 ° C was added dropwise n-butyl lithium (66). ml of a 1.6 M solution in hexane, 105 mmol). The purple solution was stirred for 15 minutes, cooled to -78 ° C and a solution of the title compound of preparation 9 (18.6 g, 84 mmol) in tetrahydrofuran (100 ml) was added dropwise. After stirring for 30 minutes, the mixture was quenched with a saturated solution of ammonium chloride (100 ml) and stirred at room temperature. The mixture was extracted with diethyl ether (x2) and the combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was dissolved in diethyl ester and washed with 1 M citric acid (x2) and then with water, dried (MgSO4), filtered and evaporated under reduced pressure. The pale yellow oily residue was purified by column chromatography on silica gel using a gradient elution of diethyl ether: hexane (0: 100 to 5:95) to obtain the title compound as a colorless oil, 23.0 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.19-1.32 (3H, m), 1.23 (9H, s), 2.42-2.52 (2H, m), 3.68 (2H, s), 3.90-4.00 (1 H, m), 4.35-4.42 (1 H, m), 6.89-6.97 (1 H, m), 7.10-7.35 (11 H, m), 7.35-7.42 (2H, m). LRMS: m / z 434.5 (MH +) PREPARATION 11 (3S) -3-Amino-3- (3-fluorophenyl) propanoate methyl A mixture of the title compound of preparation 10 (23.0 g, 53 mmol), ammonium formate (33.5 g, 531 mmol) and 20% palladium hydroxide on carbon (12.5 g) was heated to reflux in ethanol for 30 minutes ( 500 ml). The reaction was cooled and filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The residue (16.3 g, 68 mmol) was refluxed for 1 hour in methanolic hydrochloric acid (100 ml, 2.5 M). The mixture was evaporated under reduced pressure and the resulting solid was triturated with ethyl acetate to obtain the title compound as a white solid, 4.40 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 3.00-3.16 (2 H, m), 3.71 (3 H, s), 4.74-4.81 (1 H, m), 7.13-7.23 (1 H, m), 7.24 -7.34 (2H, m), 7.44-7.53 (1H, m).

LRMS: m / z 198.2 (MH +) PREPARATION 12 (3S) -3-r (tert-butoxycarbonyl) amino1-3- (3-fluorophenyl) propanoate methyl To a suspension of the title compound of preparation 11 (3.81 g, 16.3 mmol) in tetrahydrofuran (50 ml) was added di-fer-butyl dicarbonate (4.26 g, 19.5 mmol) and 2 M aqueous sodium hydroxide (20 ml). The mixture was stirred for 16 hours at room temperature. The mixture was diluted with water and extracted with diethyl ether (x3), the combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by recrystallization from hexane to obtain the title compound as a white solid, 4.10 g. 1 H NMR (400 MHz, CHCl 3): d [ppm] 1.40 (9H, s), 2.76-2.89 (2H, m), 3.63 (3H, m), 5.01-5.13 (1H, m), 5.42-5.65 ( 1 H, sa), 6.90-6.97 (1 H, m), 6.97-7.02 (1 H, m), 7.03-7.10 (1 H, m), 7.26-7.32 (1 H, m).

PREPARATION 13 1 - (tert-butoxycarbonyl) -3-azetidinocarboxylic acid Di- tert -butyl dicarbonate (3.02 g, 13.8 mmol) was added to a suspension of 3-azetidinocarboxylic acid (1 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol) in water (18 ml) and dioxane ( 18 ml) at 0 ° C with stirring and allowed to warm to room temperature. The reaction was stirred for 15 hours and then concentrated under reduced pressure. The residue was acidified to pH 4 by the addition of a 1M citric acid solution and extracted with dichloromethane (x3). The combined organic extracts were washed with water and then with brine, dried (MgSO), filtered and the solvent was evaporated under reduced pressure to obtain the title compound as a white solid, 2.10 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.44 (9H, s), 3.38 (1 H, m), 4.14 (4H, m).

PREPARATION 14 1-Acetyl-3-azetidinocarboxylic acid 3-azetidinocarboxylic acid (2.25 g, 22.2 mmol) and acetic anhydride (80 ml) were gently heated until all the acid was dissolved. The reaction was stirred at room temperature for 18 hours and then the acetic anhydride was removed under reduced pressure. Water was added and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate, filtered still hot and the filtrate was evaporated under reduced pressure to obtain the title compound as a white solid, 1.54 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 1.84 (3 H, s), 3.37-3.50 (1 H, m), 4.40-4.09 (1 H, m), 4.12-4.18 (1 H, m), 4.23 -4.41 (2H, m). LRMS: m / z 142.1 (MH +) PREPARATION 15 1-r (tert-butoxycarbonyl) amino-1-cyclopentanecarboxylic acid 1-Aminocyclopentanecarboxylic acid (1.00 g, 7.74 mmol), di-butyl dicarbonate (3.85 g, 17.6 mmol) and potassium carbonate (2.28 g, 16.5 mmol) were stirred together for 16 hours at room temperature in dioxane (20 ml. ) and water (20 ml). The solvents were removed under reduced pressure and the residue was acidified with a 1M citric acid solution and extracted with dichloromethane (x3). The organic solutions were dried (MgSO 4), filtered and evaporated under reduced pressure to obtain an oil that crystallized upon standing, it was triturated with hexane to obtain the title compound as a white solid, 1.26 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.4 (9H, s), 1.74-1.81 (4H, m), 1.85-1.97 (2H, m), 2.20-2.32 (2H, m).

PREPARATION 16 4- (Methoxymethylene) tetrahydro-2H-pyran Tetrahydro-4H-pyran-4-one (5.00 g, 50 mmol) was dissolved in tetrahydrofuran (205 ml) and cooled in an ice water bath. To this solution was added n-butyl lithium (24 ml of a 2.5 M solution in hexane, 60 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. This was then cooled to 0 ° C and a solution of (methoxymethyl) triphenyl phosphonium chloride (25.6 g, 75 mmol) in tetrahydrofuran (10 ml) was added and the reaction was stirred for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (10x), decanting the supernatant each time. The supernatants were then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of pentane: ethyl acetate (95: 5 to 90:10) to obtain the title compound, 1.80 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.05 (2H, t), 2.30 (2H, t), 3. 50 (3H, s), 3.60 (4H, m), 5.80 (1 H, s). LRMS: m / z 146 (MNH4 +) PREPARATION 17 Tetrahydro-2H-pyran-4-carboxylic acid To a stirred solution of the title compound of Preparation 16 (1.80 g, 14.0 mmol) in acetone was added 1 M hydrochloric acid (1 mL) at room temperature and the mixture was stirred for 3 hours. Then, the solution was diluted with more acetone and Jones's reagent was added until the solution became permanently brown. Then, the reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel, using ethyl acetate: pentane (75:25) as eluent, obtaining the title compound as a white solid, 1.18 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.85 (4H, m), 2.25 (1 H, m), 3. 45 (2H, m), 3.99 (2H, m), 11.10 (1 H, s a). LRMS: m / z 129 (M-H ") PREPARATION 18 1-Hydroxycyclobutanecarboxylic acid N-Butyl lithium (96 ml of a 2.5 M solution in hexane, 240 mmol) was added dropwise to a solution in tetrahydrofuran (400 ml) of diisopropylamine (34 ml, 240 mmol) at -78 ° C. The reaction was warmed to 0 ° C and a solution of cyclopentanecarboxylic acid (6.64 g, 66 mmol) in tetrahydrofuran (100 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 6 hours. The reaction was cooled to 10 ° C, oxygen was bubbled through it for 15 minutes and stirred for 1 hour, then 10% aqueous sodium sulfite was added in one portion and the reaction was warmed to room temperature. The reaction was diluted with water (200 ml) and extracted with ether (5x). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a white solid, 1.16 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.98 (2 H, m), 2.34 (2 H, m), 2.56 (2 H, m), 6.35 (1 H, s a). LRMS: m / z 231 (2M-H ") PREPARATION 19 1-Methoxycyclobutanecarboxylic acid Sodium hydride (60% dispersion in oil, 1.20 g, 30 mmol) was added, in one portion, to a solution in tetrahydrofuran (100 ml) of the title compound of preparation 18 (1.16 g, 10 mmol) and iodomethane ( 1.86 ml, 30 mmol) at 0 ° C. The reaction was allowed to warm to room temperature and was stirred for 5 days. The solvent was removed under reduced pressure and 2 M hydrochloric acid (100 ml) was added. The aqueous mixture was extracted with diethyl ether (3x) and the combined organic solutions were dried (MgSO), filtered and evaporated under reduced pressure to obtain a clear oil. The oil was purified by column chromatography on silica gel, using dichloromethane: methanol: acetic acid (90: 10: 1) as eluent, obtaining the title compound as an orange solid, 1.11 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.98 (2H, m), 2.28 (2H, m), 2.54 (2H, m), 3.38 (3H, s).

PREPARATION 20 1- (2,2,2-Trifluoroacetyl) -4-piperidinecarboxylic acid Trifluoroacetic anhydride (32.5 g, 155 mmol) was added dropwise to a suspension of 4-piperidinocarboxylic acid (16.7 g, 130 mmol) in dichloromethane (900 ml) at 0 ° C and stirred for 12 hours. The reaction mixture was washed with water and brine, dried (MgSO), filtered and evaporated under reduced pressure to obtain the title compound as a white solid, 10.0 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.80 (2H, m), 2.05 (2H, m), 2.65 (1 H, m), 2.80 (1 H, m), 3.10 (1 H, m) , 3.30 (1 H, m), 3.95 (1 H, m), 4.30 (1 H, m). LRMS: m / z 224 (2M-r?) PREPARATION 21 2.2.2-Trifluoro-1-4 4-3 3-methyl-1, 2,4-oxadiazol-5-ll) -1-piperidinyl-1-ethanone The title compound of preparation 20 (1.00 g, 4. 44 mmol) to a solution of? / '-hydroxy-acetamidine (362 mg, 4.88 mmol) [Chem. See, (1984), 17; 2746] and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.02 g, 5.33 mmol) in dichloromethane (20 ml) and the reaction was stirred at room temperature for 18 hours. Afterwards, the mixture was washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to obtain a clear oil. This intermediate was dissolved in toluene (30 ml) and heated to reflux with continuous removal of water for 18 hours. The cooled solution was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using ethyl acetate: hexane (50:50) as eluent, yielding the title compound as an oil, 590 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.88-2.05 (2H, m), 2.20 (2H, m), 2.40 (3H, s), 3.13-3.48 (3H, m), 4.01 (1H, d), 4.37 (1 H, m).

PREPARATION 22 2.2.2 -Trifluoro-1 -4- (3-phenyl-1 -2,4-oxaziazol-5-yl) -1-piperidinin-1-ethanone It was obtained from the title compound of preparation 20 and? / '- hydroxybenzenecarboximidamide [Tetrahedron, (1997), 53 (5), 1787-1796] as a brown oil, with a yield of 82%, using a procedure similar to that of preparation 21. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.04 (2H, m), 2.26 (2H, m), 3.20-3.51 (3H, m), 4.08 (1 H, m ), 4.20 (1 H, m), 7.49 (3H, m), 8.09 (2H, m). LRMS: m / z 343 (MNH4 +) PREPARATION 23 1-4-R ( {Amino (4-methoxyphenyl) methylidene-amino) -oxi) carbonn-1-piperidinyl > - 2.2.2 -trifluoro-1 -ethanone N-methylmorpholine (0.32 ml, 2.92 mmol), 4-dimethylaminopyridine (81 mg, 0.66 mmol) and 1- (3-dimethylamopropyl) -3-ethylcarbodiimide hydrochloride (306 mg, 1.59 mmol) were added. to a suspension of the title compound of preparation 20 (299 mg, 1.33 mmol) and N-hydroxy-4-methoxybenzamide [Chem. Ber; (1889), 22; 2791] (268 mg, 1.33 mmol) in dichloromethane (20 ml) and the reaction was stirred at room temperature for 40 minutes. The reaction mixture was washed with a 1M citric acid solution, a saturated aqueous sodium bicarbonate solution, water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a yellow foam, 320 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.94 (2 H, m), 2.11 (2 H, m), 2.88 (1 H, m), 3.16 (1 H, m), 3.35 (1 H, m) , 3.61 (3H, s), 4.02 (1 H, m), 4.37 (1 H, m), 4.99 (2H, s), 6.94 (2H, d), 7.64 (2H, d). LRMS: m / z 391 (MNH4 +) PREPARATION 24 2.2.2-Trifluoro-1-r4- (3- (4-methoxyphenyl) -1,2,4-oxadizol-5-yl) -1-piperidinyl-1-ethanone A solution of the title compound of preparation 23 (137 mg, 0.85 mmol) in toluene (65 ml) was heated to reflux with continued removal of water for 18 hours and the cooled mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of pentane: dichloromethane: methanol: 0.88 ammonia (50: 50: 0: 0 to 0: 98: 1: 0.3) to obtain the title compound in Form of a transparent oil, 197 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.98-2.15 (2H, m), 2.26 (2H, m), 3.22-3.52 (3H, m), 3.88 (3H, s), 4.06 (1H, m), 4.39 (1 H, m), 7.00 (2H, d), 8.01 (2H, d). LRMS: m / z 356 (MH +) PREPARATION 25 2.2.2-Trifluoro-1-r4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl-1-ethanone Obtained from the title compounds of preparations 20 and 56 in the form of an oil, with a yield of 11%, using a procedure similar to that of preparation 21. 1 H NMR (300 MHz, CDCl 3): d [ppm ] 1.81-2.02 (2H, m), 2.18 (2H, m), 3.09-3.42 (3H, m), 3.94-4.08 (3H, m), 4.36 (1H, m), 7.31 (5H, m). LRMS: m / z 357 (MH +) PREPARATION 26 4-ethyl-1,4-piperidinedicarboxylic acid 1-f tere-butyl) A solution of 1 M sodium hydroxide (50 ml, 50.0 mmol) was added to a solution of ethyl 4-piperidinocarboxylate (10.0 g, 63.6 mmol) and di-fer-butyl dicarbonate (16.7 g, 76.3 mmol) in dioxane ( 50 ml). The reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated under reduced pressure and the residue was acidified with 2M hydrochloric acid. The aqueous solution was extracted with ethyl acetate (x3), the combined organic extracts were washed brine, dried (MgSO 4), filtered and evaporated under reduced pressure to obtain the title compound as a colorless oil, 16.7 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.23 (3 H, t), 1.47 (9 H, s), 1.58-1.71 (2 H, m), 1.83 (2 H, m), 2.45 (1 H, m) , 2.78-2.88 (2H, m), 4.09 (2H, m), 4.15 (2H, q). LRMS: m / z 258 (MH +) PREPARATION 27 4- (Hydrazinocarbonyl) -1-piperidinocarboxylate tere-butyl Hydrazine hydrate (5 ml) was added to a solution of the title compound of preparation 26 (4.96 g, 19.3 mmol) in methanol (50 ml) and the reaction was heated to reflux for 48 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using ethyl acetate: methanol (95: 5) as eluent, obtaining the title compound as a white crystalline solid, 3.72. g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.40-1.58 (9H, sa), 1.60-1.85 (4H, m), 2.20-2.33 (1 H, m), 2.62-2.85 (2H, m), 4.15 (2H, m). LRMS: m / z 243 (MH +) PREPARATION 28 tere-butyl 4- (hydroxyimino) metin-1-piperidinecarboxylate A mixture of fer-butyl 4-cyano-1-piperidinecarboxylate (2.69 g, 12.8 mmol), hydroxylamine hydrochloride (4.45 g, 64 mmol) and sodium carbonate (6.78 g, 64 mmol) in water (40 ml) and methanol (40 ml) was heated to reflux for 5 hours. The cooled mixture was concentrated under reduced pressure and the remaining aqueous solution was extracted with ethyl acetate (3x). The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to obtain the title compound as a white solid, 2.60 g. H NMR (300 MHz, CDCl 3): d [ppm] 1.38-1.62 (11 H, m), 1.80 (2 H, m), 2.26 (2 H, m), 2.76 (2 H, m), 4.16 (2 H, m) , 4.58 (2H, s).

PREPARATION 29 4- (Tere-Butyl Aminor (benzoyloxy) imino-1metM.} -1-piperidinocarboxylate N-methylmorpholine (1.08 ml, 9.86 mmol), benzoic acid (1.10 g, 9.04 mmol), 4-dimethylaminopyridine (502 mg, 4.11 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.89 g) were added. , 9.86 mmol) was added to a solution of the title compound of Preparation 28 (2.00 g, 8.22 mmol) in dichloromethane (100 mL) and the reaction was stirred at room temperature for 16 hours. The mixture was washed with a 1M citric acid solution, a saturated aqueous sodium bicarbonate solution, water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a white foam. 1.84 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.46 (9H, s), 1.57-1.72 (2H, m), 1.94 (2H, m), 2.60 (1 H, m), 2.78 (2H, m) , 4.23 (2H, m), 4.80 (2H, s), 7.46 (2H, m), 7.58 (1H, m), 8.02 (2H, d).

PREPARATION 30 4- (Amino (f (2-phenylacetyl) oxylimino) mettl) -1-piperidinocarboxylate tert -butyl Obtained from the title compound of preparation 28 and phenylacetic acid in the form of a white foam, with a yield of 69%, using a procedure similar to that of preparation 29. 1 H NMR (300 MHz, CDCl 3): d [ppm ] 1.45 (9H, s), 1.55 (2H, m), 1.82 (2H, m), 2.44 (1H, m), 2.72 (2H, m), 3.78 (2H, s), 4.19 (2H, m) , 4.51 (2H, s), 7.31 (5H, m).

PREPARATION 31 4- tere-butyl 4- (3-methyl-1,2,4-oxadiazol-5-yl) -1-piperidinocarboxylate Glacial acetic acid (0.67 ml, 11.7 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.46 g, 12.8 mmol) 4-dimethylaminopyridine (635 mg, 5.54 mmol) and N-methylmorpholine ( 1.41 mL, 12.8 mmol) was added to a solution of the title compound of Preparation 28 (2.60 g, 10.7 mmol) in dichloromethane (100 mL) and the reaction was stirred at room temperature for one hour. The reaction was washed consecutively with a solution of 1 M citric acid, a saturated aqueous solution of sodium bicarbonate and water, dried (MgSO 4), filtered and evaporated under reduced pressure to give a yellow oil. A solution of this product in toluene (30 ml) was heated to reflux for 24 hours and then cooled. The solution was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using ethyl acetate: pentane (50:50) as eluent, obtaining the title compound as a clear oil, 1.10 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.47 (9H, s), 1.66-1.81 (2H, m), 1.98 (2H, m), 2.58 (3H, s), 2.92 (3H, m), 4.12 (2H, m). LRMS: m / z 268 (MHf PREPARATIONS 32 TO 33 The compounds of the following preparations presented in the table: were prepared from the corresponding amidoxime esters, using procedures similar to those described in preparation 24. 1 = isolated without column chromatography PREPARATION 34 4- (tere-butyl 5-methyl-1, 3,4-oxadiazol-2-yl) -1-piperidinocarboxylate Ethyl acetimidate hydrochloride (2.35 g, 19.0 mmol) was added to a solution of the title compound of Preparation 27 (1.83 g, 7.60 mmol) in ethanol (30 mL). The reaction mixture was heated to reflux for 18 hours and then cooled, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5: 0.5) to obtain the title compound as a clear oil ( 1.62 g). 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.45 (9H, s), 1.70-1.85 (3H, m), 2.04 (2H, m), 2.50 (3H, s), 2.92-3.06 (2H, m ), 4.08 (2H, m). LRMS: m / z 290 (MH +) PREPARATION 35 4- (5-phenyl-1, 3,4-oxadiazol-2-yl) -1-piperidinocarboxylate tere-butyl Obtained from the title compound of preparation 27 and ethyl benzoimidate hydrochloride as a white solid, with a yield of 69%, using a procedure similar to that of preparation 34. LRMS: m / z 330 (MH +) PREPARATION 36 4- (5-Benzyl-1, 3,4-oxydiazol-2-yl) -1-piperidinocarboxylate tere-butyl Obtaining from the title compound of preparation 27 and ethyl 2-phenylacetimidate in the form of an oil, with a yield of 99%, using a procedure similar to that of preparation 34. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.45 (9H, s), 1.68-1.82 (2H, m), 2.00 (2H, m), 2.84-3.06 (3H, m), 4.01-4.19 ( 4H, m), 7.22-7.40 (5H, m).

PREPARATION 37 4- (3-Phenyl-1,2,4-oxadiazol-5-yl) piperidine A mixture of the title compound of preparation 22 (520 mg, 1.6 mmol) and sodium hydroxide (96 mg, 2.40 mmol) in ethanol (10 ml) was stirred at room temperature for 2 hours. The reaction was evaporated under reduced pressure and the residue was triturated with ethyl acetate and dichloromethane. The suspension was filtered and the filtrate was evaporated under reduced pressure to obtain the title compound as a white solid, 340 mg. 1 H NMR (300 MHz, CD3OD): d [ppm] 1.78-1.92 (3H, m), 2.13 (2H, m), 2.77 (2H, t), 3.02-3.35 (3H, m), 7.48 (3H, m), 8.04 (2H, m). LRMS: m / z 230 (MH +).

PREPARATION 38 4-. { 3- (4-Methoxyphenyl) -1,2,4-oxadiazol-5-yl} piperidine Obtained from the title compound of preparation 24, with a quantitative yield, using a procedure similar to that of preparation 37 except that the product was isolated without trituration. LRMS: m / z 260 (MH +).

PREPARATION 39 4- (3-Benzyl-1,2,4-oxadiazol-5-yl) piperidine Obtained from the title compound of preparation 25 in the form of an oil, with a yield of 99%, using a procedure similar to that of Preparation 37. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.80 (2H, m), 2.05 (2H, m), 2.75 (2H, m), 3.05 (1H, m), 3.15 (2H, m), 4.05. (2H, s), 7.35 (5H, m). LRMS: m / z 244 (MH +).

PREPARATION 40 4- (5-Methyl-1,2,4-oxadiazol-3-yl) piperidine hydrochloride Hydrogen chloride gas was bubbled through an ice-cooled solution of the title compound of Preparation 31 (1.10 g, 4.12 mmol) in dichloromethane (30 mL) for 30 minutes. The reaction mixture was evaporated under reduced pressure and the solid was triturated with ether. The solid was filtered and dried to obtain the title compound as a white solid, 670 mg. 1 H NMR (300 MHz, CD 3 OD): d [ppm] 1.95-2.08 (2H, m), 2.25 (2H, m), 2.58 (3H, s), 3.19 (3H, m), 3.44 (2H, m). LRMS: m / z 168 (MH +).

PREPARATIONS 41 TO 44 The compounds of the following preparations presented in the table: were prepared from the corresponding t-butyl piperidinocarboxylates, using procedures similar to those described in preparation 40.

PREPARATION 45 4- (5-Phenyl-1, 3,4-oxidazole-2-yl) piperidine The title compound was prepared by a procedure similar to that of preparation 40, from the title compound of preparation 35. The crude product was basified with 0.88 ammonia and purified by column chromatography on silica gel, using a gradient of solvent of dichloromethane: methanol: 0.88 ammonia (95: 5: 1 to 90: 10: 1) yielding the title compound as an oil, 300 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.66-1.95 (3H, m), 2.47 (2H, d), 2.78 (2H, t), 3.02-3.24 (3H, m), 7.43 (3H, m ), 8.00 (2H, m). LRMS: m / z 230 (MH +).

PREPARATION 46 2- (3-Aminophenyl) acetonitrile 3-Nitrophenylacetonitrile (6.87 g, 42 mmol) and tin (II) chloride dihydrate (50 g, 220 mmol) in ethyl acetate (125 ml) were stirred at room temperature for 72 hours. The reaction was diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. The resulting precipitate was separated by filtration and the filtrate was extracted with ethyl acetate (3x). The combined organic solutions were dried (MgSO), filtered and evaporated under reduced pressure to obtain the title compound as a pale yellow oil, 5.33 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 3.59 (2 H, s), 3.78 (2 H, s a), 6.57-6.63 (3 H, m), 7.09-7.15 (1 H, m). LRMS: m / z 132 (MH +).

PREPARATION 47? / - r4- (Cyanomethyl) phenanmethanesulfonamide Methanesulfonyl chloride (3.22 mL, 41.6 mmol) was added dropwise to a solution of 4-aminobenzyl cyanide (5.00 g, 37.8 mmol) and triethylamine (5.79 mL, 41.6 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 1 hour and then poured into water, the organic layer was separated, dried (MgSO4), filtered and the solvent was removed under reduced pressure to obtain the title compound as a pale orange solid. 6.50 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 3.05 (3H, s), 3.79 (2H, s), 6. 60 (1H, s), 7.21 (2H, d), 7.35 (2H, d). LRMS: m / z 228 (MNH4 +).

PREPARATIONS 48 TO 49 The compounds of the following preparations presented in the table: O RN-S-H »N O were prepared from the corresponding anilines, using procedures similar to those described in preparation 47.

PREPARATION 50 3- (Cyanomethyl) benzenesulfonamide A solution of the title compound of Preparation 46 (5.00 g, 37.8 mmol) in concentrated hydrochloric acid (13 mL) and glacial acetic acid (38 mL) was cooled to 0 ° C and sodium nitrite (2.80 g) was added dropwise. , 40.5 mmol) in water (4 ml). Once the addition was complete, a suspension of copper (I) chloride (1.50 g, 15.0 mmol) and sulfur dioxide (10.0 g) in glacial acetic acid (30 mL) was added and the reaction was stirred for 1 hour at 0 ° C. The reaction was poured into ice and the yellow solid was collected by filtration, dissolved in 0.88 ammonia (30 ml) and stirred for 1 hour. The title compound was collected by filtration as a yellow solid and dried under vacuum, 5.80 g. 1 H NMR (300 MHz, DMSOd 6): d [ppm] 4.18 (2H, s), 7.34 (2H, s a), 7.58 (2H, m), 7.78 (2H, m). LRMS: m / z 214 (MNH4 +) PREPARATION 51 3- (Cyanomethyl) benzoate methyl 1,1-Tetramethylguanidine (3.21 ml, 25.6 mmol) was added dropwise to a solution of methyl 3-bromomethylbenzoate (2.80 g, 12.2 mmol) and cyanohydrin acetone (1.59 ml, 18.3 mmol) in acetonitrile ( 40 ml) at room temperature. The reaction was stirred for 3 days and the solvent was then removed under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel using ethyl acetate: pentane (50:50) as eluent, yielding the title compound as a clear oil, 1.80 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 3.79 (2H, s), 3.93 (3H, s), 7. 48 (1 H, dd), 7.58 (1 H, d), 8.02 (2H, m). LRMS: m / z 198 (MNa +).

PREPARATION 52 3- (Cyanomethyl) benzoic acid Sodium hydroxide (822 mg, 20.6 mmol) was added, in one portion, to a solution of the title compound of Preparation 51 (1.80 g, 10.3 mmol) in tetrahydrofuran (6 mL) and water (2 mL) at room temperature. The reaction was stirred for 5 hours and then poured into 2 M hydrochloric acid (20 ml) and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were dried (MgSO), filtered and the solvent was evaporated under reduced pressure to give the title compound as a white solid, 1.45 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 3.79 (2H, s), 7.48 (1 H, dd), 7. 61 (1 H, d), 8.03 (2H, m). LRMS: m / z 160 (M-H ").

PREPARATION 53 4- Methyl (Cyanomethyl) benzoate Obtained from methyl 4- (bromomethyl) benzoate as a yellow solid, with a yield of 77%, using a procedure similar to that of preparation 51. 1 H NMR (400 MHz, CDCl 3): d [ppm] 3.80 (2H, s), 3.93 (3H, s), 7.20 (2H, d), 8.17 (2H, d).

PREPARATION 54 4- (Cyanomethyl) benzoic acid Obtained from the title compound of Preparation 53 in the form of a yellow solid, in a yield of 97%, using a procedure similar to that of Preparation 52. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 3.98 (2 H, s), 7.49 (2 H, d), 8. 02 (2H, d). LRMS: m / z 160.0 (MH-).

PREPARATION 55 4- (Cyanomethyl) benzamide The composition of the title of preparation 54 (9.66 g, 60 mmol) in dichloromethane (250 ml) and cooled to 0 ° C. Oxalyl chloride (5.34 ml) was added, 61 mmol) followed by the dropwise addition of N, N-dimethylformamide (0.25 ml). The reaction was stirred at room temperature for 2 hours and then evaporated under reduced pressure to obtain a yellow solid. This residue was dissolved in tetrahydrofuran (100 ml) and 0.88 ammonia (5 ml) was added dropwise. After stirring for a further 10 minutes, the resulting precipitate was filtered off to obtain the title compound as a white solid, 6.74 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 3.97 (2 H, s), 7.48 (2 H, d), 7.89 (2 H, d). LRMS: m / z 161.1 (MH +).

PREPARATION 56? T-Hydroxy-2-phenylethanimidamide Phenylacetonitrile (20 g, 170 mmol), hydroxylamine hydrochloride (60 g, 850 mmol) and sodium carbonate (71 g, 850 mmol) in methanol (300 ml) and water (300 ml) were heated at reflux for 5 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated and extracted with dichloromethane (3x). The combined organic solutions were washed with water and brine, dried (MgSO), filtered and concentrated under reduced pressure to give the title compound as a white solid, 15.5 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 3.70 (2H, s), 7.30 (5H, m). LRMS: m / z 151 (MH +).

PREPARATIONS 57 TO 63 The compounds of the following preparations presented in the table: were prepared from the corresponding commercial nitriles, using procedures similar to those described in preparation 56.

PREPARATION 64 2- [4- (Aminosulfonyl) phenp- ?. -hydroxyethanimidamide Obtaining from 4- (cyanomethyl) benzenesulfonamide [J. Med. Chem., (1965), 8, 548] and hydroxylamine hydrochloride as a solid, with a yield of 7%, using a procedure similar to that described in Preparation 56. 1 H NMR (400 MHz, CD3OD): d [ppm] 3.42 (2H, s), 3.60 (1 H, s), 7.43 (2H, m), 7.81 (2H, d). LRMS: m / z 230 (MH +).

PREPARATION 65 2-y3-Aminosulfonyl) phenyl1- / V-hydroxyethanimidamide Obtained from the title compound of preparation 50 and hydroxylamine hydrochloride as a solid, with a yield of 52%, using a procedure similar to that of Preparation 56. 1 H NMR (300 MHz, DMSOd 6): d [ppm ] 5.43 (2H, s), 7.21 (2H, s), 7.45 (2H, m), 7.62 (1 H, m), 7.71 (1 H, s), 8.95 (1 H s). LRMS: m / z 230 (MH +).

PREPARATION 66 / V'-Hydroxy-2-f-3r (methylsulfonyl) amino-phenyl> > Ethanimidamide Obtained from the title compound of preparation 49 and hydroxylamine hydrochloride, in a yield of 21%, using a procedure similar to that of Preparation 56. 1 H NMR (400 MHz, CD3OD): d [ppm] 2.93 (3H, s), 3.38 (2H, s), 7.03-7.12 (2H, m), 7.19 (1 H, s), 7.30 (1 H, m). LRMS: m / z 243.9 (MH +).

PREPARATION 67 2- (1-Benzofuran-5-yl) -? -hydroxyethanimidamide Obtained from 2- (1-benzofuran-5-yl) acetonitrile [Chim. Ther. (1972), 7 (4), 337] and hydroxylamine hydrochloride in the form of a solid, with a yield of 31%, using a procedure similar to that of Preparation 56. 1 H NMR (400 MHz, CD3OD): d [ppm ] 3.50 (2H, s), 6.80 (1H, d), 7.25 (1H, d), 7.40 (1H, d), 7.50 (1H, s), 7.70 (1H, s). LRMS: m / z 191.2 (MH +).

PREPARATION 68 2- (4-Acetyl-1-piperazinyl) acetonitrile Chloroacetonitrile (14.7 ml, 234 mmol) was slowly added to a well-stirred suspension of sodium carbonate (32 g, 300 mmol) and acetylpiperazine (30 g, 230 mmol) in toluene (200 ml). The mixture was refluxed for 3 hours. The reaction was cooled, filtered and the filtrate was evaporated under reduced pressure. The resulting solid was recrystallized from ethyl acetate to obtain the title compound as a yellow solid, 18.6 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 2.09 (3H, s), 2.58 (4H, m), 3. 51 (4H, m), 3.67 (2H, m).

PREPARATION 69 2- (4-AcThyl-1-piperazinyl) -? F -hydroxyethanimidamide Sodium methoxide (6.6 g, 67 mmol) was added to the title compound of Preparation 68 (18.6 g, 111 mmol) and hydroxylamine hydrochloride (8.5 g, 122 mmol) in methanol (200 mL). The mixture was refluxed for 15 hours. The reaction was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to obtain the title compound as a white solid, 23.8 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 2.07 (3H, s), 2.43 (4H, m), 2. 95 (2H, s), 3.59 (4H, m). LRMS: m / z 223 (MNa +).

PREPARATION 70 4- (3-r4-Trifluoromethoxy) benzp-1, 2,4-oxadiazol-5-yl) -1 • tere-butyl piperidinocarboxylate 1- (Fer-butoxycarbonyl) -4-piperidinocarboxylic acid (250 mg, 1.09 mmol) in dichloromethane (5 ml) was treated with diisopropylethylamine (0.28 ml), 2.70 mmoles). Bís (tetramethylene) fluoroformamidinio hexafluorophosphate (413 mg, 1.31 mmol) in dichloromethane (5 ml) was added and the solution was stirred at room temperature for 1 hour. The title compound of Preparation 63 (307 mg, 1.31 mmol) and diisopropylamine (0.23 mL, 1.09 mmol) in dichloromethane (2 mL) were added, the resulting solution was stirred at room temperature for 16 hours and then warmed to 50 ° C to concentrate the solution. Dioxane (10 ml) was added and the solution was heated at 120 ° C for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and a solution of 1M citric acid. The combined organic solutions were dried (MgSO4), filtered and evaporated. reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate: pentane (25:75) as eluent, yielding the title compound as an oil, 306 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9 H, s), 1.80 (2 H, m), 2.02 (2 H, m), 2.94 (2 H, m), 3.12 (1 H, m), 4.08 (2H, s), 4.16 (2H, m), 7.15 (2H, d), 7.35 (2H, d). LRMS: m / z 427.4 (MH +) PREPARATION 71 4-r3- (1-Benzofuran-5-ylmethyl) -1, tere-butyl 2,4-oxadiazol-5-p-1-piperidinocarboxylate Obtained from the title compound of preparation 67 in the form of a clear oil, in 43% yield, using a procedure similar to that of Preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 ( 9H, s), 1.86 (2H, m), 2.04 (2H, m), 2.95 (2H, m), 3.05 (1H, m), 4.05 (2H, ma), 4.10 (2H, s), 7.10- 7.50 (5H, m) LRMS: m / z 383.4 (MH +) PREPARATION 72 4-r3- (4-chlorobenzyl) -1,4-oxadiazol-5-yl-1-tert-butylpiperidinocarboxylate Obtained from (4-chlorophenyl) acetamidoxine [Bioorg. Med. Chem. Lett. (1996), 6 (7), 833] in the form of a clear oil, with a yield of 63%, using a procedure similar to that of preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.45 ( 9H, s), 1.84 (2H, m), 2. 02 (2H, m), 2.95 (2H, m), 3.05 (1H, m), 4.02 (2H, s), 4.16 (2H, m), 7.25 (4H, m). LRMS: m / z 395.1 (MNH4 +) PREPARATION 73 4- (3-lsobutyl-1, 2,4-oxadiazol-5-yl) -1-piperidinocarboxylate tere-butyl Isovaleronitrile (14.1 g, 170 mmol) and hydroxylamine hydrochloride (60 g, 850 mmol) were heated at reflux in methanol (300 ml) and water (300 ml) for 5 hours. The reaction mixture was cooled to room temperature, solid sodium carbonate was carefully added and the mixture was filtered. The filtrate was concentrated under reduced pressure and extracted with dichloromethane (3x). The combined organic solutions were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a white solid, 15.5 g. In a separate flask, 1- (fer-butoxycarbonyl) -4-piperidinocarboxylic acid (250 mg, 1.09 mmol) in dichloromethane (5 ml) was treated with diisopropylethylamine (0.28 ml, 2.70 mmol). Bis (tetramethylene) fluoroformamidinium hexafluorophosphate (413 mg, 1.31 mmol) in dichloromethane (5 ml) was added to the solution and stirred at room temperature for 1 hour. A portion of the intermediate white solid (150 mg, 1.31 mmol) and diisopropylethylamine (0.23 ml, 1.09 mmol) in dichloromethane (2 ml) were added, the resulting solution was stirred at room temperature for 16 hours and then heated to 50 ° C. to concentrate the solution. Dioxane (10 ml) was added and the solution was heated at 120 ° C for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and a solution of 1M citric acid. The combined organic solutions were dried (MgSO4), filtered and evaporated. reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate: pentane (25:75) as eluent, obtaining the title compound as an oil, 209 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.91 (6H, d), 1.25 (9H, s), 1.84 (2H, m), 2.05 (3H, m), 2.54 (2H, d), 2.98. (2H, m), 3.05 (1 H, m), 4.07 (2H, m).

LRMS: m / z 309.9 (MH +) PREPARATION 74 4-342.5- Difluorobenzyl, 2,4-oxadiazol-5-yl} Tere-butyl-1-piperidinocarboxylate Obtained from the title compound of preparation 59 in the form of a clear oil, with a yield of 34%, using a procedure similar to that of preparation 70 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.45 (9H , s), 1.76-1.84 (2H, m), 2.02 (2H, m), 2.94 (2H, m), 3.06 (1H, m), 4.06-4.12 (4H, m), 6.90-7.06 (3H, m). LRMS: m / z 380.7 (MH +) PREPARATION 75 4-f3-y3.5-Difluorobenzyl-1-2,4-oxadiazol-5-yl) -1-piperidinocarboxylate tere-butyl Obtained from the title compound of preparation 60 in the form of a clear oil, with a yield of 24%, using a procedure similar to that of preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.44 ( 9H, s), 1.75-1.84 (2H, m), 2.03 (2H, m), 2.96 (2H, t), 3.06 (1H, m), 4.00 (2H, s), 4.06 (2H, m), 6.70 (1 H, m), 6.82 (2H, m). LRMS: m / z 380.0 (MH +).

PREPARATION 76 4- (3-r2,6-Difluorobenzill-1,2,4-oxadiazol-5-yl-tere-butyl-1-piperidinocarboxylate) Obtained from the title compound of preparation 61 in the form of a clear oil, in a yield of 39%, using a procedure similar to that of preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.47 ( 9H, s), 1.76-1.84 (2H, m), 2.02 (2H, m), 2.94 (2H, m), 3.06 (1H, m), 4.00-4.14 (4H, m), 6.94 (2H, m ), 7.23 (1 H, m). LRMS: m / z 380.0 (MH +).

PREPARATION 77 4-f3-r4-Methylbenzyl-1,2,4-oxadiazol-5-yl > -1-tert-butylpiperidinocarboxylate Obtained from 4-methylbenzyl cyanide in the form of an oil, with a yield of 60%, using a procedure similar to that of preparation 73. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.45 (9H, s ), 1.76-1.84 (2H, m), 2.02 (2H, m), 2.34 (3H, s), 2.93 (2H, t), 3.05 (1 H, m), 4.00 (2H, s), 4.05 (2H) , m), 7.11 (2H, d), 7.20 (2H, d). LRMS: m / z 358.1 (MH +).

PREPARATION 78 4-f3-f4-Tere-butyl trifluoromethylbenzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinecarboxylate Obtained from (4-trifluoromethylphenol) -acetamidoxime [Bioorg. Med. Chem. Lett. (1996), 6 (7), 833] in the form of a clear oil, with a yield of 49%, using a procedure similar to that of preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.44 ( 9H, s), 1.72-1.86 (2H, m), 2.03 (2H, m), 2.92 (2H, t), 3.03 (1H, m), 4.00-4.12 (4H, m), 7.43 (2H, d) ), 7.58 (2H, d). LRMS: m / z 411.8 (MH +).

PREPARATION 79 4-I3-I1, 3-Benzodioxol-5-ilmetill-1, tere-butyl 2,4-oxadiazol-5-8IM-piperidinocarboxylate Obtained from the title compound of preparation 62 in the form of a clear oil, with a yield of 73%, using a procedure similar to that of preparation 70. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.45 ( 9H, s), 1.70-1.84 (4H, m), 2.03 (2H, m), 2.93 (2H, t), 3.03 (1H, m), 3.95 (2H, s), 4.05 (2H, m), 6.70-6.82 (3H, m).

PREPARATION 80 (1 S) -3-r4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinylH-phenylpropylcarbamate tere-Butyl Sodium triacetoxyborohydride (1.28 g, 6.02 mmol) was added to a solution of the title compounds of preparation 7 (1.00 g, 4.01 mmol) and of preparation 39 (1.07 g, 4.41 mmol) in dichloromethane / acetic acid (40 ml. , 10% solution). The reaction mixture was stirred for 30 minutes, after which it was basified using saturated sodium carbonate and the product was extracted with dichloromethane (x3). The combined organic extracts were dried (MgSO 4), filtered and the solvent was evaporated under reduced pressure to give a brown oil. This was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, obtaining the title compound as an oil, 1.04 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.40 (9H, sa), 1.90-2.10 (7H, m), 2.30 (2H, m), 2.85 (2H, m), 2.98 (2H, m), 2.98 (1 H, m), 4.15 (2H, s), 4.80 (1 H, sa), 6.50 (1 H, sa), 7.30 (10H, m). LRMS: m / z 477 (MH +).

PREPARATION 81 (1 S) -3-f4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl-M-phenylpropylamine To a stirred solution of the title compound of preparation 80 (560 mg, 1.17 mmol) in dichloromethane (10 ml) at 0 ° C was added trifluoroacetic acid (5 ml). The reaction was allowed to warm to room temperature and was stirred for 90 minutes. Then, the mixture was concentrated, basified with saturated sodium carbonate and extracted with dichloromethane (3x). The combined organic solutions were washed with brine, dried (MgSO4), filtered and concentrated to give the title compound as a yellow oil, 314 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.90 (2H, m), 2.05 (4H, m), 2.40 (4H, m), 2.85 (2H, m), 2.95 (1 H, m), 3.99. (3H, m), 4.05 (2H, s), 7.30 (10H, m). LRMS: m / z 377 (MH +).

PREPARATION 82 4- (3-f4-r (Methylsulfonyl) amino-1-benzyl> tert-butyl-1,2-oxadiazol-5-yl) -1-piperidinocarboxylate The title compound of preparation 47 (10.0 g, 47 mmol), hydroxylamine hydrochloride (16.5 g, 238 mmol) and sodium carbonate (25 g, 238 mmol) were heated to reflux in methanol (200 ml) and water (200 ml) for 5 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated and extracted with dichloromethane (3x). The combined organic solutions were washed with water and brine, dried (MgSO), filtered and concentrated under reduced pressure to give a white solid, 8.0 g. A portion of this amodoxime (5.00 g, 20.6 mmol), 1- (fer-butoxycarbonyl) -4-piperidinocarboxylic acid (5.18 g, 22.6 mmol) and 1- (3-dimethylamidopropyl) -3-et hydrochloride 1-carbodimide (4.71 g, 24.6 mmol) was stirred for two hours in dichloromethane (100 ml). The solvent was removed under reduced pressure and the brown oil was dissolved in dioxane (50 ml) and heated to reflux for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (200 ml), washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The title compound was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a yellow foam, 3.40 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9H, s), 1.78 (2H, m), 2.01 (2H, m), 2.83-3.05 (5H, m), 4.03-4.19 (5H, m ), 6.40 (1 H, m), 7.18 (2H, d), 7.31 (2H, d). LRMS: m / z 459 (MNa +).

PREPARATION 83? - (4-t5- (4-pyridinyl, -1,2,4-oxadiazol-3-ylmethyl) phenyl) methanesulfonamide hydrochloride The title compound of preparation 82 was dissolved (3.20 g, 7. 33 mmole) in methanolic hydrochloric acid (100 ml, 2.5 M) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a white solid, 2. 50 g 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.85 (2 H, dd), 2.21 (2 H, d), 2.98 (3 H, s), 3.05 (2 H, dd), 3.38 (4 H, m), 4.00 ( 2H, s), 7.18 (2H, d), 7.24 (2H, d). LRMS: m / z 337 (MH +).

PREPARATION 84 2.2.2-Trifluoro-1-4-r3- (4-fluorobenzyl) -1, 2,4-oxadiazol-5-p-1-piperidinyl M • ethanone Obtained from the title compounds of preparations 20 and 57 in the form of an oil, with a yield of 15%, using a procedure similar to that of preparation 21. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.80 (2H, m), 2.20 (2H, m), 3.15-3.40 (3H, m), 4.00 (2H, s), 7.00 (2H, m), 7.30 (2H, m).

PREPARATION 85 4-r3- (4-Fluorobenzyl) -1.2.4-oxadiazol-5-piperidine Obtained from the title compound of preparation 84 in the form of an oil, in 75% yield, using a procedure similar to that of preparation 37. 1 H NMR (400 MHz, CDCl 3): d [ppm] 2.80 (2H , m), 2.10 (2H, dd), 2.80 (2H, m), 3.05 (1 H, m), 3.20 (2H, m), 4.00 (2H, s), 7.00 (2H, m), 7.25 (2H , m). LRMS: m / z 262 (MH +).

PREPARATION 86 3- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinocarboxylate tere-butyl Obtained from the title compounds of preparations 13 and 56 in the form of an oil, with a yield of 72%, using a procedure similar to that of preparation 21. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.45 (9H, s), 3.95 (1H, m), 4.08 (2H, s), 4.20 (2H, m), 4.30 (2H, t), 7.25 (1H, m), 7.35 (4H, m) . LRMS: m / z 338 (MNa +).

PREPARATION 87 5- (3-Azetidinyl) -3-benzyl-1,2,4-oxadiazole Obtained from the title compound of preparation 86 in the form of an oil, with a yield of 72%, using a procedure similar to that of preparation 81. 1 H NMR (400 MHz, CDCl 3): d [ppm] 3.92 (2H, m), 4.06 (4H, m), 4.13 (1 H, m), 7.25 (1H, m), 7.35 (4H, m). LRMS: m / z 216 (MH +).

PREPARATION 88 (1 S) -3-r4- (3- {4-r. MethylsulfoniDaminoIbenzyl, 2,4-oxadiazol-5-yl) -1-piperidinin-1-phenylpropylcarbamate tere-butyl Sodium triacetoxyborohydride (1.28 g, 6.02 mmol) was added to a solution of the title compounds of preparation 7 (1.00 g, 4.01 mmol) and of preparation 83 (1.65 g, 4.41 mmol) in dichloromethane / acetic acid (40 ml. , 10% solution). The reaction mixture was stirred for 30 minutes, after which the solution was basified with saturated sodium carbonate and the product was extracted with dichloromethane (x3). The combined organic extracts were dried (MgSO 4), filtered and the solvent was evaporated under reduced pressure to obtain a brown oil. This was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white foam, 1.30 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9H, s), 1.80-2.19 (10H, m), 2.30 (2H, m), 2.80-3.01 (5H, m), 4.02 (2H, s) ), 4.75 (1 H, sa), 6.38 (1 H, sa), 7.15-7.40 (9H, m). LRMS: m / z 570 (MH +).

PREPARATION 89 (1 S) -3- (4-r3- (4-Fluorobenzyl) -1.2.4-oxadiazol-5-ill-1-piperidinyl-1 • phenylpropylcarbamate tere-butyl Obtained from the title compounds of preparations 7 and 85 in the form of an oil, with a yield of 81%, using a procedure similar to that of preparation 80. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.30 (9H, sa), 1.70 (1 H, m), 1.80-2.00 (4H, m), 2.20 (2H, m), 2.80 (2H, m), 2.90 (1 H, m), 3.95 (2H, s), 4.70 (1 H, sa), 6.60 (1 H, sa), 6.90 (2H, m), 7.10 (1 H, m), 7.15-7.25 (8H, m). LRMS: m / z 495 (MH +).

PREPARATION 90 (1 S) -3-r3- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinyl-1 • phenylpropylcarbamate tere-butyl Obtained from the title compounds of preparations 7 and 87 in the form of an oil, with a yield of 64%, using a procedure similar to that of preparation 80. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.40 (9H, sa), 1.79 (2H, m), 2.45 (2H, m), 3.31 (2H, m), 3.67 (2H, m), 3.84 (1H, m), 4.05 (2H, m), 4.3-4.5 (1 H, m), 5.62 (1 H, sa), 7.25 (3H, m), 7.35 (7H, m). LRMS: m / z 449 (MH +).

PREPARATION 91? .- f4-l (5- (1-r (3S) -3-amino-3-phenylpropyl-4-piperidinyl -1, 2,4-oxadiazol-3-yl) metiphenyl) methanesulfonamide hydrochloride The title compound of preparation 88 was dissolved (1.20 g, 2. 10 mmol) in methanolic hydrochloric acid (30 ml, 2.5 M) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a white solid, 1.04 g. 1 H NMR (300 MHz, D 2 O): d [ppm] 1.95 (2H, m), 2.23 (2H, m), 2. 40 (2H, m), 2.71 (1 H, m), 2.91-3.10 (6H, m), 3.25 (1H, m), 3.48 (2H, m), 4.03 (2H, s), 4.38 (1H, t), 7.15 (2H, d), 7.23 (2H, d), 7.40 (5H, m). LRMS: m / z 470 (MH +).

PREPARATION 92 (1 S) -3- (4-r3-f4-Fluorobenzyl) -1, 2,4-oxadiazol-5-p-1-piperidinylH-phenylpropylamine Obtained from the title compound of preparation 89 in the form of an oil, with an 81% yield, using a procedure similar to that of preparation 81. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.90 (4H , m), 2.05 (4H, m), 2.40 (2H, m), 2.50 (2H, sa), 2.85 (2H, m), 2.98 (1 H, m), 4.00 (3H, m), 7.00 (2H , m), 7.30 (7H, m). LRMS: m / z 395 (MH +).

PREPARATION 93 (1 S) -3-r3- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinyl-l-phenyl-1-propanamine Obtained from the title compound of preparation 90 in the form of an oil, with a yield of 92%, using a procedure similar to that of Preparation 81. 1 H NMR (3/400 MHz, CDCl 3): d [ppm] 1.60 (2H, m), 2.51 (2H, m), 3.53 (2H, t), 3.68 (2H, m), 3.87 (1H, m), 3.98 (1H, m), 4.06 (3H, m), 4.35-4.55 (1 H, m), 7.2-7.36 (10H, m). LRMS: m / z 349 (MH +).

PREPARATION 94 3- (f M-amino-2-phenylethylideneamino> oxy) -3-oxopropanoate ethyl A solution of ethylmalonyl chloride (3.30 ml, 24 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of the title compound of preparation 56 (3.34 g, 22 mmol) and diisopropylethylamine (4.27 ml, 24 ml). mmoles) in dichloromethane (45 ml) at 10 ° C. The reaction mixture was stirred and warmed to room temperature for 1 hour, and then washed with brine, evaporated under reduced pressure and purified by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent obtaining the title compound in the form of a white foam, 1.15 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.25 (3H, t), 3.48 (2H, s), 3.57 (2H, s), 4.19 (2H, q), 4.84 (2H, sa), 7.26 ( 5H, m). LRMS: m / z 265 (MH +).

PREPARATION 95 3- ( { Ri-Amino-2-phenylethylidene-1-amino) oxy) -3-oxo-propane-nitrile To a stirred solution of the title compound of Preparation 56 (12.3 g, 82 mmol) in dichloromethane (100 mL) was added cyanoacetic acid (6.97 g, 82 mmol) and 3-ethyl-1- (3-dimethylaminopropyl) hydrochloride. -carbodiimide (15.7 g, 82 mmol). The reaction mixture was stirred for 96 hours at room temperature, then partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The resulting solid was triturated with ether to obtain the title compound as a pale yellow solid, 1.71 g. H NMR (300 MHz, CDCl 3 + DMSO 6): d [ppm] 3.47 (2H, s), 3.59 (2H, s), 5.16 (2H, s a), 7.25 (5H, m). LRMS: m / z 218 (MH +).

PREPARATION 96 3- ( { Ri-Amino-2- (4-fluorophenyl) ethylidene-1-amino) oxy) -3-oxo-propane-nitrile Obtained from the title compound of Preparation 57 as an orange solid, in 28% yield, using a procedure similar to that of Preparation 95. 1 H NMR (300 MHz, CDCl 3): d [ppm] 3.38 ( 2H, s), 3.57 (2H, s), 5.40 (2H, s), 6.88 (2H, m), 7.17 (2H, m). LRMS: m / z 236.1 (MH +).

PREPARATION 97 2- (3-Benzyl-1, 2,4-oxadiazol-5-yl) ethyl acetate A solution of the title compound of preparation 94 (8.09 g, 30 mmol) in dioxane (110 mL) was heated to reflux for 4 hours. The solvent was evaporated under reduced pressure and the residual oil was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as an oil, 4.85 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.24 (3H, t), 3.95 (2H, s), 4.08 (2H, s), 4.22 (2H, q), 7.26 (5H, m). LRMS: m / z 247 (MH +).

PREPARATION 98 ethyl 2-r5- (4-Fluorobenzyl) -1.2.4-oxadiazole-3-illacetate A solution of ethylmalonyl chloride (15 ml, 110 mmol) in dichloromethane (50 ml) was added dropwise to a stirred suspension of the title compound of preparation 57 (16.0 g, 100 mmol) and diisopropylethylamine (20 ml, 110 ml). mmoles) in dichloromethane (150 ml) with cooling in an ice bath. The reagents were stirred at room temperature overnight and then washed with water and concentrated to a gum. This gum was dissolved in dioxane (150 ml) and heated to reflux for 12 hours. Pre-adsorption silica was added to the cooled solution which was concentrated and purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give the title compound as an oil, 22.8 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.26 (3 H, t), 3.93 (2 H, s), 4. 07 (2H, s), 4.22 (2H, q), 7.00 (2H, m), 7.28 (2H, m). LRMS: m / z 265.0 (MH +).

PREPARATION 99 2- (3-Benzyl-1,2,4-oxadiazol-5-yl) acetonitrile Obtained from the title compound of preparation 95 as an oil in residual dioxane, using a procedure similar to that of preparation 97. 1 H NMR (300 MHz, CDCl 3): d [ppm] 3.70 (dioxane), 3.99 ( 2H, s), 4.11 (2H, s), 7.32 (5H, m).

PREPARATION 100 2-r3- (4-Fluorobenzyl) -1.2.4-oxadiazol-5-acetonitrile Obtained from the title compound of preparation 96 in the form of an oil, with a yield of 59%, using a procedure similar to that of preparation 97. 1 H NMR (300 MHz, CDCl 3): d [ppm] 4.02 (2H, s), 4.08 (2H, s), 7.03 (2H, m), 7.28 (2H, m).

PREPARATION 101 1 -ethyl-4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -4-piperidinecarboxylate ethyl A solution of the title compound of preparation 97 (4.85 g, 19.7 mmol) in 1-methylpyrrolidin-2-one (10 ml) was added a suspension of sodium hydride (60% dispersion in mineral oil, 2.40 g, 60 mmol ) in 1-methylpyrrolidin-2-one (30 ml). The reaction mixture was stirred for 45 minutes at room temperature before adding bis- (2-chloroethyl) benzylamine hydrochloride (5.00 g, 18.6 mmol) and tetra-n-butylammonium bromide (0.50 g, 1.5 mmol). The reaction mixture was stirred for 24 hours at 60 ° C and then cooled and partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine (3x). The organic extracts were separated, pre-adsorbed on silica gel and purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as an oil, 4.76. g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.16 (3 H, t), 2.32 (8 H, m), 3.42 (2 H, s), 4.08 (2 H, s), 4.17 (2 H, q), 7.26 ( 10H, m) LRMS: m / z 406 (MH +).

PREPARATION 102 1-Benzyl-4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -4-piperidinecarboxylate ethyl Obtained from the title compound of preparation 98 in the form of an oil, with a yield of 22%, using a procedure similar to that of preparation 101. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.18 (3H , t), 2.32 (6H, m), 2. 58 (2H, m), 3.41 (2H, s), 4.06 (2H, s), 4.15 (2H, q), 7.00 (2H, m), 7.28 (7H, m). LRMS: m / z 424.1 (MH +).

PREPARATION 103 1-Benzyl-4- (3-benzyl-1,2,4-oxadiazol-5-yl) -4-piperidinocarbonitrile Obtained from the title compound of preparation 99 in the form of an oil, in a yield of 10%, using a procedure similar to that of Preparation 101. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.26 (4H , m), 2.49 (2H, m), 2.92 (2H, m), 3.56 (2H, s), 4.08 (2H, s), 7.26 (10H, m). LRMS: m / z 359 (MH +).

PREPARATION 104 1-Benzyl-4-f3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-in-4-piperidinocarbonitrile Obtained from the title compound of preparation 100 in the form of an oil, with a yield of 22%, using a procedure similar to that of Preparation 101. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.24 (4H, m), 2.49 (2H, m), 2.92 (2H, m), 3.57 (2H, s), 4.04 (2H, s), 6.88 ( 2H, t), 7.25 (7H, m). LRMS: m / z 377.3 (MH +).

PREPARATION 105 1-Benzyl-4-r3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yn-4-piperidinocarboxylic acid ethyl ester A solution of the title compound of preparation 102 (1.50 g, 3.50 mmol) and methylamine (20 ml of a 2 M solution in tetrahydrofuran, 40 mmol) in ethanol (20 ml) was stirred in an autoclave at 100 ° C for 5 hours. hours. The solution was cooled, concentrated under reduced pressure and purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, affording the title compound as an oil, 295 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.07 (2H, m), 2.36 (4H, m), 2. 73 (5H, m), 3.40 (2H, s), 4.06 (2H, s), 5.88 (1 H, s), 7.00 (2H, m), 7.26 (7H, m) LRMS: m / z 409.1 (MH + ) PREPARATION 106 4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -4-piperidinecarboxylate ethyl A solution of 1-chloroethyl chloroformate (0.28 ml, 2.6 mmol) in dichloromethane (1 ml) was added to a solution of the title compound of preparation 101 (820 mg, 2 mmol) in dichloromethane (9 ml) at 0 °. C. The reaction mixture was stirred for 3 hours at room temperature and then the solvent was evaporated and the residual oil was dissolved in methanol (10 ml). The solution was heated to reflux for 1 hour. The solution was cooled, pre-adsorbed on silica gel, concentrated under reduced pressure and chromatographed on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, affording the title compound in Form of an oil, 195 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.18 (3 H, t), 2.57 (4 H, m), 3.06 (2 H, m), 3.24 (2 H, m), 3.46 (1 H, s), 4.06 (2H, s), 4.18 (2H, q), 7.27 (5H, m) LRMS: m / z 316 (MH +) PREPARATION 107 4- (3-Benzyl-1,2,4-oxadiazol-5-yl) - 4-piperidinocarbonitrile Obtained from the title compound of preparation 103 in the form of an oil, with a yield of 59%, using a procedure similar to that of Preparation 106. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.34 (4H , m), 3.21 (4H, m), 4.08 (2H, s), 7.26 (5H, m) LRMS: m / z 269 (MH +) PREPARATION 108 4-f3- (4-Fluorobenzyl) -1,2,4-oxadiazol-5-n-4-piperidinocarbonitrile Obtained from the title compound of preparation 104 in the form of an oil, with a yield of 44%, using a procedure similar to that of preparation 106. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.50 (4H, m), 3.26 (2H, m), 3.42 (2H, m), 4.06 (2H, s), 7.02 (2H, m), 7.27 ( 2H, m) LRMS: m / z 287.2 (MH +) PREPARATION 109 4-r3- (4-Fluorobenzyl) -1.2.4-oxadiazol-5-in-N-methyl-4- piperidinocarboxamide Obtained from the title compound of preparation 105 in the form of an oil, with a yield of 68%, using a procedure similar to that of Preparation 106. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.21 (2H , m), 2.36 (2H, m), 2. 62 (2H, m), 2.74 (3H, d), 3.03 (2H, m), 4.04 (2H, s), 5.88 (1H, s), 7.00 (2H, m), 7.26 (2H, m) LRMS : m / z 319.1 (MH +) PREPARATION 110 (1 S) -3 4-Cyano-4-r3- (4-fluorobencll) -1, tere-butyl 2,4-oxadiazol-5-n-1-piperidinyl-1-phenylpropylcarbamate Obtained from the title compounds of preparations 7 and 108 in the form of an oil, with a yield of 54%, using a procedure similar to that of preparation 80. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.28 (9H, s), 1.94 (2H, m), 2.38 (8H, m), 2.90 (2H, m), 4.06 (2H, s), 4.78 (1 H, s), 5.85 (1 H, s) , 7.02 (2H, m), 7.27 (7H, m) LRMS: m / z 520.3 (MH +) PREPARATION 111 1-r (3S) -3-Amino-3-phenylpropin-4-r3- (4-fluorobencip-1,2,4-oxadiazol-5-ill-4- piperidinocarbonitrile Obtained from the title compound of preparation 110 in the form of an oil, in 68% yield, using a procedure similar to that of Preparation 81. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.85 (1 H, m), 2.00 (1 H, m), 2.38 (8H, m), 2.85 (1 H, m), 3.02 (1 H, m), 4.04 (3H, m), 7.02 (2H, m), 7.27 (7H, m) LRMS: m / z 420.2 (MH +) PREPARATION 112 1-r (3S) -3f (tert-Butoxycarbonyl) amino > Benzyl 3-phenylpropyl-4- piperidinocarboxylate Obtained from the title compound of preparation 7 and benzyl 4-piperidinocarboxylate in the form of an oil, with a yield of 67%, using a procedure similar to that of preparation 80. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.33 (9H, s), 1.60-2.12 (11 H, m), 2.64-3.00 (2H, m), 4.75 (1 H, s), 5.10 (2H, s), 6.55 (1 H, s ), 7.10-7.45 (10H, m) LRMS: m / z 453.3 (MH +) PREPARATION 113 1 -r (3S) -3-Amino-3-phenylpropyl-4-piperidinocarboxylate benzyl Obtained from the title compound of preparation 112 in the form of an oil, with a yield of 88%, using a procedure similar to that of preparation 81. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.60-2.05 (10H, m), 2.25-2.44 (3H, m), 2.86 (2H, m), 3.97 (1H, m), 5.14 (2H, s), 7.23-7.43 (10H, m) LRMS: m / z 353.3 (MH +) PREPARATION 114 1 - ((3S) -3-r (Cyclobutylcarbonyl) amino-1,3-phenylpropyl-4-piperidinecarboxylic acid benzyl ester A solution of the title compound of Preparation 113 (10.3 g, 29.2 mmol) in dichloromethane (200 mL) was treated with diisopropylethylamine (5.72 mL, 32.1 mmol) in cyclobutanecarbonyl chloride (3.66 mL, 32.1 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 18 hours, then diluted with a sodium carbonate solution and extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (99: 1) as eluent, obtaining the title compound, 4.63 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.77-2.45 (16H, m), 2.80 (1H, m), 2.98-3.18 (2H, m), 5.11-5.26 (3H, m), 5.14 ( 2H, s), 7.18-7.45 (10H, m) LRMS: m / z 435.3, (MH +) PREPARATION 115 Acid 1 - ((3S) -3-r (Cyclobutylcarbonyl) amino1-3-phenylpropyl > -4- piperidinecarboxylic acid A solution of the title compound of Preparation 114 (7.63 g, 17.6 mmol) in ethanol (300 mL) was hydrogenated at room temperature for 12 hours at room temperature using 10% palladium on carbon catalyst (700 mg). The catalyst was removed by filtration through a glass fiber filter and then the solvent was evaporated under reduced pressure to give the title compound as a white crystalline solid, 6.04 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 1.16 (1 H, m), 1.75-2.40 (13H, m), 2.75-3.05 (4H, m), 3.12 (1H, m), 3.23-3.45 (3H, m), 4.94 (1H, m), 7.23-7.46 (5H, m) LRMS: m / z 345.0 (MH +) PREPARATION 116 1 -Benzyl-4- (4H-1, 2,4-triazol-4-yl) piperidine 1-Benzyl-4-piperidinamine (617 mg, 3.25 mmol) was added to a solution of N '- [(E) - (dimethylamino) metlidene] -N, N-dimethylhydrazonoformamide (550 mg, 3.90 mmol) [J . Am. Chem. Soc, (1995), 117 (22), 5951] and p-toluenesulfonic acid (62 mg, 0.33 mmol) in toluene (30 ml). The reaction mixture was stirred for 24 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white solid, 560 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.92-2.21 (6H, m), 3.03 (2H, d), 3.55 (2H, s), 4.04 (1H, m), 7.13-7.36 (5H, m), 8.21 (2H, s).

PREPARATION 117 1-Benzyl-4- (3,5-dimethyl-4-H-1, 2,4-triazol-4-yl) piperidine Lawesson's reagent (11.69 g, 28.9 mmol) was added to a solution of N- (1-benzyl-4-piperidinyl) acetamide (6.1 g, 26.3 mmol) [J. Med. Chem., (1996), 39 (19), 3769] in tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (93: 7: 0.3) as eluent, yielding an oil, 2.8 g. Acetylhydrazide (919 mg) was added, 12.4 mmoles) to a solution of the intermediate thioamide and mercuric oxide (2.44 g, 11.3 mmol) in butanol (50 ml). The reaction mixture was heated to reflux for 24 hours and then cooled and filtered through Arbocel®. The filtrate was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound, 1.80 g. LRMS: m / z 271 (MH +).

PREPARATIONS 118 TO 119 The compounds of the following preparations presented in the table: were prepared from the corresponding hydrazides, using procedures similar to those described in preparation 117.

PREPARATION 120 4- (3-Methyl-5-phenyl-4 V-1,2,4-triazol-4-yl) piperidine The title compound of Preparation 119 (1.00 g, 3.00 mmol) was dissolved in ethanol (30 mL) and 20% palladium hydroxide w / w over carbon (500 mg) and ammonium formate (0.95 g, 15.0 mmol) was added. ). The reaction was refluxed for 1 hour, cooled and filtered through a short bed of Arbocel®. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (80: 20: 1) as eluent, yielding the title compound as a yellow oil pale, 400 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.78 (2 H, d), 2.10 (1 H, dd), 2.18 (1 H, dd), 2.60 (2 H, m), 2.63 (3 H, s), 3.20 (2H, d), 4.10 (1 H, m), 7.50 (5H, m). LRMS: m / z 243 (MH +) PREPARATION 121 4- (3-Benzyl-5-methyl-4H-1,2,4-triazol-4-yl) piperidine Obtained from the title compound of preparation 118 in the form of an oil, with a yield of 66%, using a procedure similar to that of preparation 120. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.20-1.23 (1H, m), 1.35-1.41 (1H, m), 1.80-2.00 (4H, m), 2.38-2.48 (1H, m), 2.51 (2H, s), 3.02-3.10 (1H, m ), 3.46 (3H, m), 3.60-3.72 (1 H, m), 4.20 (1 H, s), 7.15-7.35 (5H, m). LRMS: m / z 257.2 (MH +) PREPARATION 122 1-Benzyl -? / - r (E) -fdimethylamino) methylidene-1-4-piperidinecarboxamide A mixture of N-benzyl-4-piperidinecarboxamide (2.49 g, 11.4 mmol) [J.A.C.S. (1977), 99 (6), 1858] and dimethylformamide dimethyl acetal (10 ml) was heated to 170 ° C allowing continuous removal of the solvent and the mixture was stirred for 10 minutes. Then, the reaction was cooled to 120 ° C and stirred for 90 minutes, and then 18 hours more at room temperature. The resulting crystals were removed by filtration, washed with pentane to obtain the title compound as a white crystalline solid, 1.75 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.55 (2 H, m), 1.75 (2 H, d), 1.93 (2 H, t), 2.16 (1 H, m), 2.74 (2 H, d), 2.94 (3H, s), 3.08 (3H, s), 3.40 (2H, s), 7.20-7.32 (5H, m), 8.33 (1H, s). LRMS: m / z 274 (MH +) PREPARATION 123 1-Benzyl-4- (1-methyl-1 H-1,2,4-triazol-5-yl) piperidine PREPARATION 124 1-Benzyl-4- (1-methyl-1 H-1, 2,4-triazol-3-yl) piperidine The title compound of Preparation 122 (1.89 g, 6.91 mmol) was added to a solution of methylhydrazine (0.4 mL, 7.60 mmol) in acetic acid (20 mL). The reaction mixture was heated at 92 ° C for 4 hours and the solvent was evaporated under reduced pressure. The residue was basified using sodium hydrogen carbonate and the product was extracted with ethyl acetate (4x). The combined organic extracts were washed with brine, dried (MgSO 4) and evaporated under reduced pressure to obtain the title compounds as an oil, 2.74 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.81-2.26 (6H, m), 2.88-3.06 (3H, m), 3.50-3.65 (2H, d), 3.85 (2H, d), 7.21-7.40 (5H, m), 7.79-7.92 (2H, 2 x s). LRMS: m / z 274 (MH +).

PREPARATION 125 4- Tere-Butyl 4- (Aminocarbonyl) -1-piperidinocarboxylate Ethyl chloroformate (4.6 ml, 48.3 mmol) was slowly added to a solution of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid (10 g, 43.6 mmol) in dichloromethane (100 ml) stirred at 0 ° C. Triethylamine (7.6 ml, 52.3 mmol) was added with stirring for two minutes. A 0.88 ammonia solution (40 ml) was added and the mixture was allowed to warm to room temperature with stirring. The mixture was washed with water, 1 M citric acid solution and brine, dried (MgSO 4), filtered and evaporated under reduced pressure to give the title compound as a white solid, 8.94 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.43 (9H, m), 1.64 (2H m), 1.83 (2H, m), 2.30 (1 H, m), 2.78 (2H, t), 4.16 ( 2H, d), 5.4 (2H, sa). LRMS: m / z 251 (MNa +).

PREPARATION 126 4-retoxi (imino) methyl-1-tere-butylpiperidinocarboxylate A solution of the title compound of preparation 125 (2.80 g, 12.2 mmol) in dichloromethane (30 ml) was added slowly to triethyloxonium hexafluorophosphate (3.30 g, 13.3 mmol) in dichloromethane (20 ml) at room temperature and the resulting mixture it was stirred at room temperature overnight. The mixture was basified with a sodium hydrogen carbonate solution and then extracted with dichloromethane (x2). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a dense yellow solid, 2.90 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.26 (3 H, m), 1.43 (9 H, s), 1.64 (2 H, d), 2.31 (1 H, m), 2.75 (4 H, m), 4.10 (4H, m). LRMS: m / z 257 (MH +).

PREPARATION 127 4- (5-Benzyl-1 H-1, 2,4-triazol-3-yl) -1-piperidinocarboxylate tere-butyl Phenylacetyl chloride (2.26 ml, 17.0 mmol) was added to a solution of the title compound of preparation 126 (4.00 g, 15.6 mmol) and triethylamine (2.5 ml, 1.60 mmol) in toluene (26 ml) and stirred at room temperature. environment for 90 minutes. Hydrazine hydrate was added (0.91 mL, 19.0 mmol) and the reaction mixture was stirred at room temperature for 15 hours. The mixture was acidified by the addition of a 1M citric acid solution and extracted with ethyl acetate (x3). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (99: 1) as eluent, obtaining the title compound, 1.70 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.34 (9H, s), 1.75 (2H, m), 2.00 (2H, d), 2.90 (3H, m), 4.12 (4H, m), 7.30 ( 5H, m). LRMS: m / z 343 (MH +).

PREPARATION 128 4- (5-Benzyl-1-methyl-1 H-1, 2,4-triazol-3-yl) -1-piperidinecarboxylate terebutyl A solution of the title compound of Preparation 126 (2.90 g, 11.3 mmol) and triethylamine (1.7 mL, 12.3 mmol) in toluene (20 mL) was treated with phenylacetyl chloride (1.6 mL, 12.1 mmol) and stirred at room temperature. environment for 1 hour. Methylhydrazine was added dropwise (0.66 ml, 12.5 mmol) and the mixture was stirred at room temperature for 5 hours. The mixture was acidified by the addition of a 1M citric acid solution and extracted with ethyl acetate (x3). The combined organic solutions were washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure to give a yellow oil. Purification of this residue by column chromatography on silica gel, using dichloromethane: methanol (99: 1) as eluent, yielded the title compound, 1.10 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9H, s), 1.72-1.85 (2H, m), 2.00 (2H, m), 2.83 (3H, m), 3.62 (3H, s), 4.10 (2H, s), 4.15 (2H, m), 7.15 (2H, d), 7.24-7.35 (3H, m) LRMS: m / z 357 (MH +) PREPARATION 129 4- (5-Benzyl-1 H-1, 2,4-triazol-3-yl) trifluoroacetate - piperidine A solution of the title compound of Preparation 127 (530 mg, 1.50 mmol) in dichloromethane (5 ml) at 0 ° C was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, toluene (20 ml) was added and it was removed under reduced pressure to obtain the title compound as a yellow oil, 1.09 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 2.03 (2H, m), 2.25 (2H, m), 3.20 (3H, m), 3.50 (2H, m), 4.20 (2H, m), 7.30 ( 5H, m). LRMS: m / z 243 (MH +).

PREPARATION 130 4-f 5-Benzyl-1-methyl-1 HA, 2,4-triazol-3-yl) -1-piperidine Obtained from the title compound of preparation 128 in the form of an oil, with a yield of 46%, using a procedure similar to that of preparation 81. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.72-1.85 (2H, m), 2.05 (2H, m), 2.76 (2H, t), 2.83 (1H, m), 3.17 (2H, m), 3.60 (3H, s), 4.05 (2H, s), 7.15 (2H, d), 7.21-7.35 (3H, m). LRMS: m / z 258 (MH +).

PREPARATION 131 4-r2- (tert-butoxycarbonyl) hydrazino-1-benzyl-piperidinecarboxylate Benzyl 4-oxo-1-piperidinecarboxylate (10.0 g, 42.9 mmol), tere-butyl 1-hydrazinocarboxylate (5.70 g, 42.9 mmol) and sodium triacetoxyborohydride (13.6 g, 64.1 mmol) were stirred together for 4 hours at room temperature. in dichloromethane / acetic acid (40 ml, 10% solution). The solvents were evaporated under reduced pressure. The residue was basified with a saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to obtain the title compound as a colorless gum, 14.2 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.23-1.39 (2H, m), 1.45 (9H, s), 1.71-1.87 (2H, m), 2.89-3.08 (3H, m), 3.61-3.69 (1 H, m), 3.87-3.97 (1 H, m), 3.97-4.10 (2H, m), 5.68-5.81 (1 H, sa), 5.94-6.06 (1 H, sa), 7.26-7.39 ( 5H, m). LRMS: m / z 350.0 (MH +).

PREPARATION 132 4-Hydrazino-1-piperidinocarboxylate benzyl The title compound of preparation 131 (1.00 g, 37.8 mmol) in dichloromethane (250 ml) was stirred at 0 ° C while trifluoroacetic acid (30 ml, 390 mmol) was added. The mixture was stirred for 16 hours and allowed to warm to room temperature. The solvents were removed under reduced pressure. The residue was basified with a saturated sodium carbonate solution and extracted with dichloromethane (x4). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an eluent of dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5), obtaining the title compound as a colorless gum, 4.25 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.23-1.35 (2H, m), 1.81 -1.94 (2H, m), 2.61-2.71 (1 H, m), 2.86-3.00 (2H, m), 4.00-4.24 (2H, m), 5.11 (2H, s), 7.26-7.37 (5H, m). LRMS: m / z 250.1 (MH +).

PREPARATION 133 4- (3-Benzyl-1 HA, 2,4-triazol-1-yl) -1-piperidinecarboxylate benzyl Phenyl acetimidate (2.0 g, 10.8 mmol) and the title compound of preparation 132 (3.1 g, 10.8 mmol) in dichloromethane (100 ml) were stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was refluxed for 2 hours in triethyl orthoformate (50 ml). The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (x2). The organic layer was dried (MgSO), filtered and evaporated under reduced pressure to give an oil which crystallized rapidly upon standing. The residue was purified by recrystallization from ethyl acetate to obtain the title compound as a white solid, 1.73 g. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 1.87-2.00 (2H, m), 2.03-2.16 (2H, m), 2.94-3.15 (2H, m), 4.00 (2H, s), 4.20-4.29. (2H, m), 4.40-4.50 (1H, m), 5.13 (2H, s), 7.13-7.19 (1H, m), 7.19-7.40 (9H, m). LRMS. m / z 377.2 (MH +).

PREPARATION 134 4- (3-Benzyl-1 HA, 2,4-triazoM -Dpiperidine Obtained from the title compound of preparation 133 in the form of an oil, with a yield of 88%, using a procedure similar to that of preparation 120. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.68-1.94 (2H, m), 2.10-2.20 (2H, m), 2.71-2.81 (2H, m), 3.20-3.29 (2H, m), 4.06 (2H, s), 4.16-4.26 (1H, m), 7.16-7.23 (1 H, m), 7.23-7.35 (4H, m), 7.97 (1 H, s).

PREPARATION 135 4- (2-lm8no-2-methoxyethyl) methyl benzoate To a solution of methyl 4- (bromomethyl) benzoate (5.00 g, 21. 8 mmol) in cyanohydrin acetone (3 ml, 32.7 mmol) was added with stirring at room temperature in acetonitrile (200 ml) 1.1, 3,3-tetramethylguanidine (5.8 ml, 45.8 mmol) and the mixture was stirred for 16 hours. The solvent was removed under reduced pressure. The residue was triturated with diethyl ether (x3), filtered and the filtrate was evaporated under reduced pressure. The residue was purified by filtration through a layer of silica, eluting with diethyl ether to obtain a colorless oil., 4.0 g. The oil was dissolved in 200 ml of diethyl ether and hydrogen chloride gas was bubbled through the solution until saturated, while stirring at 0 ° C. Methanol (1.5 mL, 37.2 mmol) was added and the mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the residue was basified using a saturated sodium carbonate solution and extracted with dichloromethane (x3). The combined organic solutions were dried (MgSO 4), filtered and evaporated under reduced pressure to obtain the title compound as a colorless oil, 4.20 g. 1 H NMR (400 MHz, CDCl 3): d [ppm] 3.60 (2H, s), 3.74 (3H, s), 3.92 (3H, s), 7.26-7.32 (2H, d), 8.00-8.06 (2H, d) ). LRMS: m / z 208.1 (MH +).

PREPARATION 136 4- (ri- (1-f (3S) -3-f (tert-butoxycarbonyl) amino-3-phenylpropyl) -4-piperidinyl) -1H-1, 2,4-triazole-3-immethyl > sodium benzoate The title compound of Preparation 132 (3.50 g, 14.04 mmol) and the title compound of Preparation 135 (2.90 g, 14.04 mmol) were stirred together for 1 hour at room temperature in methanol (50 mL). The solvent was removed under reduced pressure. The residue was dissolved in triethyl orthoformate (50 ml) and heated to reflux for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using an eluent of dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5). The residue (4.00 g, 9.18 mmol), ammonium formate (4.00 g, 82.49 mmol) and palladium hydroxide % w / w on carbon (400 mg) were heated to reflux for 30 minutes in ethanol (100 ml). The mixture was filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The residue (2.50 g, 8.32 mmol), the title compound of preparation 7 (2.00 g, 8.32 mmol) and sodium triacetoxyborohydride (2.50 g, 12.48 mmol) were stirred at room temperature for 1 hour in dichloromethane: acetic acid (30 mL). ml, 10%). The solvents were evaporated under reduced pressure and the residue was basified with a saturated sodium carbonate solution and extracted with dichloromethane (x3). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: 0.88 ammonia (98: 2: 0.25) as eluent to give a foam, 2.50 g. The residue (1.00 g, 1.87 mmol) and sodium hydroxide (150 mg, 3.74 mmol) were stirred for 2 hours at 50 ° C in a dioxane: water mixture (5: 1). The solvents were removed under reduced pressure to obtain a white solid, 993 mg. LRMS: m / z 520.1 (MH +).

PREPARATION 137 N- (4-f (1-f 1 -p - (benzyloxy) vinin-4-piperidinyl M H-1, 2,4-triazol-3-yl) methylphenol) methanesulfonamide The title compound of preparation 131 (1.90 g, 9.04 mmol) was stirred at room temperature in diethyl ether: methanol (100 mL, 4: 1) while hydrogen chloride gas was bubbled through the solution until saturated. The mixture was stirred for 16 hours and the solvents were removed under reduced pressure. The residue was basified with a saturated sodium carbonate solution and extracted with dichloromethane (x3). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure. In a separate flask, the title compound of Preparation 47 (1.00 g, 4.76 mmol) was dissolved in 20 mL of diethyl ether and hydrogen chloride was bubbled through the solution until it was saturated while stirring at 0 ° C. . Methanol (1.5 mL, 37.2 mmol) was added and the mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the residue was basified using a saturated sodium carbonate solution and extracted with dichloromethane (x3). The combined organic solutions were dried (MgSO 4), filtered and evaporated under reduced pressure. Crude hydrazine (595 mg, 2.46 mmol) and intermediate amidoxime (600 mg, 2.41 mmol) were stirred together at room temperature for 3 hours in 40 ml of methanol. The solvent was removed under reduced pressure. The residue was dissolved in triethyl orthoacetate (30 ml) and heated to reflux for 30 minutes. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent to obtain the title compound as a foam, 560 mg. 1 H NMR (400 MHz, CD 3 OD): d [ppm] 1.68-2.00 (2H, m), 2.05-2.15 (2H, m), 2.90 (3H, s), 2.97-3.11 (2H, m), 3.99 (2H , s), 4.21-4.31 (2H, m), 4.40-4.50 (1H, m), 5.15 (2H, s), 7.11-7.16 (2H, d), 7.16-7.26 (2H, d), 7.30- 7.39 (4H, m), 8.35 (1 H, s). LRMS: m / z 492.1 (MNH4 +).

PREPARATION 138 (1 S) -3-r4- (3-f4-r (methylsulfonyl) amino1benzyl> -1 H-1, 2,4-triazoM -yl) -1-piperidinip-1-phenylpropylcarbamate tere-butyl The title compound of preparation 137 (500 mg, 1.06 mmol), ammonium formate (500 mg, 7.93 mmol) and 20% palladium hydroxide) w / w over carbon (50 mg) were heated together under reflux in ethanol ( 20 ml) until the evolution of gas ceased. The mixture was filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient elution in dichloromethane: methanol: 0.88 ammonia (90: 10: 1 to 80: 20: 4). The residue (300 mg, 0.89 mmol), the title compound of preparation 7 (222 mg, 0.88 mmol) and sodium triacetoxyborohydride (285 mg, 1.34 mmol) were stirred together at room temperature for 30 minutes in a dichloromethane mixture: acetic acid (30 ml, 10%). The solvents were removed under reduced pressure and the residue was basified with a saturated sodium carbonate solution and extracted with ethyl acetate (3x). The combined organic solutions were dried (MgSO), filtered and evaporated under reduced pressure to obtain the title compound as a white solid, 407 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.31-1.48 (9H, m), 1.48-1.60 (2H, m), 1.77-1.90 (1 H, m), 1.90-2.23 (4H, m), 2.26-2.44 (2H, m), 2.95 (3H, s), 3. 02-3.10 (1 H, m), 3.66-3.74 (1 H, m), 4.03 (2H, s), 4.06-4.16 (1 H, m), 4.74- 5.02 (2H, m), 6.16-6.26 ( 1 H, m), 6.35-6.44 (1 H, m), 7.10-7.15 (2H, d), 7.19-7.37 (7H, m), 7.00 (1 H, s) PREPARATION 139 4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazoM -yl) -1-piperidinocarboxylate benzyl Hydrogen chloride gas was bubbled through a solution of the title compound of preparation 131 (3.00 g, 8.59 mmol) in methanol (50 ml) at 0 ° C, for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (50 ml) and triethylamine (2.51 ml, 18.00 mmol) and phenyl acetimidate hydrochloride (1.59 g, 8.59 mmol) was added. The reaction was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure, the residue was dissolved in triethyl orthoacetate (20 ml) and heated to reflux for 12 hours. The reaction was cooled, the solvent was removed under reduced pressure and the resulting brown oil was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia, 0.88 (95: 5: 0.5) as eluent, obtaining the title in the form of a pale yellow oil, 2.20 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.83 (2 H, d), 2.08 (1 H, dd), 2.20 (1 H, dd), 2.40 (3 H, s), 2.85 (2 H, m), 3.95 (2H, s), 4.10 (1H, m), 4.38 (2H, m), 5.18 (2H, m), 7.05-7.39 (10H, m). LRMS: m / z 391 (MH +).

PREPARATION 140 4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazol-1-iQpiperidine Obtained from the title compound of preparation 139 in the form of an oil, in 100% yield, using a procedure similar to that of preparation 120. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.03-2.38 (4H, m), 2.41 (3H, s), 3.01 (2H, m), 3.43 (2H, m), 4.01 (2H, s), 4.23 (1H, m), 7.18 (5H, m), 8.43 (1 H, s).

LRMS: m / z 257 (MH +).

PREPARATION 141 (1 S) -3-y4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazoM -yl) -1-piperidinyl M • phenylpropylcarbamate tere-butyl Obtained from the title compounds of preparations 7 and 140 in the form of an oil, with a yield of 59%, using a procedure similar to that of preparation 80. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.41 (9H, s), 1.85 (4H, m), 2.05 (4H, m), 2.38 (4H, m), 2.41 (3H, s), 2.98 (1H, d), 3.14 (1H, d) , 4.00 (2H, s) 4.81 (1 H, s), 7.28 (10H, m). LRMS: m / z 491 (MH +).

PREPARATION 142 (1 S) -3-r4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazoM -yl) -1-piperidinyl-M-phenyl-1-propanamine The title compound of Preparation 141 (1.70 g, 3.50 mmol) was dissolved in methanolic hydrochloric acid (30 mL, 2.5 M) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and saturated sodium carbonate was added. The aqueous phase was extracted with dichloromethane (3x), the combined organic solutions were dried (MgSO4), filtered and the solvent was removed under reduced pressure to obtain the title compound as a clear oil, 1.40 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.68-1.91 (6H, m), 1.98-2.18 (3H, m), 2.21 (2H, m), 2.38 (4H, m), 3.13 (2H, m ), 3.89-4.03 (4H, m), 7.18-7.41 (10H, m). LRMS: m / z 390 (MH +).

PREPARATION 143 N-1 (1 S) -3-r 4 - (3-Benzyl-5-methyl-1 H-1, 2,4-triazol-1-yl) -1-piperidinyl-M-phenylpropyl} -3-azetidinocarboxamide 1- (3-Dimethylaminopropyl) -3-etylcarbodiimide hydrochloride (177 mg, 0.93 mmol) was added to a stirred solution of the title compound of preparation 13 (186 mg, 0.93 mmol) and the title compound of the Preparation 142 (300 mg, 0.76 mmol) in dichloromethane (20 ml). After 1 hour, trifluoroacetic acid (5 ml) was added and the reaction was stirred for 12 hours. The solvent was removed under reduced pressure and the resulting oil was loaded directly onto a silica column and eluted with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) to obtain the title compound as a white foam, 200 mg . 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.78-2.40 (15H, m), 2.96 (1H, d), 3.12 (1H, d), 3.39 (2H, m), 3.66-4.02 (6H , m), 5.06 (1H, dd), 7.08-7.19 (9H, m), 8.03 (1H, d). LRMS: m / z 473 (MH +).

PREPARATION 144 1-Benzyl-N-methyl-4-piperidnancarboxamide N-Benzyl-4-piperidinocarboxylic acid (5.00 g, 22.8 mmol), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (5.25 g, 27.4 mmol) and 1-hydroxybenzotriazole hydrate (3.84 g) were added. , 25.1 mmoles) to a solution of methylamine (11.4 ml of a 2.0 M solution in tetrahydrofuran, 22.8 mmole) in dichloromethane (100 ml). The mixture was stirred for 1 hour at room temperature and then partitioned between dichloromethane and water. The organic layer was separated and washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to obtain a pale yellow solid, 3.50 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.78 (3H, m), 2.05 (3H, m), 2. 79 (3H, d), 2.98 (3H, m), 3.50 (2H, s), 7.21 (5H, m). LRMS: m / z 233 (MH +).

PREPARATION 145 1-Benzyl-4- (5-benzyl-4-methyl-4H-1, 2,4-triazol-3-yl) piperidine Lawesson's reagent (6.76 g, 16.7 mmol) was added in one portion, to a solution of the title compound of preparation 144 (3.50 g, 15.2 mmol) in toluene (100 mL) and the mixture was stirred at room temperature for one hour. night. The reaction mixture was filtered through a short pad of silica gel washing with dichloromethane (100 ml) and the solvent was removed under reduced pressure to obtain a yellow foam, 5.00 g. The foam was dissolved in n-butanol (100 ml) and mercury (II) oxide (4.81 g, 22.2 mmol) and phenylacetic hydrazide (3.02 g, 20.2 mmol) was added. The reaction was refluxed for 12 hours, cooled, filtered through a plug of Arbocel® and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a pale yellow oil, 0.85 g. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.60-2.20 (6H, m), 2.80 (3H, m), 3.28 (3H, s), 3.58 (2H, m), 4.19 (2H, s), 7.19-7.40 (10H, m). LRMS: m / z 347 (MH +).

PREPARATION 146 4- (5-Benzyl-4-methyl-4H-1,2,4-triazol-3-yl) piperidine Obtained from the title compound of preparation 145 in the form of an oil, with a yield of 41%, using a procedure similar to that of preparation 120. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.95 (4H , m), 2.20-2.60 (4H, ma), 2.80 (3H, m), 3.31 (2H, m), 4.20 (2H, s), 7.10-7.40 (5H, m). LRMS: m / z 257 (MH +).

PREPARATION 147. { 1-Benzyl-4-r3- (4-fluorobenzyl) -1, 2,4-oxadiazol-5-ill-4-piperidinyl) methanol Sodium borohydride (160 mg, 4.20 mmol) was added to a stirred solution of the title compound of Preparation 102 (1.35 g, 3.53 mmol) in methanol (15 mL) and the reagents were stirred at room temperature for 2 hours. The methanol was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic extract was separated, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) as eluent, obtaining the title compound as a oil, 860 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.79 (2H, m), 2.23 (4H, m), 2.65 (2H, m), 3.46 (2H, s), 3.74 (2H, s), 4.05 ( 2H, s), 7.02 (2H, m), 7.26 (7H, m). LRMS: m / z 382.4 (MH +).

PREPARATION 148 1-Benzyl-4-r3- (4-fluorobenzyl) -1.2.4-oxadiazol-5-ip-4- (methoxymethyl) piperidine To a stirred solution of the title compound of the preparation 147 (495 mg, 1.31 mmol) in dry acetonitrile (8 ml) was added potassium tert-butoxide (184 mg, 1.56 mmol) and methyl p-toluenesulfonate (296 mg, 1.56 mmol) and the reaction was stirred at room temperature for 5 days. The solution was partitioned between ethyl acetate and water. The organic layer was separated, concentrated under reduced pressure and purified by column chromatography on silica gel using methanol: dichloromethane (95: 5) as eluent to obtain the title compound as an oil, 270 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.82 (2H, m), 2.05 (2H, m), 2. 50 (2H, m), 2.70 (2H, m), 3.22 (3H, s), 3.42 (2H, s), 3.52 (2H, s), 4.04 (2H, s), 7.02 (2H, m), 7.26 (7H, m). LRMS: m / z 396.5 (MH +).

PREPARATION 149 4- [3- (4-fluorobenzyl) -1,4, 2,4-oxadiazol-5-in-4- (methoxymethyl) piperidine 1-Chloroethyl chloroformate (0.96 ml, 0.87 mmol) was added to a solution of the title compound of preparation 148 (265 mg, 0.67 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 24 hours at room temperature, then concentrated under reduced pressure. The residual oil was dissolved in methanol (5 ml) and the reaction mixture was heated to reflux for 2 hours. Silica gel was added to the cooled solution, which was concentrated under reduced pressure and purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, obtaining the title compound in form of a gum, 160 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.01 (2H, m), 2.39 (2H, m), 2.81 (2H, m), 3.24 (5H, m), 3.53 (2H, s), 4.05 ( 2H, s), 7.02 (2H, m), 7.26 (2H, m). LRMS: m / z 306 (MH +).

PREPARATION 150 (1 S) -3-r4-r3- (4-fluorobenzyl) -1, 2,4-oxadiazol-5-yl) -4- (methoxymethyl) -1-piperidinyl-1-phenylpropylcarbamate tere-butyl Obtained from the title compounds of preparations 7 and 149 in the form of an oil, with a yield of 93%), using a procedure similar to that of preparation 80. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.28 (9H, s), 1.87 (6H, m), 2.28 (4H, m), 2.66 (1 H, m), 2.78 (1 H, m), 3.22 (3H, s), 3.49 (2H, s), 4.04 (2H, s), 4.77 (1H, m), 6.72 (1H, m), 6.98 (2H, t), 7.25 (7H, m) . LRMS: m / z 539.6 (MH +).

PREPARATION 151 (1 S) -3-T4-r3- (4-fluorobenzyl) -1, 2,4-oxadiazol-5-n-4- (methoxymethyl) -1-piperidinin-1-phenyl-1-propanamine Obtained from the title compound of preparation 150 in the form of an oil, with a yield of 98%, using a procedure similar to that of Preparation 81. LRMS: m / z 439.7 (MH +).

EXAMPLE 1 N-f (1 S) -3-r4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl-M-phenylpropiD-cyclobutanecarboxamide The title compounds of preparation 39 (200 mg, 0.82 mmol) and of preparation 8 (285 mg, 1.23 mmol) were triturated together with sodium triacetoxyborohydride (209 mg, 0.98 mmol) in dichloromethane-acetic acid (10 ml, 10%) for 4 hours at room temperature. A saturated aqueous solution of sodium bicarbonate was added and the product was extracted with dichloromethane (3x). The combined organic layers were washed with water and brine, dried (MgSO 4), filtered and the solvent was evaporated under reduced pressure. The product was purified by chromatography on silica gel, using ethyl acetate: methanol (95: 5) as eluent and then dissolved in diethyl ether saturated with hydrogen chloride gas. Evaporation to dryness afforded the title compound as the hydrochloride salt, 60 mg. Found C, 64.68; H, 7.26; N, 10.51% C28H34N402; 1 HCl; 1.4 H20 requires C, 64.64; H; 7.32; N, 10.77% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.78-2.20 (13H, m), 2.20-2.40 (3H, m), 2.81-2.95 (2H, m), 2.95-3.00 (2H, m), 4.05 (2H, s), 5.10 (1H, m), 7.17-7.25 (2H, m), 7.25-7.35 (7H, m), 7.45-7.55 (1H, m). LRMS: m / z 459 (MH +). [a] D: -45.6 (c = 0.34, methanol) EXAMPLE 2 N-f 1 -phenyl-3-r 4 - (4H-1, 2,4-triazol-4-yl) -1-piperidinylpropyl > Cyclobutanecarboxamide The title compound of preparation 116 (560 mg, 2.31 mmol) was dissolved in ethanol (20 ml) and 20% palladium hydroxide w / w over carbon (500 mg) and ammonium formate (728 mg, 11.5 mmol) was added. ). The reaction was refluxed for 1 hour, cooled and filtered through a short bed of Arbocel®. The filtrate was concentrated under reduced pressure and the resulting oil and the title compound of Preparation 3 were used to prepare the title compound using a procedure similar to that of Example 1. The reaction mixture was purified by gel column chromatography. silica using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent, yielding the title compound as a white foam, 50 mg. Found C, 66.90; H, 7.92; N, 18.68% C2? H29N50; 0.5 H2O; requires C, 66.64; H; 7.95; N, 19.06% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.82-2.45 (17H, m), 2.95-3.12 (3H, m), 4.05 (1 H, m), 5.13 (1 H, m) , 7.21-7.40 (5H, m), 8.21 (2H, m). LRMS: m / z 368 (MH +).

EXAMPLE 3-5 The compounds of the following examples presented in the table with general formula: were prepared using a procedure similar to that of Example 2, from the title compound of preparation 3 and the corresponding benzylamine. 1 = Product obtained in the form of the hydrochloride salt EXAMPLE 6 N-f 1-Phenyl-3-r 4 - (3-methyl-1,2,4-oxadiazol-5-yl) -1 • piperidinylpropiD-cyclobutanecarboxamide A mixture of the title compound of preparation 21 (566 mg, 2.27 mmol) and sodium hydroxide (136 mg, 3.41 mmol) in ethanol (20 ml) was stirred for 2 hours at room temperature and the solvent was evaporated under reduced pressure. This intermediate and the title compound of preparation 3 were then used to prepare the title compound using a procedure similar to that of Example 1. The reaction mixture was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 (98: 2: 0.25). The product was dissolved in methanolic hydrochloric acid (3 ml, 2.5 m) and the solvent was evaporated under reduced pressure to obtain the title compound, 85 mg. Found C, 62.16; H, 7.53; N, 12.19% C 22 H 3 o N 402; HCl; 0.6 MeOH; requires C, 61.69; H; 7.70; N, 12.73% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.80-2.45 (16H, m), 3.06-3.40 (6H, m), 3.62-3.80 (2H, m), 5.00 (1H, dd ), 7.20-7.40 (5H, m). LRMS: m / z 383 (MH +).

EXAMPLE 7 N-f 1-Phenyl-3-r 4 - (3-phenyl-1, 2,4-oxydiazol-5-yl) -1-piperidinyl-propy-D-cyclobutanecarboxamide The title compounds of preparations 3 and 37 were used to prepare the title compound using a procedure similar to that of Example 1. The reaction mixture was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 ( 98: 2: 0.25) as eluent, yielding the title compound, 218 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.60 (3H, s), 1.78-2.48 (14H, m), 2.93 (1H, d), 3.04 (2H, m), 5.13 (1H, m), 7.20-7.40 (5H, m), 7.50 (3H, m), 8.09 (2H, m). LRMS: m / z 445 (MH +).

EXAMPLES 8-15 The compounds of the following examples presented in the table with general formula: were prepared using a procedure similar to that of Example 1, from the title compound of preparation 3 and the corresponding amine. 1 = Product obtained in the form of the hydrochloride salt EXAMPLE 16 N - \ (S.-3-r4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl M - (3-fluorophenyl) propin-2-cyclopropylacetamide Diisobutylaluminum hydride (42.1 ml of a 1.0 M solution in dichloromethane, 42.1 mmol) was added dropwise to a solution of the title compound of preparation 12 (5.7 g, 19.1 mmol) in dichloromethane (100 ml) at -78 ° C. The reaction mixture was stirred at this temperature for 1 hour, then methanol (5 ml) was added pre-cooled to -78 ° C. The mixture was warmed to room temperature and washed with 2 M hydrochloric acid, water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to obtain the aldehyde as a yellow oil, 3.3 g. From this oil (485 mg, 1.81 mmol), the title compound of preparation 39 (420 mg, 1.81 mmol) and sodium triacetoxyborohydride (578 mg, 2.73 mmol) were stirred together for 72 hours at room temperature in dichloromethane: acetic acid (30 ml, 10%). The solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and then with water. The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. The residue (700 mg, 1.42 mmol) was stirred for 1 hour at room temperature in dichloromethane (14 ml) and trifluoroacetic acid (14 ml). The solvents were evaporated under reduced pressure. The residue was basified with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) as eluent. A portion of the residue (100 mg, 0.25 mmol), 2-cyclopropylacetic acid (28 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (41 mg, 0.3 mmol), 1- (3-dimethylaminopropyl) -3-ethyl hydrochloride carbodiimide (63 mg, 0.33 mmole) and triethylamine (46 μl, 0.33 mmole) were stirred for 2 hours at room temperature in dichloromethane (20 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (98: 2: 0.25), as eluent to obtain the title compound as an oil, 97 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.16-0.23 (2H, m), 0.58-0.65 (2H, m), 0.97-1.08 (1 H, m), 1.81-1.97 (3H, m), 1.97-2.23 (7H, m), 2.23-2.40 (2H, m), 2.82-2.95 (2H, m), 2.95-3.05 (1 H, m), 4.05 (2H, s), 5.08-5.16 (1 H , m), 6.89-7.00 (2H, m), 7.00-7.06 (1H, d), 7.23-7.35 (6H, m), 7.63-7.71 (1H, m) LRMS: m / z 477.3 (MH +) EXAMPLE 17 N - ((1 S> -3f4-r3- (4-Methylbenzyl, 2,4-oxadiazol-5-ill-1-piperidinyl M • phenylpropiD-cyclobutanecarboxamide The title compound of preparation 77 (200 mg, 0. 56 mmole) in dichloromethane (10 ml) with trifluoroacetic acid (4 ml). The solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium carbonate and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (131 mg, 0.51 mmol), the title compound of preparation 8 (130 mg, 0.56 mmol) and sodium triacetoxyborohydride (162 mg, 0.76 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 3 days. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (High Performance Liquid Chromatography) (phenomonex magellen Cis (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 38 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.71-2.60 (16H, m), 2.61-2.82 (1 H, m), 2.81-3.25 (4H, m), 3.32-3.83 (2H, m), 4.02 (2H, s), 4.95 (1 H, s), 6.75 (1 H, m), 7.15-7.47 (9H, m) LRMS: m / z 473.3 (MH +) EXAMPLE 18 N-f (1 S-3-f4-r4-Trifluoromethylbenzyl, -1, 2,4-oxadiazol-5-yl-1-piperidinyl M • phenylpropiD-cyclobutanecarboxamide The title compound of Preparation 78 (221 mg, 0.54 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (4 mL). The solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue obtained (164 mg, 0.53 mmol), the title compound of preparation 8 (134 mg, 0.58 mmol) and sodium triacetoxyborohydride (168 mg, 0.70 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 3 days. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (phenomonex magellen C-ts (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 40 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.46-2.61 (13H, m), 2.61-3.25 (5H, m), 3.45 (1H, m), 3.72 (1H, m), 4.13 (2H , s), 4.95 (1 H, m), 6.65 (1 H, m), 7.13-7.45 (7H, m), 7.42 (1 H, d), 7.58 (1H, d) LRMS: m / z 527.4 ( MH +) EXAMPLE 19 N-ff 1 S) -3-f4-.3-.1, 3-Benzodioxol-5-ylmethin-1, 2,4-oxadiazol-5-iM-1-piperidinyl} -1-phenylpropiP-cyclobutanecarboxamide (UK-383290-51) The title compound of preparation 79 (258 mg, 0.67 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml). The solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (175 mg, 0.44 mmol), the title compound of preparation 8 (113 mg, 0.49 mmol) and sodium triacetoxyborohydride (141 mg, 0.66 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 3 days. The reaction mixture was basified with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine., dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (phenomonex magellen C-is (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 31 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.74-3.35 (18 H, m), 3.46 (1 H, m), 3.70 (1 H, m), 3.96 (2 H, s), 4.90 (1 H, m), 4.95 (1 H, m), 5.95 (2H, s), 6.65-6.85 (3H, m), 7.25-7.51 (5H, m), LRMS: m / z 503.4 (MH +) EXAMPLE 20 N- (1 S) -3-f 4 -3- (3,5-Difluorobenzyl) -1,2,4-oxadiazol-5-ill-1-piperidinium-1-phenylpropiP-cyclobutanecarboxamide The title compound of Preparation 75 (100 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (4 mL). The solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (69 mg, 0.25 mmol), the title compound of preparation 8 (63 mg, 0.27 mmol) and sodium triacetoxyborohydride (79 mg, 0.37 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 3 days. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (phenomomex magellen C18 (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 39 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.74-3.35 (18H, m), 3.45 (1 H, m), 3.70 (1 H, m), 4.04 (2H, s), 4.93 (1 H, m), 6.65-6.91 (3H, m), 7.23-7.45 (6H, m) LRMS: m / z 495.0 (MH +) EXAMPLE 21 NTd S) -3-r4- (3-Benzyl-1,2,4-oxadiazol-5-iP-1-piperidinyl M - (3-fluoropheniPpropylcyclobutanecarboxamide Diisobutylaluminum hydride (42.1 ml of a 1.0 M solution in dichloromethane, 42.1 mmol) was added dropwise to a solution of the title compound of preparation 12 (5.7 g, 19.1 mmol) in dichloromethane (100 ml) at -78 ° C. C. The reaction mixture was stirred at -78 ° C for one hour, then methanol (5 ml) was added pre-cooled to -78 ° C. The mixture was warmed to room temperature and washed with 2M hydrochloric acid, water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to obtain the title compound as a yellow oil, 3.3 g . From this oil (485 mg, 1.81 mmol), the title compound of preparation 39 (420 mg, 1.81 mmol) and sodium triacetoxyborohydride (578 mg, 2.73 mmol) were stirred together for 72 hours at room temperature in dichloromethane: acetic acid (30 ml, 10%). The solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and then with water. The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure. The residue (700 mg, 1.42 mmol) was stirred for 1 hour at room temperature in dichloromethane (14 ml) and trifluoroacetic acid (14 ml). The solvents were evaporated under reduced pressure. The residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) as eluent. A portion of the residue (100 mg, 0.25 mmole), cyclobutanecarboxylic acid (28 mg, 0.28 mmole), hydroxybenzotriazole hydrate (41 mg, 0.3 mmole), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiom hydrochloride Da (63 mg, 0.33 mmol) and triethylamine (46 μl, 0.33 mmol) were stirred for 2 hours at room temperature in dichloromethane (20 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (98: 2: 0.25) as the eluent to obtain the title compound as a gum which solidified upon standing, 108 mg. Found C, 70.26; H, 7.00; N, 11.66%) C28H33FN4O2; 0.1 H2O requires C, 70.30; H, 7.00; N, 11.71% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.31-2.44 (14H, m), 2.80-3.10 (5H, m), 4.02-4.15 (3H, m), 5.06-5.18 (1H , m), 6.84-7.03 (4H, m), 7.18-7.42 (5H, m), 7.71-7.84 (1H, m) LRMS: m / z 477.3 (MH +) EXAMPLE 22? -f (1S) -3-f4- (3-f4-r, MethylsulfoniDamino-1-benzyl) -1,2,4-oxadiazol-5-yl) -1-piperidin-1-phenylpropyl) cyclobutanecarboxamide The title compound of preparation 47 (6.50 g, 30.9 mmol), hydroxylamine hydrochloride (10.7 g, 154 mmol) and sodium carbonate (16.3 g, 154 mmol) in methanol (100 mL) and water (100 mL) were heated reflux for 5 hours. The reaction was cooled, filtered and the methanol was evaporated under reduced pressure. The remaining aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried (MgSO), filtered and the solvent was evaporated under reduced pressure to obtain a pale orange solid. Then, the solid and carbonyldiimidazole (158 mg, 0.97 mmol) were added to a solution of carbonyldiimidazole (158 mg, 0.97 mmol) and the title compound of preparation 115 in DMF (2 ml) which had been stirred at room temperature for 1 hour. The reaction was heated at 115 ° C for 6 hours, cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent, yielding the title compound as a pale orange oil which was lyophilized in water / acetonitrile to obtain a pale orange foam, 43 mg. Found C, 62.23; H, 6.82; N, 12.60% C 29 H 37 N 5 SO 4; 0.3 H2O requires C, 62.52; H, 6.80; N, 12.57% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.78-2.40 (18H, m), 2.80-3.05 (7H, m), 4.03 (2H, s), 5.08 (1H, dd), 7.15-7.45 (9H, m) LRMS: m / z 552 (MH +) [a] D -32.6 (c = 1.97, MeOH) EXAMPLE 23 4-fr5- (1f (3S) -3-r (cyclobutylcarboniP amino-3-phenylpropyl) -4-piperidinD-1, 2,4-oxadiazol-3 -n-methynedbenzamide The title compound of preparation 55 (7.00 g, 43.8 mmol), hydroxylamine hydrochloride (15.2 g, 218 mmol) and sodium carbonate (23.1 g, 218 mmol) in methanol (100 mL) and water (100 mL) were heated reflux for 5 hours. The reaction was cooled, filtered and the methanol was evaporated under reduced pressure. The remaining aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to obtain a light orange solid. The solid and carbonyldiimidazole (158 mg, 0.97 mmol) were then added to a solution of carbonyldiimidazole (158 mg, 0.97 mmol) and the title compound of preparation 115 in DMF (2 mL) which had been stirred at room temperature for 1 h. hour. The reaction was heated at 115 ° C for 6 hours, allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent, obtaining the title compound as a clear oil which was lyophilized in water / acetonitrile obtaining a white solid, 12 mg. + H NMR (400 MHz, CDCl 3): d [ppm] 1.78-2.40 (17H, m), 2.80- 3.05 (4H, m), 4.03 (2H, s), 5.08 (1 H, dd), 5.58 (1 H, sa), 6.01 (1 H sa), 7.15-7.30 (5H, m), 7.40 (2H, d), 7.75 (2H, d) LRMS: m / z 502 (MH +) EXAMPLE 24 N-U 1 S) -3- (4-r 3 - (2,5-Difluorobenzyl-1,2,4-oxadiazol-5-ill-1-piperidinyl-1-phenylpropiD-cyclobutanecarboxamide The title compound of Preparation 74 (142 mg, 0.37 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (4 mL) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (107 mg, 0.38 mmol), the title compound of preparation 8 (97 mg, 0.42 mmol) and sodium triacetoxyborohydride (122 mg, 0.59 mmol) were stirred in dichloromethane: acetic acid (20 ml., 10%) at room temperature for 3 days. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined aqueous extracts were washed with brine, dried (MgSO 4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen Cie (2) 0.1% aqueous TFA): acetonitrile 1: 19-19: 1) to obtain the title compound, 9 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.43-2.05 (4H, m), 2.05-2.41 (8H, m), 2.50 (1H, sa), 2.66-2.83 (1H, m), 2.85- 3.36 (4H, m), 3.45 (1Hm), 3.70 (1H, sa), 4.08 (2H, s), 4.95 (1H, s), 6.70 (1H, sa), 6.93-7.14 (2H, m), 7.27-7.41 (6H, m) LRMS: m / z 495.1 (MH +) EXAMPLE 25 N - ((1 S.-3-f4-r3- (2,6-Difluorobenzyl) -1,4, 2,4-oxadiazol-5-n-1-piperidinyl M • phenylpropiP-cyclobutanecarboxamide The title compound of preparation 76 (163 mg, 0.43 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO, *), filtered and evaporated under reduced pressure. The obtained residue (118 mg, 0.42 mmol), the title compound of preparation 8 (107 mg, 0.47 mmol) and sodium triacetoxyborohydride (143 mg, 0.63 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 3 days. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO 4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen C18 (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 10 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.33-2.05 (4H, m), 2.05-2.45 (8H, m), 2.41-2.82 (2H, m), 2.86-3.25 (4H, m), 3.35. -3.87 (2H, m), 4.15 (2H s), 4.95 (1 H, s), 6.85 (1 H, m), 6.95 (2H, m), 7.23-7.45 (6H, m) LRMS: m / z 495.1 (MH +) EXAMPLE 26 / V - ((1S) -1-Phenyl-3-f4-r3- (3-pyridinylmethyl) -1, 2,4-oxadiazol-5-n-1 • piperidinyl) propyl) cyclobutanecarboxamide A solution of the title compound of preparation 115 (300 mg, 0.87 mmol) in dichloromethane (20 ml) was treated with diisopropylethylamine (0.36 ml, 2.09 mmol) and bis (tetramethylene) fluoroformamidine hexafluorophosphate (331 mg, 1.05 mmol). ). After 1 hour, / V-hydroxy-2- (3-pyridinyl) ethanimidamide [WO 9600720] (171 mg, 1.13 mmol) was added and stirring continued for 12 hours. The reaction was diluted with dioxane (30 ml) and then heated at 120 ° C for 4 hours. The cooled mixture was diluted with dichloromethane (100 ml) and washed with a saturated aqueous sodium carbonate solution and brine, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (94.5.5: 0.5) as eluent. The resulting oil was dissolved in dichloromethane (10 ml), treated with 1 M hydrochloric acid in dioxane (4 ml) and evaporated under reduced pressure. Freeze drying in water / acetonitrile gave the title compound as a yellow solid, 191 mg. Found C, 51.85; H, 7.06; N, 11.02% C 27 H 33 N 5 O 2; 5 H2O; 2 HCl requires C, 52.09; H, 7.29; N, 11.25% 1H NMR (400 MHz, DMSOd6): d [ppm] 1.70 (1 H, m), 1.86 (1 H, m), 1.92-2.14 (10H, m), 2.91-3.17 (5H, m) , 3.28-4.02 (2H and H2O), 4.36 (2H, s), 4.83 (1 H, m), 7.22 (1 H, m), 7.30 (3H, m), 7.94 (1 H, m) 8.24 (1 H, d), 8.41 (1 H, d), 8.78 (1 H, d), 8.88 (1 H, s) LRMS: m / z 460.2 (MH +) EXAMPLE 27? / - ((1 S) -1 - Phenyl-3-f4-r3- (4-pyridinylmetn-1, 2,4-oxadiazol-5-in-1 • piperidinyl) propyl) cyclobutanecarboxamide A solution of the title compound of preparation 115 (300 mg, 0.87 mmol) in dichloromethane (20 ml) was treated with diisopropylethylamine (0.36 ml, 2.09 mmol) and bis (tetramethylene) fluoroformamidinium hexafluorophosphate (331 mg, 1.05 mmol). After 1 hour,? / - hydroxy-2- (4-pyridinyl) ethanamidamide [WO document] was added. 9600720] (171 mg, 1.13 mmol) and stirring was continued for 12 hours. The reaction was diluted with dioxane (30 ml) and then heated at 120 ° C for 4 hours. The cooled mixture was diluted with dichloromethane (100 ml) and washed with a saturated aqueous sodium carbonate solution and brine, dried (MgSO 4), filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (94.5: 5: 0.5) as eluent. Freeze drying in water / acetonitrile gave the title compound as a yellow foam, 121 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.75-2.20 (12H, m), 2.20-2.40 (4H, m), 2.80-3.10 (4H, m), 4.05 (2H, s), 5.14 (1 H, m), 7.16-7.37 (8Hm), 8.57 (1H, d) LRMS: m / z 460.2 (MH +) EXAMPLE 28? / - f (1S) -3-r4- (3-f2-r (Methylsulfonyl-amino-benzyl> -1, 2,4-oxadiazol-5-yl) -1-piperidin-1-phenylpropyl > cyclobutanecarboxamide The title compound of preparation 48 (5.60 g, 28.5 mmol), hydroxylamine hydrochloride (9.9 g, 142 mmol) and sodium carbonate (15.1 g, 142 mmol) in methanol (100 mL) and water (100 mL) was heated reflux for 5 hours. The reaction was cooled, filtered and the methanol was evaporated under reduced pressure. The remaining aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to obtain a red solid. Then, the solid and carbonyldiimidazole (158 mg, 0.97 mmol) were added to a solution of carbonyldiimidazole (158 mg, 0.97 mmol) and the title compound of preparation 115 in DMF (2 mL) which had been stirred at room temperature for 1 hour. The reaction was heated at 115 ° C for 6 hours, cooled to room temperature and the solvent was evaporated under reduced pressure, the resulting brown oil was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 (95 : 5: 0.5) as eluent, obtaining the title compound as a clear oil which was lyophilized in water / acetonitrile to obtain a white solid, 24 mg. Found C, 62.83; H, 6.84; N, 12.95% C 29 H 37 N 5 SO 4; 0.1 H2O requires C, 62.93; H, 6.77; N, 12.65%) 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.80-2.40 (17H, m), 2.80- 3.05 (4H, m), 3.11 (3H, s), 4.08 (2H, s), 5.05 (1 H, dd), 7.15-7.45 (8H, m), 7.60 (1 H, d), 9.73 (1 H, sa) LRMS: m / z 552 (MH +) [a] D -31.0 (C = 1.16, MeOH) EXAMPLE 29? .- ((1S) -1-Phenyl-3-f4-r3- (2-pyridinylmethyl-1,2,4-oxadiazol-5-in-1-p-peridinyl) propyl) cyclobutanecarboxamide A solution of the title compound of preparation 115 (300 g, 0.87 mmol) in dichloromethane (20 ml) was treated with diisopropylethylamine (0.36 ml, 2.09 mmol) and bis (tetramethylene) fluoroformamidinium hexafluorophosphate (331 g, 1.05 mmol). After 1 hour, N'-hydroxy-2- (2-pyridinyl) ethanamide was added [WO document] 9600720] (171 g, 1.13 mmol) and stirring was continued for 12 hours. The reaction was diluted with dioxane (30 ml) and then heated at 120 ° C for 4 hours. The cooled mixture was diluted with dichloromethane (100ml) and washed with a saturated aqueous sodium carbonate solution and brine, dried (MgSO), filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (94.5: 5: 0.5) as eluent. The resulting oil was dissolved in dichloromethane (10 ml), treated with hydrochloric acid 1 M in dioxane (4 ml) and evaporated under reduced pressure. Freeze drying in water / acetonitrile gave the title compound as a green gum, 95 mg. Found C, 52.25; H, 6.97; N, 11.14% C27H33N5? 2; 4.9 H2O; 2 HCl requires C, 52.24; H, 7.27; N, 11.28% 1 H NMR (400 MHz, DMSOd 6): d [ppm] 1.72 (1 H, m); 1.86 (1 H, m); 1.9-2.1 (10H, m); 2.9-3.1 (5H, M), 3.2-4.0 (2H and H20), 4.45 (2H, s), 4.83 (1H, m), 7.23 (1H, m), 7.30 (3H, m), 7.65 ( 1 H, t), 7.70 (1 H, d), 8.15 (1 H, t), 8.23 (1 H, d), 8.67 (1 H, d) LRMS: m / z 460.2 (MH +) EXAMPLE 30? / - f (1 S) -3-r4- (3-isobutyl-1,2,4-oxadiazol-5-yl-1-piperidinyl-M-phenylpropiD-cyclobutanecarboxamide The title compound of preparation 73 (305 g, 0.98 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue obtained (161 mg, 0.76 mmol), the title compound of Preparation 8 (213 mg, 0.923 mmol) and sodium triacetoxyborohydride (244 mg, 1.15 mmol) were stirred in dichloromethane: acetic acid (20 mL, 10%) at room temperature for 2 weeks . The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen C? 8 (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 52 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.95 (6H, d); 1.80-2.20 (13H, m); 2.22-2.40 (4H, m); 2.60 (2H, d), 2.90 (2Hm), 3.05 (2H, m), 5.10 (1H, m), 7.20 (3H, d), 7.30 (2H, m), 7.50 (1H, d). LRMS: m / z 425 (MH +) EXAMPLE 31? / -, (1 S) -3-f4-r3- (3-chlorobenzyl) -1, 2,4-oxadiazol-5-n-1-piperidinyl • phenylpropiD-cyclobutanecarboxamide The title compound of preparation 72 (260 g, 0.68 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue obtained (145 mg, 0.52 mmol), the title compound of preparation 8 (145 mg, 0.62 mmol) and sodium triacetoxyborohydride (166 mg, 0.78 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 2 weeks. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen C? 8 (2) 0.1% aqueous TFA >: acetonitrile 1: 19-19: 1) to obtain the title compound, 9 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.82-2.00 (4H, m); 2.00-2.22 (8H, m); 2.25-2.32 (4H, m); 3.00 (4H, m), 4.02 (2H, s), 5.05 (1H, m), 7.20-7.35 (9H, m), 7.38 (1H, d). LRMS: m / z 494 (MH +) EXAMPLE 32? / - ((1 S) -3-f4-f3-1-Benzofuran-5-ylmethyl) -1,2,4-oxadiazol-5-ill-1-piperidinyl-1-phenylpropyl) cyclobutanecarboxamide The title compound of preparation 71 (176 mg, 0.45 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane and the aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (130 mg, 0.45 mmol), the title compound of preparation 8 (127 mg, 0.55 mmol) and sodium triacetoxyborohydride (146 mg, 0.68 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 2 weeks. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen C-? 8 (2) 0.1% aqueous TFA: acetonitrile 1: 19-19: 1) to obtain the title compound, 44 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.82-2.00 (5H, m); 2.00 (2H, s); 2.05-2.30 (8H, m); 2.40 (2H, m), 2.90 (2H, m), 3.05 (1H, m), 4.10 (2H, s), 5.05 (1H, m), 5.25 (1H, sa), 6.70 (1H, s), 7.20 (3H, m), 7.30 (2H, m), 7.40 (1H, d), 7.42 (1H, d), 7.58 (2H, d). LRMS: m / z 499 (MH +) EXAMPLE 33? .- K1 S) -1-phenyl-3- (4-f3-r4- (trifluoromethoxy) benzyl-1, 2,4-oxadiazol-5-ip-1 • piperidinyl.} Propylcyclobutanecarboxamide The title compound of preparation 70 (306 mg, 0.71 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (4 ml) and the solution was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium carbonate solution and dichloromethane and the aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The obtained residue (204 mg, 0.62 mmol), the title compound of preparation 8 (173 mg, 0.74 mmol) and sodium triacetoxyborohydride (198 mg, 0.93 mmol) were stirred in dichloromethane: acetic acid (20 ml, 10%) at room temperature for 2 weeks. The reaction mixture was basified with a saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (Phenomonex magellen C? 8 (2) 0.1% aqueous TFA ?: acetonitrile 1: 19-19: 1) to obtain the title compound, 38 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.81-2.30 (14H, m); 2.40 (2H, m); 2.92 (2H, m), 3.05 (2H, m), 4.05 (2H, s), 5.05 (2H, m), 7.18 (2H, d), 7.22 (3H, m), 7.32 (4H, m) LRMS: m / z 543 (MH +) EXAMPLE 34 N-S) -3-r4- (3-f 3-r (methylsulfonyl) amino-1-benzyl> -1.2.4-oxadiazol-5-yl) -1-piperidin-H-1-phenylpropyl} Cyclobutanecarboxamide To a solution of the title compound of Preparation 66 (220 mg, 0.91 mmol) in dichloromethane (10 mL) was added the title compound of Preparation 115 (340 mg, 0.99 mmol), 1- (3-dimethylaminopropyl) hydrochloride ) -3-ethyl-carbodiimide (210 mg, 1.09 mmole) and triethylamine (1.08 ml, 7.12 mmole). The reaction was stirred at room temperature for 18 hours and then water was added and the layers were separated. The organic layer was washed with brine, dried (MgSO) and evaporated under reduced pressure. Toluene (25 ml) was added and the solution was heated to reflux for 5 hours. The reaction mixture was cooled and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a brown oil. This was lyophilized in water / acetonitrile to give the title compound as a brown foam, 100 mg. Found C, 62.37; H, 6.92; N, 12.29% C29H37H504S; 0.4 H2O requires C, 62.32; H, 6.82; N, 12.53%) 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.79-1.99 (5H, m); 2.00-2.19 (8H, m); 2.20-2.40 (4H, m), 2.82-3.09 (7H, m), 3.43 (1H, m), 4.02 (2H, s), 5.09-5.17 (1H, m), 7.10-7.41 (9H, m ) LRMS: m / z 552.1 (MH +) [a] D-45.3 (c = 2.12, methanol) EXAMPLE 35 3,3,3-Tififluoro-V-f (1S) -3-r4- (3-f4-r (methylsulfonamino-1-benzyl) -1,2,4-oxadiazol-5-yl) -1-piperidinyl-M-phenylpropyl) propanamide 1- (3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (49 mg, 0.25 mmol) was added to a stirred solution of 3,3,3-trifluoropropionic acid (29 mg, 0.23 mmol) and the title of preparation 91 (100 mg, 0.21 mmol) in dichloromethane (10 ml). After 1 hour, the reaction mixture was loaded directly onto a silica column and eluted with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) to obtain the title compound as a white foam, 55 mg . 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.73-2.35 (12H, m), 2.81-3.18 (8H, m), 4.03 (2H, s), 5.12 (1H, dd), 7.05-7.19 ( 8H, m), 8.34 (1H, d) LRMS: m / z 580 (MH +) EXAMPLE 36 2-Cyclopropyl-? / - f (1S) -3-r4- (3-f4-r (methylsulfonyl) amino-1-benzyl) -1,2,4-oxadiazol-5-yl) -1-piperidinyl-1-phenylpropiDacetamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (49 mg, 0.25 mmol) was added to a stirred solution of cyclopropyl acetic acid (24 mg, 0.23 mmol) and the title compound of preparation 91 ( 100 mg, 0.21 mmol) in dichloromethane (10 ml). After 1 hour, the reaction mixture was loaded directly onto a silica column and eluted with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) to obtain the title compound as a white foam, 75 mg . Found C, 62.06; H, 6.83; N, 12.49% or C29H37N5SO4; 0.5 H2O requires C, 62.12; H, 6.83; N, 12.49% 1 H NMR (300 MHz, CDCl 3): d [ppm] 0.20 (2H, m); 0.58 (2H, m); 1.01 (1 H, m), 1.81-2.00 (3H, m), 2.03-2.19 (7H, m), 2.21-2.43 (2H, m), 2.98 (6H, m), 4.02 (2H, s), 5.11 (1 H, dd), 7.09-7.38 (9H, m) LRMS: m / z 552 (MH +) [a] D -90.0 (c = 1.00, MeOH) EXAMPLE 37? -f (1 S) -3-r4- (3-f4-Kmethylsulfoninamino-1-benzyl) -1, 2,4-oxadiazol-5-yl) -1-pyridinyl-1-phenylpropyl) tetrahydro-2H-pyrano- 4-carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (49 mg, 0.25 mmol) was added to a stirred solution of the title compound of preparation 17 (30 mg, 0.23 mmol) and the title compound of the Preparation 91 (100 mg, 0.21 mmol) in dichloromethane (10 ml). After 1 hour, the reaction mixture was loaded directly onto a silica column and eluted with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) to obtain the title compound as a white foam, 45 mg. Found C, 55.39; H, 6.73; N, 11.21% C30H39N5SO5; 1.5 H2O requires C, 59.19; H, 6.95; N, 11.50% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.71-2.15 (14H, m); 2.18- 2.50 (3H, m); 2.84-3.12 (6H, m), 3.38 (2H, m), 3.89-4.09 (4H, m), 5.09 (1H, dd), 7.09-7.39 (8H, m), 7.81 (1H, d) LRMS: m / z 582 (MH +) EXAMPLE 38 1-Acetyl-? .- f (1 S) -3-y4- (3-f4-r (methylsulfonamino-1-benzyl > -1, 2,4-oxadiazole-5 - il) -1-piperidinin-1-phenylpropyl) -3-azetidinecarboxamide To a solution of the title compound of Preparation 91 (100 mg, 0.21 mmol) in dichloromethane (3 mL) was added the title compound of Preparation 14 (35 mg, 0.23 mmol) and 1- (3-dimethylaminopropyl) hydrochloride. ) -3-ethyl-carbodiimide (50 mg, 0.25 mmol). The reaction was stirred at room temperature for 1 hour. The crude material was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) as eluent, yielding the title compound as a white foam, 102 mg. Found C, 59.51; H, 6.59; N, 13.71% C3oH38N605; 0.6 H2O requires C, 59.51; H, 6.53; N, 13.88% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.69-2.20 (10H, m); 1.88 (3H, s); 2.25-2.35 (1 H, m), 2.38-2.49 (1 H, m), 2.81-3.10 (6H, m), 3.18-3.23 (1 H, m), 4.05 (2H, s), 4.10-4.20 ( 3H, m), 4.38-4.45 (1H, m), 5.10-5.19 (1H, m), 7.17-7.38 (8H, m), 8.02-8.10 (0.5H, m), 8.30-8.39 (0.5H , m) LRMS: m / z 595.2 (MH +) [a] D: -33.2 (c = 1.93, methanol) EXAMPLE 39? / - f (1 S) -3-r4- (3-Benzyl-1, 2, 4-oxadiazol-5-yl) -1-piperidinyl M • phenylpropyl} tetrahydro-2H-pyrn-4-carboxamide The title compound of preparation 81 (77 mg, 0.20 mmol), the title compound of preparation 17 (26 mg, 0.20 mmol), and 1- (3-dimethylaminopropyl) -3-ethyl-carbodimide hydrochloride (51 mg, 0.26 mmol) was stirred in dichloromethane (10 ml) at room temperature for 2 hours. Then, the reaction mixture was washed with brine (2x), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as a white foam, 57 mg. Found C, 69.85; H, 7.45; N, 11.11% C 29 H 36 N 4 O 3; 1 H2O requires C, 71.30; H, 7.40; N, 11.50% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.80-2.10 (12H, m); 2.20-2.40 (3H, m); 2.90 (2H, m), 3.05 (1H, d), 3.40 (2H, m), 4.00 (2H, m), 4.05 (2H, s), 5.10 (1H, m), 7.20-7.35 (10H, m), 7.90 (1 H, d) LRMS: m / z 489 (MH +) [a] D: -32 (c = 1.0, MeOH) EXAMPLE 40 1-Acetyl-JV-f (1 S-3-r 4 -3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl M • phenylpropyl-3-azetidinecarboxamide The title compound of preparation 81 (58 mg, 0.15 mmol), the title compound of preparation 14 (33 mg, 0.23 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmole) was stirred in dichloromethane (10 ml) at room temperature for 2 hours. The reaction mixture was then washed with brine (2x), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as a white solid, 23 mg. Found C, 66.88; H, 7.25; N, 13.45% C29H35N5O3; 1 H2O requires C, 69.44; H, 7.03; N, 13.96% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.85 (3H, s); 1.90-2.40 (10H, m); 2.90-3.00 (2H, m), 3.20 (1H, m), 4.05 (2H, s), 4.18 (4H, m), 4.40 (1H, m), 5.15 (1H, m), 7.20-7.35 (10H, m), 8.00-8.15 (1H, dd) LRMS: m / z 502 (MH +) [a] D-42 (c = 1.00, MeOH) EXAMPLE 41 1- (Acetylamino) -? .- f (1 S) -3-r 4 - (3-benzyl-1,2,4-oxadiazol-5-yl) -1-piperidinium-1-phenylpropiP-cyclopentanecarboxamide The title compound of preparation 81 (58 mg, 0.15 mmol), 1- (acetylamino) cyclopentanecarboxylic acid [Bull. Soc. Chim. Fr., (1965), 2942] (26 mg, 0.15 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) were stirred in dichloromethane (10 ml) at room temperature for 2 h. hours. The reaction mixture was then washed with brine (2x), dried (MgSO4), filtered and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent, yielding the title compound as a white solid, 42 mg. Found C, 68.37; H, 7.49; N, 12.78% C 31 H 39 N 5 O 3; 1 H2O requires C, 70.30; H, 7.42; N, 13.2% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.90 (3H, s); 1.95-2.10 (14H, m); 2.30-2.35 (4H, m), 2.90 (2H, m), 2.95 (1 H, m), 4.02 (2H, s), 5.05 (1 H, m), . 90 (1 H, s), 7.20-7.30 (10H, m), 8.15 (1 H, d) LRMS: m / z 530 (MH +) [a] D -36 (c = 1.0, MeOH) EXAMPLE 42? / - f (1 S) -3-r4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl-1-phenylpropyl H-methoxycyclobutanecarboxamide The title compound of preparation 81 (58 mg, 0.15 mmol), the title compound of preparation 19 (20 mg, 0.15 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmoles) were stirred together in dichloromethane (10 ml) at room temperature for 2 hours. The reaction mixture was then washed with brine (2x), dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (99: 1) as eluent, yielding the title compound as a yellow oil, 31 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.75-2.40 (16H, m); 2.85-2.95 (3H, m); 3.20 (3H, s), 4.05 (2H, s), 5.10 (1H, m), 7.20-7.35 (10H, m), 8.00 (1H, d) LRMS: m / z 489.2 (MH +) EXAMPLE 43 3-fr5- (1-f (3S) -3-r (Cyclobutylcarbonyl) amino-3-phenylpropyl &4-piperidinyl) -1,2,4-oxadiazol-3-ipmethyl) benzamide Oxalyl chloride (0.86 ml, 9.90 mmol) was added dropwise to a solution of the title compound of preparation 52 (1.45 g, 9.00 mmol) in dichloromethane (20 ml) and dimethylformamide (3 drops) at 0 ° C. The reaction was allowed to warm to room temperature and stirred for 12 hours and then 0.88 ammonia (1 ml) was added carefully and the solvent was evaporated under reduced pressure to obtain a yellow solid. The yellow solid was dissolved in methanol (30 ml) and water (30 ml) and hydroxylamine hydrochloride (3.15 g, 45.0 mmol) and sodium carbonate (4.77 g, 45.0 mmol) were added. The reaction was refluxed for 5 hours, then cooled, filtered and the solvent was evaporated under reduced pressure to give a yellow oil. The yellow oil was dissolved in dioxane (10 ml) and the title compound of preparation 115 (344 mg, 1.00 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (210 mg, 1.10 g) were added. mmoles) and the reaction was heated to reflux for 12 hours. The reaction was cooled and the solvent was evaporated under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white foam, 16 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.83-2.41 (16H, m); 2.80-3.09 (5H, m); 4.15 (2H, s), 5.08 (1H, dd), 5.71 (1H, sa), 6.18 (1H, sa), 7.19-7.58 (7H, m), 7.71 (1H, d), 7.80 ( 1 H, s) LRMS: m / z 502 (MH +) EXAMPLE 44 4- (3-benzyl-1,2,4-oxadiazol-5-yl) -1-f (3S) -3-f (cyclobutylcarbonyl) amino-3-phenylpropyl) -4-piperidinecarboxylate ethyl ester A suspension of the title compound of Preparation 106 (195 mg, 0.62 mmol), the title compound of Preparation 8 (215 mg, 0.93 mmol) and sodium triacetoxyborohydride (207 mg, 0.93 mmol) were stirred for 18 hours in dichloromethane. acetic acid (10 ml, 10%) at room temperature and then washed with a saturated aqueous sodium carbonate solution. The organic extract was separated, pre-adsorbed on silica gel, concentrated and purified by column chromatography on silica gel using ethyl acetate as eluent, yielding the title compound as an oil, 170 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.16 (3H, t); 2.18 (19H, m); 3. 00 (1H, m), 4.06 (2H, s), 4.15 (2H, q), 5.10 (1H, m), 7.24 (10H, m) LRMS: m / z 531 (MH +) EXAMPLE 45? .- f ( 1 S) -3-r4-3-benzyl-1, 2,4-oxadiazol-5-yl) -4-cyano-1-piperidinyl-M-phenylpropiD-cyclobutanecarboxamide Sodium triacetoxyborohydride (294 ml, 1.32 mmol) was added to a solution of the title compound of preparation 107 (236 g, 0.88 mmol) and the title compound of preparation 8 (305 mg, 1.32 mmol) in dichloromethane: acetic acid (10 ml, 10% >). The reaction mixture was stirred for 18 hours at room temperature, then partitioned between dichloromethane and saturated aqueous sodium carbonate solution. The organic extract was separated, concentrated under reduced pressure and purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as a foam, 150 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.93 (6H, m); 2.30 (9H, m); 2. 93 (4H, m), 4.09 (2H, s), 5.10 (1H, dd), 6.48 (1H, d), 7.26 (10H, m) LRMS: m / z 484.2 (MH +) [CC] D -38 ( C = 1, methanol) EXAMPLE 46? 7-r (1 S) -3- (4- (3-f3- (ammonosulfonyl) benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl) - l-phenylpropylcyclobutanecarboxamide The title compound of preparation 115 (400 mg, 1.16 mmol), the title compound of preparation 65 (320 mg, 1.39 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (267 mg , 1.39 mmol) were stirred in dioxane (30 ml) at room temperature for 1 hour. The reaction was then heated to reflux for 12 hours, cooled and the solvent was evaporated under reduced pressure. The resulting brown oil was dissolved in ethyl acetate (100 ml), washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a foam, 250 mg. Found C, 61.33; H, 6.56; N, 12.93% C28H35N5SO4; 0.5 H2O requires C, 61.52; H, 6.64; N, 12.81% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.78-2.41 (16H, m); 2.80-3.10 (5H, m); 4.18 (2H, s), 4.89 (2H, sa), 5.09 (1 H, dd), 7.18-7.40 (5H, m), 7.42 (1 H, m), 7.58 (1 H, d), 7.81 (1 H, d), 7.91 (1 H, s) LRMS: m / z 538 (MH +) EXAMPLE 47 1-f (3S) -3-r (cyclobutylcarbonyl) amino-3-phenylpropyl > -4-r3- (4-fluorobenzyl) -1,4,4-oxadiazol-5-in -? / - methyl-4-piperidinocarboxamide Sodium triacetoxyborohydride (159 mg, 0.71 mmol) was added to a solution of the title compound of preparation 109 (153 mg, 0.48 mmol) and the title compound of preparation 8 (164 mg, 0.71 mmol) in dichloromethane: acetic acid (10 ml, 10%). The reaction mixture was stirred for 18 hours at room temperature, then partitioned between dichloromethane and saturated aqueous sodium carbonate solution. The organic extracts were separated, concentrated and purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as a foam, 60 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.41-2.53 (18 H, m), 2.6-2.9 (4 H, m), 3.02 (1 H, q), 4.04 (2 H, s), 5.12 (1 H, dd), 5.88 (1 H, s), 7.00 (2H, m), 7.26 (7H, m). LRMS: m / z 534.5 (MH +) [a] D -28 (c = 1, methanol) EXAMPLE 48 N - ((1 S) -3-f4-r3- (4-fluorobenzyl-1, 2,4-oxadiazol-5-yl-1-piperidinyl-M-phenylpropyl) -tetrahydro-2H-pyran-4-carboxamide The title compound of preparation 92 (150 mg, 0.38 mmol), the title compound of preparation 17 (59 mg, 0.45 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (87 mg, 0.45 g) mmoles) were stirred together in dichloromethane (10 ml) at room temperature for 2 hours. Then, the reaction mixture was washed with brine (2x), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent, yielding the title compound as a white solid, 113 mg. Found C, 67.77; H, 6.99; N, 10.84%; C 29 H 35 N 4 O 3 F; 0.5 H2O requires C, 67.55; H, 7.04; N, 10.87%. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.80-2.10 (11H, m), 2.20-2.40 (4H, m), 2.90 (2H, m), 3.05 (1H, m), 3.40 (2H, t ), 3.98 (2H, m), 4.00 (2H, s), 5.10 (1H, m), 7.00 (2H, m), 7.18-7.30 (7H, m), 7.90 (1H, d) LRMS: m / z 507 (MH +) [] D -30.6 (c = 1.0 MeOH) EXAMPLE 49 3, 3. 3-trifluoro-N - ((1S) -3-f4-r3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-ip-1-piperidinyl} -1-phenylpropyl) propanam The title compound of preparation 92 (15 mg, 0.38 mmol), 3,3,3-trifluoropropionic acid (58 mg, 0.45 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (87 mg, 0.45 g) mmoles) were stirred together in dichloromethane (10 ml) at room temperature for 2 hours. The reaction mixture was then washed with brine (2x), dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent, yielding the title compound as an oil, 100 mg. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.80-2.00 (3H, m), 2.00-2.20 (5H, m), 2.28 (1 H, m), 2.40 (1 H, m), 2.82-2.99 (2H, m), 3.00 (3H, m), 4.00 (2H, s), 5.18 (1H, dd), 7.00 (2H, m), 7.20-7.35 (7H, m), 8.40 (1H, d) ) LRMS: m / z 505 (MH +).

EXAMPLE 50 N - ((1 S) -3-f4-r3- (4-morpholinylmethyl) -1,2,4-oxadiazol-5-iM-1-piperidinyl-M-phenylpropiP-cyclobutanecarboxamide 1- (3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (190 mg, 0.91 mmol) was added to a solution of triethylamine (0.15 ml, 0.93 mmol) and the title compound of preparation 115 (300 mg, 0.91). mmoles) in dichloromethane (30 ml) and the mixture was stirred for 10 minutes. It was added for 2 hours, then it was concentrated under reduced pressure. The residue was dissolved in dioxane (30 ml) and heated to reflux for 15 hours. The mixture was concentrated under reduced pressure and the residue was taken up in saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: amine 0.88 (97: 3: 0.3) as eluent, yielding the title compound as a white foam, 40 mg. Found C, 64.92; H, 8.05; N, 14.68% C 26 H 37 N 5 O 3; 0.75 H2O, requires C, 64.91; H, 8.07; N, 14.56%. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.81-2.42 (16 H, m), 2.60 (4 H, m), 2.84-3.08 (4 H, m), 3.67 (2 H, s), 3.75 (4 H, m), 5.12 (2H, m), 7.20-7.25 (2H, m), 7.30-7.37 (3H, m). LRMS: m / z 469 (MH +) EXAMPLE 51 N - ((1 S) -3-f4-cyano-4-r3- (4-flurobencm-1, 2,4-oxadiazol-5-in-1-piperidinyl M • phenylpropyl) tetrahydro-2H-pyran -4-carboxamide To a stirred solution of the title compound of the preparation 111 (68 mg, 0.16 mmol) in dichloromethane (2 ml) was added the title compound of preparation 17 (25 mg, 0.19 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (36 mg , 0.19 mmoles). The reaction mixture was stirred for 2 hours at room temperature, then partitioned between dichloromethane and water. The organic extract was separated, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (90:10) to obtain the title compound as a white foam, 31 mg. 1 H NMR (300 MHz, CDCl 3 + DMSO 6): d [ppm] 0.85 (1 H, m), 1.54 (4 H, m), 1.74 (2 H, m), 1.98 (2 H, m), 2.33 (6 H, m) , 2.94 (2H, m), 3.38 (2H, m), 3.97 (2H, m), 4.06 (2H, s), 5.09 (1H, dd), 6.73 (1H, d), 7.03 (2H, m ), 7.26 (7H, m) LRMS: m / z 532.6 (MH +) EXAMPLE 52 N - ((1 S) -3-f4-cyano-4-y3- (4-flurobenzyl-1, 2,4- oxadiazol-5-ill-1-piperidinill-1 • phenylpropyl) -2-cyclopropylacetamine To a stirred solution of the title compound of preparation 111 (68 mg, 0.16 mmol) in dichloromethane (2 ml) was added cyclopropanoacetic acid (19 mg, 0.19 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl ester. -carbodiimide (36 mg, 0.19 mmol). The reaction mixture was stirred for 2 hours at room temperature, then partitioned between dichloromethane and water. The organic extract was separated, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (90:10) as eluent, yielding the title compound as a white foam, 35 mg . 1 H NMR (300 MHz, CDCl 3 + DMSO 6): d [ppm] 0.18 (2H, m), 0. 59 (2H, m), 0.90 (1 H, m), 2.22 (12H, m), 2.90 (2H, m), 4.04 (2H, s), 5.12 (1H, dd), 6.58 (1H, d) ), 7.02 (2H, m), 7.26 (7H, m) LRMS: m / z 502.6 (MH +) EXAMPLE 53 1 -acetyl-N- ((1 S) -3-f4-cyano-4-r3- (4 -flurobenzyl) -1.2.4-oxadiazol-5-n-1 • p -peridinyl-1-phenolpropyl) -3-azetidylcarboxamide To a stirred solution of the title compound of preparation 111 (68 mg, 0.16 mmol) in dichloromethane (2 ml) was added the title compound of preparation 14 (27 mg, 0.19 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (36 mg, 0.19 mmol). The reaction mixture was stirred for 2 hours at room temperature, then partitioned between dichloromethane and water. The organic extract was separated, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (90:10) as eluent, yielding the title compound as a white foam, 33 mg . 1 H NMR (300 MHz, CDCl 3 + DMSO 6): d [ppm] 1.23 (2H, m), 1. 83 (2H, m), 2.00 (3H, s), 2.38 (7H, m), 2.90 (2H, m), 3.08 (1H, m), 4.04 (2H, s), 4.12 (2H, m), 4.38 (1 H, m), 5.12 (1 H, dd), 7.02 (2H, m), 7.23 (7H, m) LRMS: m / z 545.6 (MH +) EXAMPLE 54 N - ((1 S) -3- (4-cyano-4-, 3- (4-flurobenzyl) -1.2.4-oxadiazol-5-ill-1-piperidinyl-M-phenylpropyl) -3,3,3-trifluoropropanamide To a stirred solution of the title compound of preparation 111 (68 mg, 0.16 mmol) in dichloromethane (2 ml) was added 3,3,3-trifluoropropionic acid (24 mg, 0.19 mmol) and 1- (3-dimethylamino). nopropyl) -3-ethyl-carbodiimide (36 mg, 0.19 mmol). The reaction mixture was stirred for 2 hours at room temperature, then partitioned between dichloromethane and water. The organic extract was separated, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (90:10) as eluent, yielding the title compound as a white foam, 39 mg . 1 H NMR (300 MHz, CDCl 3): d [ppm] 2.00 (2H, m), 2.38 (8H, m), 2. 94 (2H, m), 3.05 (2H, q), 4.06 (2H, s), 5.18 (1H, dd), 7.02 (2H, m), 7.26 (7H, m) LRMS: m / z 530.6 (MH + ) EXAMPLE 55 N - [(1 S) -3- (4- (3-r4- (aminosulfoninbenzyl-1, 2,4-oxadiazol-5-yl -piperidinyl) -1-phenylpropycyclobutanecarboxamide A solution of the title compound of preparation 64 (175 mg, 0.77 mmol), the title compound of preparation 115 (290 mg, 0.85 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride ( 176 mg, 0.92 mmol) in dioxane (25 ml) was stirred for 72 hours at room temperature and then heated to reflux for 5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white solid, 10 mg. Found C, 61.78; H, 6.74; N, 12.62% C 27 H 35 N 5 SO 4; 0.1CH2Cl2 requires C, 61.80; H, 6.50; N, 12.82%. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.18-1.22 (1 H, m), 1.78-1.98 (5H, m), 2.00--2.19 (7H, m), 2.20-2.40 (4H, m), 2.82-3.09 (4H, m), 3.42-3.51 (1H, m), 4.10 (2H, m), 5.02-5.19 (2H, m), 7.18-7.28 (5H, m), 7.46 (2H, d) , 7.86 (2H, d) LRMS: m / z 538.5 (MH +) EXAMPLE 56 Nf (1 S) -3- [3-benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinyl-1. phenylpropyl > tetrahydro-3-furanocarboxamide The title compound of preparation 93 (150 mg, 0.43 mmol) was added to a solution of tetrahydro-3-furoic acid (50 μl, 0.50 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmole) in dichloromethane and stirred for 4 hours. The mixture was basified by the addition of a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white foam, 90 mg. Found C, 68.57; H, 6.86; N, 12.33% C 29 H 30 N 4 O 3; 0.5 H2O requires C, 68.55; H, 6.86; N, 12.30% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.76 (1 H, m), 1.84 (1 H, m), 2.13 (2 H, m), 2.47 (1 H, m), 2.52 ( 1 H, m), 2.95 (1 H, m), 3.45 (2 H, m), 3.63 (2 H, m), 3.82 (2 H, m), 3.90 (3 H, m), 4.11 (2 H, s), 5.12 (1 H, dd), 7.2-7.36 (10 H, m), 7.70 (1 H, m) LRMS: m / z 447 (MH +) EXAMPLE 57 N-H 1 S -3- (4-f 3-r 4 -acetyl-1-piperazine Dmethyl, 2,4-oxadiazol-5-yl.} -1-piperidinyl) -1-phenylpropylcyclobutanecarboxamide 1- (3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (305 mg, 1.61 mmol) was added to a solution of triethylamine (0.22 ml, 1.63 mmol) and the title compound of preparation 115 (500 mg, 1.45 mM). mmoles) in dichloromethane (25 ml) and stirred for 10 minutes. The title compound of preparation 69 (350 mg, 1.81 mmol) was added and the mixture was stirred for 2 hours, then the mixture was concentrated under reduced pressure. The residue was dissolved in dioxane (25 ml) and heated to reflux for 15 hours. The mixture was concentrated under reduced pressure and the residue was taken up in saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) as eluent, yielding the title compound as a white foam, 45 mg. Found C, 63.49; H, 8.10; N, 15.90% or C28H40N6O3; 1 H2O, requires C, 63.85; H, 8.04; N, 15.96%. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.8-2.2 (16 H, m), 2.2-2.4 (4 H, m), 2.54 (4 H, m), 2.85-3.05 (4 H, m), 3.51 ( 2H, m), 3.59 (2H, m), 3.62 (1H, s), 5.12 (1H, dd), 7.2-7.35 (2H, m), 7.37 (4H, m). LRMS: m / z 510 (MH +) EXAMPLE 58 N-f (1 S) -3-r 3 -benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidylnill-1-phenolpropyl > tetrahydro-3-furanocarboxamide The title compound of Preparation 93 (150 mg, 0.43 mmol) was added to a solution of tetrahydro-3-furoic acid (50 μL, 0.52 mmol) and 1- (3-dimethylaminopropyl) -3-et hydrochloride. 1-carbodiimide (100 mg, 0.52 mmol) in dichloromethane and stirred for 4 hours. The mixture was basified by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound, 90 mg. Found C, 68.57; H, 6.86; N, 12.33% C 26 H 3 o N 403; 0.5 H2O requires C, 68.55; H, 6.86; N, 12.30% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.76 (1 H, m), 1.84 (1 H, m), 2.13 (2 H, m), 2.47 (1 H, m), 2.52 ( 1 H, m), 2.95 (1 H, m), 3.45 (2 H, q), 3.63 (2 H, q), 3.82 (2 H, m), 3.90 (3 H, m), 4.11 (2 H, s), 5.12 (1 H, q), 7.2-7.36 (10 H, m), 7.70 (1 H, m) LRMS: m / z 447 (MH +) EXAMPLE 59 N-f (1 S) -3-r4-r3-.4-fluorobenzyl) -1,2,4-oxadiazol-5-in-4- (methoxymethyl) -1 • piperidinin-1-phenylpropyl acetamide To a stirred solution of the title compound of the preparation 151 (88 mg, 0.2 mmol) was added acetyl chloride (16 μl, 0.22 mmol) and triethylamine (31 μl, 0.22 mmol). The reaction mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (90:10) as eluent, obtaining the title compound in the form of a white foam, 45 mg. 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.94 (9H, m), 2.31 (4H, m), 2.68 (1 H, m), 2.84 (1 H, m), 3.22 (3H, s), 3.52 (2H, s), 4.04 (2H, s), 5.09 (1H, q), 6.99 (2H, t), 7.26 (7H, m), 7.64 (1H, m) LRMS: m / z 481.3 (MH + EXAMPLE 60 N-f3-r4- (3-methyl-5-phenyl-4H-1, 2,4-triazol-4-yl) -1-piperidinyl-M-phenylpropylcyclobutanecarboxamide Sodium triacetoxyborohydride (525 mg, 2.47 mmol) was added to a solution of the title compound of preparation 120 (400 mg, 1.65 mmol) and of preparation 3 (419 mg, 1.82 mmol) in dichloromethane / acetic acid (10 ml, 10%). The reaction mixture was stirred for 30 minutes, after which the solution was basified using a saturated aqueous solution of sodium carbonate and the product was extracted using dichloromethane (3x). The combined organic extracts were dried (MgSO 4), filtered and the solvent was evaporated under reduced pressure to give a brown oil. This was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (98: 2: 0.3) as eluent, obtaining the title compound as a white foam which was lyophilized in water / acetonitrile obtaining a white solid , 130 mg. Found C, 71.54; H, 7.77; N, 14.88% C28H35N5O; 0.6 H2O, requires C, 71.80; H, 7.79; N, 14.95%. 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.78-2.00 (8H, m), 2.06 (3H, m), 2.18-2.20 (5H, m), 2.61 (3H, s), 2.98 (3H, m ), 4.01 (1 H, m), 5.09 (1 H, dd), 6.58 (1 H, d), 7.18-7.30 (5H, m), 7.40-7.48 (5H, m) LRMS: m / z 458 ( MH +) EXAMPLE 61 N-f (1 S) -3-r4-benzyl-5-methyl-4H-1, 2,4-triazol-4-yl) -1-piperidinyl-1-phenylpropiD-cyclobutanecarboxamide The title compound of Preparation 121 (500 mg, 1.95 mmol) and the title compound of Preparation 8 (902 mg, 3.91 mmol) were dissolved in dichloromethane (20 mL) and stirred for 5 minutes. Then, sodium triacetoxyborohydride (620 mg, 2.93 mmol) was added and the mixture was stirred for a further 2 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution, water and brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a white foam, 330mg. Found C, 71.70; H, 8.11; N, 14.35% > C29H37N5O; 0.8 H2O requires C, 71.66; H, 8.00; N, 14.41% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.29-1.42 (2H, m), 1.60-2.09 (9H, m), 2.10-2.18 (2H, m), 2.20-2.31 (3H, m), 2.53 (3H, s), 2.82-3.01 (3H, m), 3.70-3.82 (1 H, m), 4.09 (2H, s), 5.00-5.10 (1 H, m), 6.50-6.58 ( 1 H, m), 7.17-7.38 (10H, m) LRMS: m / z 473 (MH +) [a] D -34.3 (c = 2.00 methanol) EXAMPLE 62 N-f (1 S) -3-r4- (5-benzyl-4-methyl-4H-1, 2,4-triazol-3-iD-1-piperidinyl M • phenylpropiP-cyclobutanecarboxamide Sodium triacetoxyborohydride (318 mg, 1.50 mmol) was added to a solution of the title compounds of preparation 146 (256 mg, 1.00 mmol) and of preparation 8 (231 mg, 1.00 mmol) in dichloromethane: acetic acid (10 ml. , 10% o). The reaction mixture was stirred for 30 minutes, after which it was made basic using a saturated aqueous solution of sodium carbonate and the product was extracted using dichloromethane (3x). The combined organic extracts were dried (MgSO 4), filtered and evaporated under reduced pressure to give a brown oil. This was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) to obtain the title compound as a white foam, 70 mg. Found C, 71.91; H. 7.78; N, 14.04% C 29 H 37 N 5 O; 0.8 H20 requires C, 71.66; H, 8.00; N, 14.41% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.78-2.40 (17H, m), 2.59 (1 H, m), 2.89-3.17 (3H, m), 3.30 (3H, m), 4.20 (2H, m), 5.18 (1H, dd), 7.16-7.40 (9H, m), 7.63 (1H, d) LRMS: m / z 472 (MH +) EXAMPLE 63 N-f (1 S.-3-r4- (3-benzyl-1 H-1,2,4-triazoM -iP-1-piperidinyl-M-phenylpropyl) -cyclobutanecarboxamide Sodium triacetoxyborohydride (190 mg, 0.92 mmol) was added to a solution of the title compound of preparation 134 (220 mg, 0.61 mmol) and the title compound of preparation 8 (200 mg, 0.82 mmol) in dichloromethane: acetic acid (20 ml, 10% solution) and stirred at room temperature for 15 hours. The mixture was basified by the addition of a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The organic extracts were washed with brine and dried (MgSO), filtered and the solvent was evaporated under reduced pressure. This residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) as eluent. This gave a brown oil which was further purified by column chromatography on silica gel using toluene: ethyl acetate: diethylamine (90: 10_1) as eluent, yielding the title compound as a white solid, 106 mg.

Found C, 72.01; H, 7.81; N, 14.72% C28H35N5O; 0.5 H2O requires C, 72.07; H, 7.78; N, 15.01% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.80-2.40 (17H, m), 3.00 (3H, m), 4.05 (2H, s), 4.10 (1 H, m), 5.15 ( 1 H, dd), 7.25-7.35 (10H, m), 8.00 (1 H, s) LRMS: m / z 458 (MH +) [a] D -39.6 (c = 0.1 methanol) EXAMPLE 64 N-f (1 S) -3-r4- (5-benzyl-1-methyl-1 H-1, 2,4-triazol-3-yl) -1-piperidinyl-M-phenylpropiP-cyclobutanecarboxamide Sodium triacetoxyborohydride (290 mg, 1.40 mmol) was added to a solution of the title compound of preparation 8 (310 mg, 1.34 mmol) and the title compound of preparation 130 (230 mg, 0.93 mmol) in dichloromethane: acetic acid (10 ml, 10% solution) and stirred at room temperature for 15 hours. The reaction mixture was basified by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3x). The combined organic layers were washed with brine, dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using toluene: ethyl acetate: diethylamine (80: 20: 1) as eluent, yielding the title compound, 210 mg. Found C, 70.94; H, 8.05; N, 14.28% C 29 H 37 N 5 O; H2O requires C, 71.13; H, 8.03; N, 14.30% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.71-2.42 (16H, m), 2.70 (1 H, m), 2.80 (1 H, d), 3.10 (2H, m), 3.61. (3H, s), 4.16 (2H, s), 5.10 (1H, m), 7.15-7.35 (10H, m), 8.05 (1H, sa) LRMS: m / z 473 (MH +) [a] D -42 (c = 0.1 methanol) EXAMPLE 65 N-f3-.4- (5-Benzyl-1 H-1,2,4-triazol-3-iP-1-piperidinyl-1-phenylpropiD-cyclobutanecarboxamide Sodium triacetoxyborohydride (490 mg, 2.32 mmol) was added to a solution of the title compound of preparation 129 (1.09 mg, 1.55 mmol) and the title compound of preparation 8 (717 mg, 3.01 mmol) in dichloromethane (20 ml. ) and stirred at room temperature for 15 hours.

The mixture was basified by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (190: 10: 1), yielding an impure material which was further purified by preparative HPLC (phenomonex magellen C-? 8 (2) aqueous TFA 0.1%: acetonitrile 1: 19-19: 1) and lyophilized in acetonitrile: water to obtain the title compound as a white foam, 75 mg. Found C, 53.65; H, 5.48; N, 9.51% C28H35N5O; 2 CF3CO2H; 1.5 H2O requires C, 53.93; H, 5.66; N, 9. 83% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.77-2.00 (2H, m), 2.12-2.41 (9H, m), 2.85-2.95 (2H, m), 3.0-3.2 (4H, m) , 3.40 (2H, m), 3.60 (2H, d), 4.20 (2H, m), 5.00 (1H, m), 6.40 (1H, d), 7.23-7.44 (10H, m) LRMS: m / z 459 (MH +) EXAMPLE 66 Nf (1 S) -3-r4- (3-f4-r (methylsulfoniPamino-1-benzyl-1 H-1, 2,4-triazol-1-yl) -1-piperidn-1-phenylpropyl-tetrahydrate -2H-pyrano-4-carboxamide The title compound of Preparation 138 (135 mg, 0.24 mmol) was stirred for 1 hour at 37 ° C in a mixture of trifluoroacetic acid: dichloromethane (4 mL, 10: 1). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (6x). The combined organic layers were dried (MgSO 5), filtered and evaporated under reduced pressure. The residue (90 mg, 0.19 mmol), the title compound of preparation 17 (25 mg, 0.19 mmol), 1-hydroxybenzotriazole hydrate (29 mg, 0.21 mmol) and 1- (3-dimethylaminopropyl) -3- hydrochloride. ethyl carbodiimide (44 mg, 0.23 mmol) were stirred together for 3 hours at room temperature in dichloromethane (5 ml). The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous sodium carbonate solution and then with water. The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with diethyl ether yielded a solid which was recrystallized from ethanol: isopropyl alcohol to obtain the title compound as a crystalline solid, 60 mg. Found C, 61.30; H, 6.89; N, 14.27% C3oH 0N6? 4S; 0.4 H2O requires C, 61.29; H, 6.99; N, 14.29% 1 H NMR (400 MHz, CD3OD): d [ppm] 1.60-1.84 (4H, m), 1.90-2.03 (2H, m), 2.03-2.26 (6H, m), 2.32-2.44 (2H, m), 2.44-2.55 (1 H, m), 2.89 (3H, s), 2.98-3.08 (2H, m), 3.39-3.50 (2H, m), 3.90-4.00 (2H, m), 4.08 (2H , s), 4.19-4.29 (1 H, m), 4.94-5.00 (1 H, m), 7.13-7.18 (2H, d), 7.19-7.26 (3H, d), 7.26-7.35 (4H, m) , 8.37 (1 H, s) LRMS: m / z 581.2 (MH +) Melting point [° C]: 210-211 EXAMPLE 67 2-Cyclopropyl-N-f (1S) -3-r4- (3-f4-r (methylsulfonyl) aminolbenzyl H-1,2,4-triazol-1-iP-1-piperidinyl-l-phenylpropiPacetamide The title compound was prepared using a procedure similar to that described in Example 66, from the title compound of preparation 138 and 2-cyclopropylacetic acid, in 35% yield and recrystallized from isopropyl alcohol / ethyl acetate. Found C, 62.45; H, 6.95; N, 15.02% C 29 H 38 N 6 O 3 S; 0.4 H2O requires C, 62.43; H, 7.0; N, 15.06% 1H NMR (400 MHz, CD3OD): d [ppm] 0.16-0.20 (2H, m), 0.48- 0.52 (2H, m), 1.00-1.08 (1H, m), 1.94-2.03 (2H , m), 2.03-2.26 (8H, m), 2.32-2.47 (2H, m), 2.90 (3H, s), 3.00-3.08 (2H, m), 4.00 (2H, s), 4.18-4.27 (1 H, m), 4. 94-5.00 (1 H, m), 7.13-7.20 (2H, d), 7.20-7.26 (3H, m), 7.26-7.35 (4H, m), 8.35 (1H, d) LRMS: m / z 551.2 (MH +) Melting point [° C]: 185-186 EXAMPLE 68 3.3.3-Trifluro-Nf (1 S) -3-r4- (3-f4-r (methylsulfoniPamino-1-benzyl> -1 H-1, 2,4-triazol-1-yl) -1-piperidinyl-M-phenylpropiPpropanamide The title compound was prepared using a procedure similar to that described in Example 66, from the title compound of preparation 138 and 3,3,3-trifluoropropionic acid, in 35% yield and recrystallized from ethyl acetate Found C, 55.88; H, 5.95; N, 14.67% C 27 H 33 F 3 N 6 O 4 S; requires C, 56.04; H, 5.75; N, 14.52% 1H NMR (400 MHz, CD3OD): d [ppm] 1.95-2.03 (2H, m), 2.03-2.21 (6H, m), 2.34-2.44 (3H, m), 2.90 (3H, s) , 2.97-3.05 (2H, m), 3.10-3.24 (2H, m), 3.29 (1 H, s), 4.00 (2H, s), 4.20-4.27 (1 H, m), 4.95-5.02 (1 H , m), 7.13-7.16 (2H, d), 7.20-7.26 (3H, m), 7.32-7.35 (4H, m), 8.37 (1H, s) LRMS: m / z 579.1 (MH +) Melting point [° C]: 162-163 EXAMPLE 69 N- 1 S -f 3-r 4 - (3-benzyl-1-methyl-1 H-1, 2,4-triazol-5-yl) -1-piperidinyl-M-phenylpropi-P-cyclobutanecarboxamide Methyl iodide (0.41 ml, 6.42 mmol) to a suspension of the title compound of Preparation 127 (1.00 g, 2.90 mmol) and potassium carbonate (480 mg, 3.51 mmol) in acetonitrile (20 ml) compound and the mixture was added was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residue was taken up in water (100 ml) and extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried (MgSO), filtered and concentrated under reduced pressure, the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (98: 2) as eluant to give a white solid. Trifuroacetic acid (2 ml) was added to a solution of the white solid in dichloromethane (10 ml) at 0 ° C and the mixture was allowed to warm to room temperature for 15 hours. The mixture was evaporated under reduced pressure and the residue was taken up in a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the filtrate was evaporated under reduced pressure to obtain a pale yellow oil. Sodium triacetoxyborohydride (420 mg, 2 mmol) was added to a solution of piperidine, acetic acid (0.10 ml, 5.70 mmol) and the title compound of preparation 8 (310 mg, 1.32 mmol) in dichloromethane (15 mL) and stirred at room temperature for 15 hours. The mixture was treated with 2 M hydrochloric acid (1 ml). The mixture was basified by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane: methanol: ammonia 0.88 (92: 8: 1) as eluant to afford a crude material which was further purified by HPLC (Phenomonex Lunac Phenomonex Magellen C 8 and C 8 (2? ) using a solution of ammonium acetate and acetonitrile as eluent) and lyophilized in water / acetonitrile to obtain the title compound as a white foam, 40 mg. Found C, 71.11; H, 7.99; N, 14.18% C 29 H 37 N 5 O; 1 H20 requires C, 71.13; H, 8.03; N, 14.30% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.74-1.42 (16H, m), 2.63-2.72 (1 H, m), 2.90-2.98 (1 H, m), 3.00-3.16 ( 2H, m), 3.75 (3H, s), 4.02 (2H, s), 5.12 (1H, m), 7.15-7.37 (10H, m), 7.72 (1H, d) LRMS: m / z 473 ( MH +) EXAMPLE 70 4-fri- (1-f (3S) -3-Phenyl-3-r (3,3,3-trifluoropropanoiPamino-1-propyl-4-piperidin-P-1 H-1, 2,4-triazole-1- nmetiPbenzamida The title compound of Preparation 136 (700 mg, 1.35 mmol), cyanuric chloride (125 mg, 0.67 mmol) and triethylamine (0.23 mL, 1.35 mmol) were stirred together at room temperature for 1 hour in acetone (30 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (10 ml) and 0.88 ammonia (10 ml) was added. The solvents were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, obtaining a solid, 280 mg. The solid (280 mg, 0.54 mmole) was stirred for 2 hours at room temperature in 10 ml of a mixture of trifluoroacetic acid: dichloromethane (1: 1). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (x6). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue (70 mg, 0.17 mmol), 3,3,3-trifluoropropanoic (21 mf, 0.17 mmoles), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and triethylamine (28 μl, 0.20 mmol) were stirred together for 16 hours at room temperature in dichloromethane (5 ml). The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium carbonate and then with water. The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure, the residue was recrystallized and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate: hexane to obtain the title compound as a crystalline solid, 21 mg. Found C, 60.14; H, 6.07; N, 15.44% C 27 H 29 F 3 N 6 O 2; 0.6 H2O requires C, 60.12; H, 6.02; N, 15.58% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.82-1.92 (1 H, m), 1.92-2-26 (7H, m), 2.26-2.37 (1 H, m), 2.37- 2.47 (1 H, m), 2.92-3.01 (1 H, m), 3.01-3.16 (3 H, m), 4.10 (3 H, s), 5.13-5.21 (1 H, m), 5.40-5.70 (1 H , sa), 5.90-6-20 (1 H, sa), 7.20-7.29 (3H, m), 7.29-7.37 (2H, m), 7.37-7.45 (2H, d), 7.71-7.79 (2H, d ), 7.97 (1 H, s), 8.03-8.10 (1 H, m) LRMS: m / z 529.3 (MH +) EXAMPLE 71 N-f (1 S) -3-r4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazoH -iP-1-piperidinyl-M-phenylpropyl-tetrahydro-2H-pyrn-4-carboxamide 1- (3- (Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (59 mg, 0.31 mmol) was added to a stirred solution of the title compound of preparation 17 (40 mg, 0.31 mmol) and the title compound of Preparation 142 (100 mg, 0.25 mmol) in dichloromethane (10 ml) After 1 hour, the reaction mixture was loaded directly onto a column of silica gel and eluted with dichloromethane: methanol: 0.88 ammonia (95: 5 : 0.5), obtaining the title compound in the form of a white foam, 98 mg Found C, 69.01; H, 7.63; N, 13.27% C30H39N5O2; 1.1 H2O requires C, 69.10 H, 7.96; N, 13.43% 1H NMR (300 MHz, CDCl 3): d [ppm] 1.76-2.08 (13H, m), 2.10-2.51 (6H, m), 2.99 (1H, d), 3.20 (1H, d), 3.49 (2H, m ), 3.82-4.17 (5H, m), 5.18 (1 H, dd), 7.12-7.36 (9H, m), 8.20 (1 H, d) LRMS: m / z 503 (MH +) EXAMPLE 72 Nf (1 S) -3-r4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazoH -iP-1-piperidinyl-M-phenylpropyl-tetrahydro-3-furancarboxamide 1- (3- (Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (59 mg, 0.31 mmol) was added to a solution of tetrahydro-3-furoic acid (36 mg, 0.31 mmol) and the title compound of the preparation 142 (100 mg, 0.25 mmol) in dichloromethane (10 ml). After 1 hour, the reaction mixture was loaded directly onto a column of silica gel and eluted with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5), yielding the title compound as a white foam , 107 mg. Found C, 67.51; H, 7.44; N, 13.40% C29H37N502; 1 H20; 0.15 CH2Cl2 requires C, 67.54 H, 7.64; N, 13.51% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.80-1.99 (3H, m), 2.00-2.41 (14H, m), 3.00 (2H, m), 3.18 (1H, m), 3.80 (1 H, m), 3.98 (5H, m), 5.17 (1 H, m), 7.18-7.35 (9H, m), 8.82 (1H, d). LRMS: m / z 488 (MH +) EXAMPLE 73 1 -Amino-Nf (1 S) -3-r 4 - (3-benzyl-5-methyl-1 H-1, 2,4-triazol-1-iP-1-piperidinium -1 • PhenylpropiP-cyclopentanecarboxamide 1- (3- (Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (118 mg, 0.62 mmol) was added to a stirred solution of the title compound of preparation 15 (141 mg, 0.62 mmol) and the title compound of Preparation 142 (200 mg, 0.50 mmol) in dichloromethane (20 ml) After 1 hour, trifluoroacetic acid (5 ml) was added and the reaction was stirred for 12 hours.The solvent was evaporated under reduced pressure and the resulting oil it was loaded directly onto a column of silica gel and eluted with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5), yielding the title compound as a white foam, 170 mg Found C, 70.24; H, 8.05; N, 16.35%> C30H4oN60; 0.6 H2O requires C, 70.45 H, 8.12; N, 16.43%> 1H NMR (300 MHz, CDCI3): d [ppm] 1.40 (4H, m), 1.62-2.09 (10H, m), 2.15-2.41 (9H, m), 2.98 (1H, d), 3.10 (1H, d), 3.98 (3H, m), 5.10 (1H, dd), 7.06-7.38 ( 10H, m) 8.95 (1 H, d) LRMS: m / z 501 (MH +) EXAMPLE 74 Nf (1 S) -3-r4- (3-benzyl-1 H-1, 2,4-triazole-1 - iP-1 -piperidinyl-l • phenylpropi-tetrahydro-3-f-ranocarboxamide The title compound of preparation 134 (1.17 g, 4.83 mmol), the title compound of preparation 7 (1.20 g, 4.83 mmol) and sodium triacetoxyborohydride (1.53 g, 7.24 mmol) were stirred together for 30 minutes at room temperature in dichloromethane: acetic acid (30 ml, 10%). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO), filtered and evaporated under reduced pressure. The residue (2.3 mg, 4.83 mmol) was stirred for 16 hours in a mixture of dichloromethane: trifluoroacetic acid (30 ml, 5: 1). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO 4), filtered and evaporated under reduced pressure. A part of the residue (200 mg, 0.53 mmol), tetrahydro-3-furancarboxylic acid (65 mg, 0. 53 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (125 mg, 0.65 mmol) were stirred together for 1 hour at room temperature in dichloromethane (5 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and then with water. The organic layer was dried (MgSO), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent to obtain the title compound as a gum, 183 mg. Found C, 69.42; H, 7.53; N, 14.46% C28H35N5O2; 0.6 H2O requires C, 69.36; H.7.55; N, 14.49% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.84-1.94 (1 H, m), 2.00-2.23 (9H, m), 2.23-2.32 (1 H, m), 2.32-2.44 ( 1 H, m), 2.89-3.02 (2H, m), 3.02-3.11 (1H, m), 3.74-3.82 (1H, m), 3.90-3.97 (3H, m), 4.06 (2H, s), 4.06 -4.16 (1 H, m), 5.08-5.16 (1H, m), 7.16-7.37 (10H, m), 7.37-7.48 (1 H, m), 7.97-8.00 (1 H, m) LRMS: m / z 475 (MH +) EXAMPLE 75 N-f (1 S. -3-r4- (3-benzyl-1 H-1, 2,4-triazoM -iP-1-piperidinyl M • phenylpropiDtetrahydro-2H-pyran-4-carboxamide The title compound was obtained using a procedure similar to that described in Example 74, from the title compounds of preparations 134, 7 and 17, in 67% yield. Found C, 69.72; H, 7.67; N, 14.11% C 29 H 37 N 5 O 2; 0.6 H2O requires C, 69.88; H, 7.72; N, 14.05% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.78-1.92 (5H, m), 2.00-2.21 (7H, m), 2.24-2.32 (1 H, m), 2.32-2.45 (2H , m), 2.95-3.06 (1 H, m) 3.0-3.16 (1 H, m), 3.39-3.48 (2H, m), 4.00-4.06 (4H, m), 4.06-4.19 (1 H, m) , 5.10-5.18 (1 H, m), 7.16-7.35 (10H, m), 7.55-7.61 (1 H, m), 8.00 (1 H, s). LRMS: m / z 388.4 (MH +) EXAMPLE 76 1 -Amino-N-f (1 S) -3-.4- (3-benzyl-1 H-1, 2,4-triazoM -iP-1-piperidinyl M • phenylpropiP-cyclopentanecarboxamide The title compound of preparation 134 (1.17 g, 4.83 mmol), the title compound of preparation 7 (1.20 g, 4.83 mmol) and sodium triacetoxyborohydride (1.53 g, 7.24 mmol) were stirred together for 30 minutes at room temperature in dichloromethane: acetic acid (30 ml, 10% >). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO) filtered and evaporated under reduced pressure. The residue (2.3 g, 4.83 mmol) was stirred for 16 hours in a mixture of dichloromethane: trifluoroacetic acid (30 ml, 5: 1). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO 4), filtered and evaporated under reduced pressure. Part of the residue (200 mg, 0.53 mmol), the title compound of preparation 15 (121 mg, 0.53 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (125 mg, 0.65 mmol) were stirred together for 1 hour at room temperature in dichloromethane (5 ml) and then acid was added trifluoroacetic acid (5 ml) and the reaction was stirred for 12 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and water. The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a gum, 58 mg. Found C, 69.89; H, 7.96; N, 16.94% C 29 H 38 N 6 O; 0.6 H2O requires C, 70.02; H.7.94; N, 16.89% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.27-1.53 (4H, m), 1.68-1.90 (4H, m), 1.90-2.40 (12H, m), 2.94-3.06 (2H, m), 4.03-4.15 (1 H, m), 4.05 (2H, s), 5.03-5.11 (1 H, m), 7.16-7.35 (10H, m), 7.97 (1 H, s), 8.61-8.69 (1 H, m). LRMS: m / z 488 (MH +) EXAMPLE 77 1-Acetyl-N-f (1 S) -3-r 4 - (3-benzyl-1 H-1, 2,4-triazol-1-iP-1-piperidinyl-M-phenylprop-P-3-azetidinecarboxamide The title compound was obtained using a procedure similar to that described in Example 74, from the title compounds of preparations 134, 7 and 14, with a yield of 48%. Found C, 67.53; H, 7.51; N, 16.66% C 29 H 36 N 6 O 2; 0.7 H2O requires C, 67.86; H.7.34; N, 16.37% 1 H NMR (400 MHz, CDCl 3): d [ppm], 1.80-2.26 (8H, m), 1.84 (3H, s), 2.26-2.35 (1 H, m), 2.35-2.45 (1 H , m), 2.94-3.11 (2H, m), 3.18-3.29 (1H, m), 4.03-4.26 (4H, m), 4.06 (2H, s), 4.32-4.44 (1H, m), 5.10 -5.27 (1 H, m), 7.16-7.35 (1 OH, m), 7.60-7.65 and 7.77-7.83 (1 H, m), 8.00 (1 H, s). LRMS: m / z 501.6 (MH +) EXAMPLE 78 N-f (1 S-3-r4- (3-benzyl-1 H-1, 2,4-triazol-1-yl) -1-piperidinyl-M-phenylpropiD-1 • propynyl-3-azetidinecarboxamide The title compound of preparation 134 (1.17 g, 4.83 mmol), the title compound of preparation 7 (1.20 g, 4.83 mmol) and sodium triacetoxyborohydride (1.53 g, 7.24 mmol) were stirred together for 30 minutes at room temperature in dichloromethane: acetic acid (30 ml, 10%). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO 4) were filtered and evaporated under reduced pressure. The residue (2.3 g, 4. 83 mmol) was stirred for 16 hours in a mixture of dichloromethane: trifluoroacetic acid (30 ml, 5: 1). The solvents were evaporated under reduced pressure and the residue was basified with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (3x). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. A portion of the residue (200 mg, 0.53 mmol), the title compound of preparation 13 (106 mg, 0.53 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodimidate hydrochloride (125 mg , 0.65 mmoles) were stirred together for 1 hour at room temperature in dichloromethane (5 ml) and then trifluoroacetic acid (5 ml) was added and the reaction was stirred for 12 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and then with water. The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure to obtain an oil. To a solution of this oil (100 mg, 0.22 mmol) and triethylamine (36 μl, 0.26 mmol) was added propionyl chloride (20 μl, 0.24 mmol) with stirring at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution and then with water. The organics were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (98: 2: 0.25) as eluent, yielding the title compound as a gum, 41 mg. Found C, 66.89; H, 7.66; N, 15.75% C30H38N6O2; 1 H2O; 0.06 CH2Cl2 requires C, 67.14; H, 7.52; N, 15.63% 1 H NMR (400 MHz, CDCl 3): d [ppm] 1.06-1.13 (3H, t), 1.74-2.47. (12H, m), 2.94-3.13 (2H, m), 3.19-3.32 (1H, m), 4.03-4.26 (4H, m), 4.05 (2H, s) 4.32-4.42 (1H, m), 5.11 -5.16 (1H, m), 7.18-7.37 (10H, m), 7.55-7.60 and 7.74-7.80 (1 H, m), 8.02 (1 H, s).

LRMS: m / z 515.3 (MH +) EXAMPLE 79 1-Acetyl-N-f (1S) -3-r4- (3-benzyl-5-methyl-1H-1, 2,4-triazoH -iP-1-piperidinyl-1 • phenylpropiP-3-azetidinecarboxamide 1- (3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (96 mg, 0.50 mmol) was added to a stirred solution of acetic acid (28 μl, 0.50 mmol) and the title compound of preparation 143 (200 mg , 0.42 mmol) in dichloromethane (10 ml). After 1 hour, the reaction mixture was loaded directly onto a column of silica gel with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent, yielding the title compound as a soft foam, 102 mg . Found C, 67.74; H, 7.44; N, 16.03%, C30H38N6O2; 1 H2O requires C, 67.64; H.7.57; N, 15.78% 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.76-2.50 (18H, m), 3.00 (1 H, m), 3.18 (1 H, dd), 3.30 (1 H, ddd), 3.98 (3H, m), 4.18 (2H, m), 4.38 (1H, m), 5.16 (1H, dd), 7.08-7.40 (9H, m), 8.26 (0.5H, d), 8.44 (0.5 H, dd). LRMS: m / z 515 (MH +) The following compounds have been prepared using procedures similar to those described above N-f (1 S) -3-f4- (3- (4-Fluorobenzyl) -1 H-1, 2,4-triazol-1 -iP-1-piperidinyl-1-phenylpropyl) -1-propyl-3-azetidinecarboxamide 1 - . 1-Acetyl-Nf (1S) -3-r4- (3-.4-flurobenzyl-1 H-1, 2,4-triazole-1-1, -1-p -peridinyl-1 -phenylpropyl) -3-azetidinecarboxamide 2-Methoxy-N-f M S. -3-r4- (3- (4-fluorobenzyl) -1 H-1.2.4-triazol-1-iP-1-piperidinyl-1-phenylpropyl) -acetamide 3-Methoxy-Nf (1S. -3-r4- (3- (4-fluorobenz-P-1 H-1, 2,4-triazol-1-yl) -1-piperidinyl-1-phenolpropyl. -propanamide

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - Regions of a compound, of formula (I) [Region a] - [Region ß] - [Region?] - [Region d] (I) in which [Region a] is selected from the group consisting of: - A arylheterocyclyl substituent components comprising: -1 hetero-phenylmethylene radicals of partial formula (1.0.0): - in which: the symbol "*" indicates the point of union of the rest of the formula pair to (1.0.0) to the Region ß, as defined below: - R5 is a member selected from the group consisting of a link direct: -O-; -C (= O) -; -NR4- and -S (= O) p-; wherein: R4 is hydrogen or alkyl (CrC2); R6 is a member selected from the group consisting of hydrogen; alkyl (CrC2); alkoxy (Cr C2); -CN; -OH; and -C (= O) NH2; j is an integer selected from 0, 1 and 2; m is an integer selected from 0, 1 and 2; each of R7 and R8 is a member selected from the group consisting of -F; -Cl; -CO2R4; -OH; -CN; - CONR4aR4b; -NR4a-; -NR4aC (= 0) R4b; -NR4aC (= O) OR4b; - NR4aS (= O) pR4b; -S (= O) pNR4aR4; alkyl (C -? - C4) and (C 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (CrC2); alkylcarbonyl (d-C2); and alkylcarbonyloxy (C C2); wherein: p is an integer selected from 0, 1 and 2; each of R4a and R4 is independently selected from hydrogen and alkyl (CrC2); the rest represented by the partial formula (1.0.1): in the partial formula (1.0.0) represents a monocyclic heterocyclic group, or a benzo-fused bicyclic ring system containing said heterocyclic group, wherein said heterocyclic group contains a total of 5 or 6 members of which one or two of said members is nitrogen, the presence of the second optional nitrogen atom being represented by: "[N]"; wherein said heterocyclic group or ring system is selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperazinyl; indolyl; indazolinyl; benzoimidazolyl; quinolinyl; / so-quinolinyl; and quinazolinyl; wherein: R12a is a member selected from the group consisting of hydrogen; F; Cl; -CO2R4; oxo; -OH; CN; NH2; NH-alkyl (C C2); N-dialkyl (C C2) 2; -CF3; alkyl (C C4); alkenyl (C2-C4); (C 1 -C 4) alkoxy; cycloalkyl (C3-C); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with from 0 to 2 substituents R9 wherein: R9 is a member independently selected from the group consisting of F; Cl; -CO2R4; -OH; cyano; -CONR4aR4b; -NR4aR4b; NR4aC (= O) R4b; NR4aC (= O) OR4b; NR4aS (= O) pR4b; -S (= O) pNR4bR4b; (C 1 -C 4) alkyl including dimethyl, and (C 1 -C 4) alkoxy, wherein said alkyl and alkoxy are independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C C2); alkylcarbonyl (C C2); and alkylcarbonyloxy (CrC); and R12b is absent or is a member selected from the group consisting of hydrogen; alkyl (C -? - C4); alkenyl (C2-C); alkoxy (C C2); cycloalkyl (C3-C7); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R9, wherein R9 has the same meanings as above, with the exception that it is independently selected from them; and 2.- hetero-phenylmethylene radicals of partial formula (1.1.0): where: the symbol "*"; R5; R6; R7; R8; j and m are as defined in detail above, with the exception that all the aforementioned substituents are independently selected from their previous selection; the rest represented by the partial formula (1.1.1): (R a) J (1.1.1) in the partial formula (1.1.0) represents: a.- a monocyclic heterocyclic group containing a total of 5 or 6 members of which one of said members is nitrogen and Q is selected between O and S, wherein S may optionally be in the sulfonate form, S (= O) 2; wherein said heterocyclic group is selected from the group consisting of oxazolyl; oxazolidinyl; isoxazolyl; thiazolyl; thiazolidinyl; so-thiazolyl; morpholinyl; and thiomorpholinyl; or b.- a monocyclic heterocyclic group containing a total of 5 or 6 members of which two of said members are nitrogen and a third or fourth of said members is independently selected from N, O and S, wherein said S may be optionally in the sulfonate form, -S (= O) 2; wherein said heterocyclic group is selected from the group consisting of triazolyl, triazinyl, tetrazolyl; Oxadiazolyl; thiadiazolyl; and R13a is selected from the group consisting of hydrogen; F, Cl; -C02R4; oxo; -OH; -CN; NH2; NH-alkyl (C C2); N-dialkyl (C C2) 2; -CF3; alkyl (C C4); alkenyl (C2-C4); alkoxy (C C2); cycloalkyl (C3-C); and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein: R11 is a member selected from the group consisting of F; Cl; -CO2R4; -OH; -CN; -CONR4aR4b; -NR4aR4b; -NR4aC (= O) R4b; -NR4aC (= O) OR4b; -NR4aS (= O) pR4b; -S (= O) PNR4aR4b; (C 4 C) alkyl including dimethyl, and (C 1 -C 4) alkoxy, wherein each of said alkyl and alkoxy is independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C1-C2); alkylcarbonyl (C -? - C2); and alkylcarbonyloxy (C C2); and R13b is a member selected from the group consisting of hydrogen; (C 1 -C 4) alkyl; alkenyl (C2-C); (C 1 -C 2) alkoxy; cycloalkyl (C3-C); C (= O) alkyl (C C4); S (= O) 2 (C 1 -C 4) alkyl and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein R11 has the same meaning as above, with the exception that it is independently selected; B. an amido-aryl or heterocyclyl (substituted) moiety selected from the group consisting of 1.- amido-aryl alkyl-, alkenyl- and alkynyl-substituted moieties of partial formula (2.0.0): where: the symbol "*"; R4 and R6 are as defined above, with the exception that all the above mentioned substituents are selected independently of their previous selection; A is a member selected from the group consisting of: 1. The rest of the partial formula (2.0.3) (2.0.3) in which: the symbols R7; R8 and m are as defined above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and the symbol "*" indicates the point of union of residue A to the remaining portions of partial formula (2.0.0); 2. the rest of the partial formula (2.0.4) representing a monocyclic heterocyclic group, selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; or pyrimidinyl; in which; the symbols R12a and R12b are as defined above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and the symbol "*" indicates the point of union of residue A to the other remaining portions of partial formula (2.0.0); 3. the rest of the partial formula (2.0.5) (2.0.5) that represents a. a monocyclic heteroaromatic group containing a total of 5 members, of which one of said members is nitrogen and Q is selected from O and S, wherein said S may optionally be in the sulfonate form, -S (= O) 2; selected from the group consisting of oxazolyl; isoxazolyl; thiazolyl; e / so-thiazolyl; or b. a monocyclic heterocyclic group containing a total of 5 or 6 members, of which two of said members are nitrogen and a third or fourth of said members is independently selected from N, O and S, wherein said S may be optionally the sulfonate form, -S (= O) 2; selected from the group consisting of triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl; and wherein: R13a, R13b and j are as defined above, with the exception that all mentioned substituents are independently selected from their previous selection; and the symbol "*" indicates the point of union of residue A to the other remaining portions of partial formula (2.0.2); R5a is a member selected from the group consisting of a direct link; -C (= O) -; and -S (= O) 2-; W1 is (1.) a direct link; (2.) in the case where R5a is -C (= O) - or -S (= O) 2, W is a direct bond or-(C1-C3) alkylene-, in which any carbon atom simple thereof is substituted with 0 to 2 substituents R23, wherein R23 is a member selected from the group consisting of -F; -Cl; -CO2R4; -OH; -CN; alkoxy (C C4); cycloalkyl (C3-C7); and phenyl; wherein said alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R11, wherein said R11 is as defined above, with the exception that all substituents mentioned above are selected independently from their previous selection; or (3.) is a member selected independently from the group consisting of the remnants of partial formulas (2.0.6) to (2.0.16), including: (2.0.6) (2.0.7) (2.0.8) (2.0.9) (2.0.10) (2.0.11) (2.0.12) (2.0.13) (2 0 14) (2.0.15) (2.0.16) wherein: the symbol "-" indicates the point of attachment of the remainder W1 to the nitrogen atom in the partial formula (2.0.0), and the symbol "*" indicates the point of attachment of the remainder W1 to the other remaining portions of partial formula (2.0.0); and R4 is as defined in detail above, but selected in an independent manner; R24 is selected from the group consisting of hydrogen and alkyl (C -? - C4); and each of R25 and R26 are selected from the group consisting of -OH; (C -? - C2) alkyl substituted with 0 to 3 substituents selected from F; and OH; and alkoxy (CrC2); and R27 is selected from the group consisting of alkyl (C-i-Cß); alkenyl (C2-C6); and (C2-C6) alkynyl; wherein said alkyl, alkenyl and alkynyl groups comprising R27 are substituted with 0 to 3 substituents R28, wherein: R28 is selected from the group consisting of phenyl; F or Cl; oxo; hydroxy; alkyl (C -? - C2); alkoxy (C C3); -C (= O) OR29; -C (= O) (C 1 -C 4) alkyl; -S (= 0) 2alkyl (d-C4); C (= O) NR29R30; -NR29R30; -NR29C (= O) R30; -NR29C (= 0) OR30; -NR29S (= 0) PR30; and -S (= O) 2NR29R30, wherein: each of R29 and R30 is a member independently selected from the group consisting of hydrogen and alkyl (CrC) substituted with 0 to 3 substituents selected from the group consisting of F and Cl; 2. cycloalkyl-substituted amido-aryl radicals of partial formula (2.1.0): wherein: A; W1; the symbol "*"; R4; R5a and R6 have the same meaning as indicated above, with the exception that all the substituents mentioned above are selected independently from their previous selection; and R32 is a member selected from the group consisting of - (CH2) n-cycloalkyl (C3-C7), wherein n is an integer selected from 0, 1 and 2; in case n is 0, then the a carbon atom of said (C3-C7) cycloalkyl is substituted with 0 (C1-C4) alkyl or phenyl groups, wherein said alkyl or phenyl is substituted with 0 , 1 or 2 CH3, OCH3, OH or NH2 groups; and in case n is 1 or 2, the resulting methylene or ethylene is substituted with 0 or 1 F groups; NH2; N (CH3) 2; OH; OCH3; (C 1 -C 4) alkyl; or phenyl; wherein said alkyl and phenyl are substituted with 0, 1 or 2 CH3, OCH3, OH and NH2 groups; and wherein said cycloalkyl (C3-C7) is further substituted with 0 to 3 substituents R28, wherein R28 is as defined previously above, but independently selected 3. aryl and heterocyclyl-substituted amido-aryl residues of partial formula (2.2.0): wherein: A; W1; the symbol: "*"; R4; R5a; and R6 have the same meanings indicated above, with the exception that all the aforementioned substituents are independently selected from their previous selection; and R35 is selected from the group consisting of phenyl; Furyl tetrahydrofuranyl; tetrahydropyranyl; oxetanyl; thienyl; pyrrolyl; pyrrolidinyl; oxazolyl; Soxazolyl; thiazolyl; isothiazolyl; imidazolyl; pyrazolyl; Oxadiazolyl; thiadiazolyl; triazolyl; pyridyl; pyrazinyl; pyridazinyl; piperazinyl; pyrimidinyl; pyranyl; azetidinyl; morpholinyl; parathiazinyl; indolyl; indolinyl; benzo [b] furanyl; 2,3-dihydrobenzofuranyl; benzothienyl; 1H-indazolyl; benzoimidazolyl; benzoxazolílo; benzoisoxazolyl; benzothiazolyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; and quinoxalinyl; wherein (1.) said R35 group can be substituted on any one or more carbon atoms with 0 to 3 substituents R28, wherein R28 is as defined above, with the exception that it is independently selected; (2.) said R35 group is substituted with respect to any one or more nitrogen atoms that are not a point of attachment of said aryl or heterocyclic moiety, with 0 to 3 substituents R13, wherein R13b is as defined above , with the exception that it is selected independently; and (3.) said R35 group with respect to any sulfur atom thereof which is not a point of attachment of said heterocyclic moiety, it is substituted with 0 to 2 oxygen atoms; the [Region ß] is an element of alkyl union of partial formula (3.0.0): R40 I R41 (3.0.0) in which: "*" is a symbol that represents the point of union of the rest of partial formula (3.0.0) to Region a; "-" is a symbol representing the point of union of the rest of partial formula (3.0.0) to the Region?; R40 and R41 are independently selected from the group consisting of hydrogen; alkyl (CrC2), including dimethyl; hydroxy; and (C 1 -C 3) alkoxy; the [Region?] is an aza-monocyclic residue of partial formula (4.0.0): (4.0.0) where: "*" is a symbol representing the point of attachment of the remainder of partial formula (4.0.0) to the Region β of the compound of formula (I); "-» "is a symbol representing a covalent bond joining any carbon atom of said aza-monocyclic moiety of partial formula (4.0.0) to Region d; the rest of the partial formula (4.0.1): R46 (4.0.1) in the partial formula (4.0.0) represents a monocyclic heterocyclic group containing a total of 4 to 7 members, of which one of said members is nitrogen, wherein said heterocyclic group is a selected member independently between the group consisting essentially of azetidinyl; pyrrolidinyl; piperidinyl; and azepinyl; R45 is absent or is a member independently selected from the group consisting essentially of (C1-C4) alkyl including dimethyl; cycloalkyl (C3-C6); (C 1 -C 4) alkoxy; alkoxy (C? -C2) alkyl (CrC2); CF3; -CO2R4 wherein R4 is as defined in detail above; oxo; -OH; cyano; -C (= O) NR4aR b; -NR4aR4b; -NR4aC (= O) R4b; - NR4aC (= O) OR4b; - NR4aS (= O) pR4b; -S (= O) pNR4aR4; alkoxycarbonyl (C C2); alkylcarbonyl (C C2); alkylcarbonyloxy (C C2); and alkoxy (CrC2) alkyl (C -? - C2); it being understood that in the rest of the partial formula (4.0.0) R45 is a substituent attached to a single carbon atom thereof; wherein: each of R4a and R4b is independently selected from hydrogen and alkyl (C? -C2); R46 is absent or is a member independently selected from the group consisting essentially of hydrogen; and (C1-C4) alkyl substituted with 0 or 1 substituents independently selected from (C1-C2) alkoxy and -C02R4, wherein R4 is as defined in detail above; I; it being understood that in the case that it is chosen that the substituent R46 is not absent, it results that said nitrogen atom and said partial formula residue (4.0.0) are in quaternary form; [Region d] is a heterocyclyl radical (substituted) selected from the group consisting of: 1. a heterocyclyl residue of partial formula (5.3.0): where: the symbol: "*" indicates the point of union of the partial formula (5.3.0) to the Region?; Q is N, O or S and the partial formula (5.3.0) represents: a. a monocyclic heterocyclic group containing a total of 5 members, of which one of said members is nitrogen and a second member is selected from O and S, wherein said S may optionally be in the sulfonate form, wherein said group heterocyclic is selected from the group consisting of oxazolyl; isoxazolyl; thiazolyl; e / 'so-thiazolyl; or b. a monocyclic heterocyclic group containing a total of 5 members, of which two of said members are nitrogen and a third or fourth of said members is independently selected from N, O and S, wherein said S may optionally be in the form sulfonate, -S (= O) 2; wherein said heterocyclic group is independently selected from the group consisting of triazolyl; triazinyl; tetrazolyl; Oxadiazolyl; and thiadiazolyl; and each of R90a and R90b is a member independently selected from the group consisting of hydrogen, alkylcarbonyl (CrC2); -alkyl (C1-C4); - (CH2) n- (C3-C7) cycloalkyl; -alkenyl (C2-C3); - (CH2) n- (phenyl); and - (CH2) n- (HET-i), wherein n is an integer independently selected from 0, 1 and 2; wherein said (C -? - C4) alkyl, alkenyl, cycloalkyl, phenyl and HET1 groups are independently substituted with 0 to 3 substituents R91, wherein: j has the same meanings as indicated above, but is selected from an independent form among them; HET-i is a heterocyclyl group selected from the group consisting of thienyl; oxazolyl; Soxazolyl; thiazolyl; isothiazolyl; pyrazolyl; Oxadiazolyl; thiadiazolyl; triazolyl; pyridyl; pyrazinyl; pyridazinyl; pyrimidinyl; parathiazinyl; and morpholinyl; wherein: R91 is selected from the group consisting of -F; -Cl; -CO2R4; oxo; -OH; -CN; -CONR93R94; -NR93R94; C (= O) alkyl (C C); -NR93C (= O) R94; -NR93C (= O) OR94; -NR93S (= O) R94; -S (= O) NR93R94; alkyl (C C) and (C 1 -C 4) alkoxy wherein each of said alkyl and alkoxy are independently substituted with 0 to 3 substituents independently selected from F and Cl; alkoxycarbonyl (C -? - C2); alkylcarbonyl (d-C2) and alkylcarbonyloxy (C C2); wherein: each of R93 and R94 is a member independently selected from the group consisting of hydrogen; and (C1-C2) alkyl; and 2. a heterocyclyl moiety of partial formula (5.4.0): wherein: R90a; R90b; and j have the same meanings indicated above, but are independently selected.

2. - A compound that is selected from the group consisting of

3. - A compound that is selected from the group consisting of:? / -. { (1S) -3- [4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; / V- (1-phenyl-3- [4- (4 / - / - 1, 2,4-triazol-4-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; / V-. {3- 3- [ 4- (1-methyl-1 HA, 2,4-triazol-5-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; / V- { 3- [4- (1-methyl-1 HA, 2 , 4-triazol-3-yl) -1-piperidinyl] -1-phenylpropyl.} Cyclobutanecarboxamide;? / -. {3- [4- (3,5-dimethyl-4H-1, 2,4-triazole; -4-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; N-. {1-phenyl-3- [4- (3-methyl-1, 2,4-oxadiazol-5-yl) -1 -p Peridinyl] propyl, cyclobutanecarboxamide,? / -. {1-phenyl-3- [4- (3-phenyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] propyl} cyclobutanecarboxamide; / V- { 3- [4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropyl.} cyclobutanecarboxamide; N- (3 - { 4- [3- (4-methoxyphenyl) -1,4, 2,4-oxadiazoI-5-yl] -1-piperidinyl.} -1-phenylpropyl) cyclobutanecarboxamide; / S / -. 3- [4- (5-methyl-1, 2,4-oxadiazol-3-yl) -1-piperidinyl] -1-phenylpropyl-cyclobutanecarboxamide; / V-. {1-phenyl-3- [4- (5- phenyl-1, 2,4-oxadiazol-3-yl) -1- piperidinyl] propyl} Cyclobutanecarboxamide; / V-. { 3- [4- (5-benzyl-1, 2,4-oxadiazol-3-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; N-. { 3- [4- (5-methyl-1, 3,4-oxadiazol-2-yl) -1-piperidinyl] -1-phenylpropyl} Cyclobutanecarboxamide; / V-. { 1-phenyl-3- [4- (5-phenyl-1, 3,4-oxadiazol-2-yl) -1-piperidinyl] propyl} Cyclobutanecarboxamide; ? / -. { 3- [4- (5-benzyl-1, 3,4-oxadiazol-2-yl) -1-piperidinyl] -1-phenolpropyl} Cyclobutanecarboxamide; N - [(1 S) -3- [4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1- (3-fluorophenyl) propyl] -2-cyclopropylacetamide; ? / - ((1 S) -3- { 4- [3- (4-methylbenzyl-1, 2,4-oxadiazol-5-yl] -1-piperidinyl}. -1-phenylpropyl) cyclobutanecarboxamide; / V - ((1 S) -3- { 4- [3- (4-trifluoromethyl-benzyl-1, 2,4-oxadiazol-5-yl] -1-piperidinyl} -1-phenylpropyl) -cyclobutanecarboxamide; / V - ((1 S) -3- { 4- [3- (1, 3-benzodioxol-5-ylmethyl) -1, 2,4-oxadiazol-5-yl] -1-piperidinyl. -1-phenylpropyl) cyclobutanecarboxamide (document UK-383290-51);? / - ((1 S) -3- { 4- [3- (3,5-difluorobenzyl) -1,2,4-oxadiazole- 5-yl] -1-piperidinyl.} -1-phenylpropyl) cyclobutanecarboxamide;? / - [(1S) -3- [4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1 -piperidinyl] -1- (3-fluorophenyl) propyl] cyclobutanecarboxamide;? / -. {(1 S) -3- [4- (3. {4 - [(methylsulfonyl) amino] benzyl] - 1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; 4 { [5- (1- { (3S) -3 - [(Cyclobutylcarbonyl) amino] -3 -phenylpropyl.} -4-piperidinyl) -1, 2,4-oxadiazol-3-yl] methyl.} benzamide; / V - ((1 S) -3- { 4- [3- (2 , 5-difluorobenzyl) -1, 2,4-oxadiazol-5-yl] -1-piperidinyl. -1-phenylpropyl) cyclobutanecarboxamide (document UK-384644-51); / V - ((1 S) -3- { 4- [3- (2,6-difluorobenzyl) -1, 2,4-oxadiazol-5-yl] -1-piperidinyl.} -1-phenylpropyl Cyclobutanecarboxamide; (document UK-384647-51); / V - ((1S) -1-phenyl-3- { 4- [3- (3-pyridinylmethyl) -1,2,4-oxadiazol-5-yl] -1-piperidinyl.} Propyl Cyclobutanecarboxamide; ? / - ((1 S) -1-phenyl-3- { 4- [3- (4-pyridinylmethyl) -1, 2,4-oxadiazol-5-yl] -1- piperidinyl, propyl) cyclobutanecarboxamide; TO/-. { (1 S) -3- [4- [3-. { 2 - [(methylsulfonyl) amino] benzyl} -1, 2,4-oxadiazol-5-yl) -1-piperidinyl} -1-phenylpropyljcyclobutanecarboxamide; N - ((1 S) -1-phenyl-3- { 4- [3- (2-pyridinylmethyl) -1,2,4-oxadiazol-5-yl] -1-piperidinyl}. Propyl) cyclobutanecarboxamide; ? / -. { (1 S) -3- [4- (3-Isobutyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropylj-cyclobutanecarboxamide; ? / - ((1 S) -3- { 4- [3- (3-chlorobenzyl) -1,4, 2,4-oxadiazol-5-yl] -1-piperidinyl}. -1-phenylpropyl) cyclobutanecarboxamide; ? / - ((1 S) -3- { 4- [3- (1-benzofuran-5-ylmethyl) -1,2,4-oxadiazol-5-yl] -1-piperidinyl}. -1-phenylpropyl) cyclobutanecarboxamide; N - [(1 S) -1-phenyl-3- (4-. {3- [4- (trifluoromethoxy) benzyl] -1,2,4-oxadiazol-5-yl] -1-piperidine] .}. propyl] cyclobutanecarboxamide; A / - { (1 S) -3- [4- (3 { 3 - [(methylsulfonyl) amino] benzyl] -1, 2,4-oxadiazole- 5-yl) -1-piperidinyl] -1-phenylpropyl) cyclobutanecarboxamide; 3,3,3-Trifluoro-A / -. { (1 S) -3- [4- (3-. {4- [(methylsulfonyl) amino] benzyl] -1, 2,4-oxadiazol-5-yl] -1-piperidinyl] -1-phenylpropyljpropanamide; 2-Cyclopropyl- / V- { (1 S) -3- [4- (3-. {4- [(methylsulfonyl) amino] benzyl] -1, 2,4-oxadiazole- 5-yl] -1-piperidinyl] -1-phenylpropylactamide; / V- { (1S) -3- [4- (3. {4 - [(methylsulfonyl) amino] benzyl] - 1, 2,4-oxadiazol-5-yl] -1-piperidinyl] -1-phenolpropyl.} Tetrahydro-2 / - / - pyran-4-carboxamide; 1-Acetyl- / V- { (1S) -3- [4- (3- { 4 - [(methylsulfonyl) amino] benzyl] -1, 2,4-oxadiazole-5-yl] -1- piperidinyl] -1-phenylpropyl.} - 3-azetidinecarboxamide; / V- { (1 S) -3- [4- (3-benzyl-1, 2,4-oxadol-5-yl ) -1-p-pentyldyl] -1-phenylpropyl.}. Tetrahydro-2 - / - pyran-4-carboxamide; 1-Acetyl- / V- { (1S) -3- [4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropyl.} - 3-azetidinocarboxamide; 1 - (Acetylamino) -? / -. {(1 S) -3- [4- (3-benzyl-1, 2,4-oxadiazol-5-yl) -1-piperidinyl] -1-phenylpropyl.} Cyclopentanecarboxamide; / V-. {(1S) -3- [4- (3-benzyl-1, 2,4-oxadi azol-5-yl) -1-piperidinyl] -1-phenylpropyl} -1-methoxycyclobutanecarboxamide; 3-. { [5- (1- { (3S) -3 - [(cyclobutylcarbonyl) amino] -3-phenylpropyl] -4- piperidinyl) -1,4, 2,4-oxadiazol-3-yl] methyl} benzamide; 4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -1-. { (3S) -3 - [(Cyclobutylcarbonyl) amino] -3-phenylpropyl} Ethyl 4-piperidinocarboxylate; / \ / -. { (1S) -3- [4- (3-Benzyl-1, 2,4-oxadiazol-5-yl) -4-cyano-1-piperidinyl] -1-phenylpropyl} Cyclobutanecarboxamide; / V - [(1 S) -3- (4- { 3- [3- (Aminosulfonyl) benzyl] -1,2,4-oxadiazol-5-yl.} -1-piperidinyl] -1- phenylpropyljcyclobutanecarboxamide; 1- {(3S) -3 - [(Cyclobutylcarbonyl) amino] -3-phenylpropyl} -4- [3- (4-fluorobenzyl) -1,2,4-oxadiazole-5-yl ] -N-methyl-4-piperidinocarboxamide;? / - ((1 S) -3- { 4- [3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] - 1-piperidinyl.} -1-phenylpropyl) tetrahydro-2H-pyran-4-carboxamide; 3,3,3-Trifluoro-? / - ((1S) -3- { 4- [3 - (4-fluorobenzyl) -1,4, 2,4-oxadiazol-5-yl] -1-piperidinyl} -1-phenylpropyl) propanamide; / V - ((1 S) -3-. {4 - [3- (4-morpholinylmethyl) -1,4,4-oxadiazol-5-yl] -1-piperidinyl] -1- phenylpropyl) cyclobutanecarboxamide; / V - ((1 S) -3 - { 4-cyano-4- [3- (4-fluorobenzyl-1, 2,4-oxadiazol-5-yl] -1-piperidinyl.} - 1 -phenylpropyl) tetrahydro-2 / - / - pyran 4-carboxamide;? / - ((1S) -3-. {4-cyano-4- [3- (4-fluorobenzyl-1, 2,4-oxadiazol-5-yl] -1-piperidinyl}. -1-phenoxypropyl) -2-cyclopropylacetamide; 1-Acetyl- / V - ((1 S) -3-. {4-cyano-4- [3- (4-fluorobenzyl) -1, 2, 4-oxa diazol-5-yl] -1-piperidinyl} -1-phenylpropyl) -3-azetidinecarboxamide; ? / - ((1 S) -3- { 4-cyano-4- [3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] -1-piperidinyl.} -1 phenylpropyl) -3,3,3-trifluoropropanamide; ? / - [(1 S) -3- (4- { 3- [4- (aminosulfonyl) benzyl] -1,2,4-oxadiazol-5-yl) -1-piperidinyl) -1 - phenylpropyljcyclobutanecarboxamide; / V-. { (1 S) -3- [3-benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinyl] -1-phenylpropyl} tetrahydro-3-furanocarboxamide; ? / - [(1S) -3- (4- { 3 - [(4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-5-yl.} -1-piperidinyl) -1-phenylpropyl] cyclobutanecarboxamide; / V-. { (1 S) -3- [3-benzyl-1, 2,4-oxadiazol-5-yl) -1-azetidinyl] -1-phenylpropyl} tetrahydro-3-furanocarboxamide; / V-. { (1 S) -3- [4- [3- (4-Fluorobenzyl) -1,2,4-oxadiazol-5-yl] -4- (methoxyphenyl) -1-piperidinyl] -1-phenylpropyl} acetamide; ? / -. { 3- [4- (3-methyl-5-phenyl-4 / - / - 1, 2,4-triazol-4-yl) -1-pipehdinyl] -1-phenylpropyl} Cyclobutanecarboxamide; / V-. { (1 S) -3- [4- (3-Benzyl-5-methyl-4 / -1,2,4-triazol-4-yl) -1-piperidinyl] -1-phenylpropyljcyclobutanecarboxamide; ? / -. { (1 S) -3- [4- (5-Benzyl-4-methyl-4H-1, 2,4-triazol-3-yl) -1-piperidinyl] -1-phenylpropylj-cyclobutanecarboxamide; ? / -. { (1 S) -3- [4- (3-benzyl-1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} -cyclobutanecarboxamide; ? / -. { (1S) -3- [4- (5-Benzyl-1-methyl-1 HA, 2,4-triazol-3-yl) -1-piperidinyl] -1-phenylpropyl-cyclobutanecarboxamide; ? / -. { 3- [4- (5-benzyl-1 HA, 2,4-triazol-3-yl) -1-p-peridinyl] -1-phenylpropyl} Cyclobutanecarboxamide; N-. { (1 S) -3- [4- (3- { 4- [(methylsulfonyl) amino] benzyl] -1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1 - phenylpropyl} tetrahydro-2 / - / - pyran-4-carboxamide; 2-Cyclopropyl- / V-. { (1S) -3- [4- [3-. { 4 - [(Methylsulfonyl) amino] benzyl} -1 HA, 2,4-triazol-1 -yl) -1-piperidinyl] -1-phenylpropyl} acetamide; 3,3,3-Trifluoro-A / -. { (1 S) -3- [4- [3-. { 4- [(methylsulfonyl) amino] benzyl} -1 HA, 2,4-triazol-1 -yl) -1-piperidinyl] -1-phenylpropyljpropamide; ? / - (1 S) -. { 3- [4- (3-benzyl-1-methyl-1 HA, 2,4-triazol-5-yl) -1-piperidinyl] -1-phenylpropyl-cyclobutanecarboxamide; 4-. { [1 - (1 - { (3S) -3-Phenyl-3 - [(3,3,3-trifluoropropanoyl) amino] propyl] -4- p -peridinyl) -1 HA, 2, 4-triazol-3-yl] methyl} benzamide; N-. { (1 S) -3- [4- (3-Benzyl-5-methyl-1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} tetrahydro-2 /-. pyran-4-carboxamide; / V-. { (1 S) -3- [4- (3-Benzyl-5-methyl-1 / - / - 1, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} tetrahydro-3-furanocarboxamide; 1 -Amino - / \ / -. { (1 S) -3- [4- (3-benzyl-5-methyl-1 HA, 2,4-triazol-1-yl) -1-piperidinyl-cyclopentanecarboxamide; / V-. { (1 S) -3- [4- (3-Benzyl-1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} tetrahydro-3-furanocarboxamide; N-. { (1 S) -3- [4- (3-Benzyl-1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} tetrahydro-2 / -pyran-4-carboxamide; 1-Amíno -? / -. { (1S) -3- [4- (3-Benzyl-1H-1, 2,4-triazol-1-yl) -1- piperidinyl] -1-phenylpropyl-cyclopentanecarboxamide; 1 -Acetyl- / V-. { (1 S) -3- [4- (3-Benzyl-1H-1, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} -3-azetidinocarboxamide; ? / -. { (1 S) -3- [4- (3-Benzyl-1H-1, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} -1-propionyl-3-azetidinocarboxamide; 1 -Acetyl- / V-. { (1 S) -3- [4- (3-Benzyl-5-methyl-1 H-1, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenyl-propyl} -3-azetidinocarboxamide; ? / -. { (1 S) -3- [4- (3- (4-Fluorobenzyl) -1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} -1-propionyl-3-azetidinocarboxamide; 1 -Acetyl- / V-. { (1 S) -3- [4- (3- (4-fluorobenzyl) -1 H-1, 2,4-triazol-1-yl) -1-pyridinyl] -1-phenylpropyl} -3-azetidinocarboxamide; 2-Methoxy -? / -. { (1 S) -3- [4- (3- (4-fluorobenzyl) -1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropyl} acetamide; 3-Methoxy1 -? / -. { (1 S) -3- [4- (3- (4-Fluorobenzyl) -1 HA, 2,4-triazol-1-yl) -1-piperidinyl] -1-phenylpropylpropanamide.

4. The use of a compound as claimed in any preceding claim for the manufacture of a medicament for treating or preventing a disease or condition mediated by or associated with the modulation of the activity of the CCR5 receptor of chemokines in a patient or which is a likely beneficiary of such prevention.

5. A pharmaceutical composition for the treatment or prevention of a disease or condition mediated by or associated with the modulation of chemokine CCR5 receptor activity, comprising an amount of a compound according to any preceding claim that is therapeutically effective for treating or preventing said disease or condition, together with a pharmaceutically acceptable vehicle therefor.

6. - The use of a compound as claimed in any previous claim for the manufacture of a medicament for treating or preventing infection with the human immunodeficiency virus (HIV) in a patient or patient which is a likely beneficiary of such prevention, including the treatment or prevention of the acquired immunodeficiency syndrome (AIDS) resulting from such infection.

7. The use as claimed in claim 6, wherein a compound as claimed in any of claims 1 to 3 in combination with one or more additional therapeutic agents comprising one or more members selected from the group composed of (1) HIV protease inhibitors; and (2) inhibitors of HIV reverse transcriptase, is coadministered with said medicament to the patient.

8. The use as claimed in claim 7, wherein: (1) said HIV protease inhibitors comprise one or more members selected from the group consisting of indinavir, ritonavir, saquinavir, nelfinavir and amprenavir; and (2) said inhibitors of HIV reverse transcriptase comprise one or more members selected from the group consisting of (a) non-nucleoside reverse transcriptase inhibitors (NNRTI) selected from nevirapine, delavirdine and efavirenz; and (b) nucleoside / nucleotide inhibitors (NRTI) selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and adefovir dipivoxil.

9. - The use as claimed in claim 7, wherein said inhibitors of HIV protease and said inhibitors of HIV reverse transcriptase comprise one or more members selected from the group consisting of indinavir; ritonavir; saquinavir; nelfinavir; amprenavir; nevirapine; elavirdine; efavirenz; zidovudine; didanosine; zalcitabine; stavudine; lamivudine; abacavir; adefovir; dipivoxil; FTC; PMPA; fozivudine tidoxil; talviraline; S-1153; MKC-442; MSC-204; MSH-372; DMP450; PNU-140690; ABT-378; and KNI-764.

10. The use as claimed in claim 7, wherein said patient being treated is avirhemic and / or asymptomatic and is potentially or effectively infected with HIV, and wherein a combination of therapeutic agents comprising a member selected from the group consisting of: (i) a compound according to claim 1; (ii) a non-nucleoside reverse transcriptase inhibitor (NNRTI) in addition to a compound of (I); (iii) a nucleoside / nucleotide inhibitor (NRTI) in addition to a compound of (I); (V) an NRTI in addition to the combination of (ii); and (v) a compound selected from HIV protease inhibitors used in place of said NRTI in combinations (iii) and (iv) is administered to the patient.

11. The use as claimed in claim 7, wherein said patient being treated has a detectable viraemia or an abnormally low CD4 number, and wherein a combination of therapeutic agents comprising (A) a member selected from the group consisting of a compound of formula (I) as defined in claim 1; and a therapeutic agent comprising a protease inhibitor in combination with two NRTIs; or (B) the combination of therapeutic agents mentioned in (A) wherein said protease inhibitor component or one or both of said NRTIs are replaced by a compound of formula (I) as defined in claim 1, is administered at patient.

12. The use as claimed in claim 7, wherein said patient has not responded adequately to the antiviral therapy and wherein a combination of therapeutic agents comprises (A) a member selected from the group consisting of a compound according to claim 1; or (B) a therapeutic agent comprising a protease inhibitor in combination with two NRTIs, wherein said protease inhibitor component or one or both of the NRTIs mentioned is replaced by a compound of formula (I) as defined in claim 1, it is administered to the patient.

13. The use as claimed in claim 8, wherein said compound of formula (I) as defined in claim 1 in combination with one or more supplementary therapeutic agents that provide the auxiliary treatment of diseases or conditions. that result directly from or indirectly accompanying HIV infection, including AIDS resulting from such infection, wherein said supplemental therapeutic agent is one or more members selected from the group consisting of proliferation inhibitors; immunomodulators; interferons or interferon derivatives; fusion inhibitors, integrase inhibitors; RnasaH inhibitors; and inhibitors of viral transcription and RNA replication, is coadministered with said drug to the patient.

14. The use as claimed in claim 13, wherein said proliferation inhibitor is hydroxyurea; said nomomodulator is sargramostim; said fusion inhibitor is AMD3100, T-20, PRO-542, AD-349 or BB-10010; and said integrase inhibitor is AR177.

15. A pharmaceutical composition for the treatment or prevention of infection by the human immunodeficiency virus (HIV) is a patient in need of such treatment or is a likely beneficiary of such prevention, including the treatment or prevention of acquired immunodeficiency syndrome. (AIDS) resulting from said infection, comprising an amount of a compound according to claim 1 which is therapeutically effective to treat or prevent said HIV infection or AIDS resulting from said infection, together with a pharmaceutically acceptable carrier therefor. .

16. A pharmaceutical composition according to claim 15 including, in combination with a compound of formula (I) according to claim 1, one or more additional therapeutic agents for the treatment or prevention of HIV infection comprising one or more members independently selected from the group consisting essentially of (1) HIV protease inhibitors; Y (2) inhibitors of HIV reverse transcriptase.

17. A pharmaceutical composition according to claim 16 wherein: (1) said HIV protease inhibitors comprise one or more members independently selected from the group consisting of indinavir, ritonavir, saquinavir, nelfinavir and amprenavir; Y (2) said inhibitors of HIV reverse transcriptase comprise one or more members selected from the group consisting of (a) non-nucleoside reverse transcriptase inhibitors selected from nevirapine; delavirdina and efavírenz; and (b) nucleoside / nucleotide inhibitors selected from zidovudine; didanosine; zalcitabine; stavudine; lamivudine; abacavir and adefovir dipivoxil.

18. A pharmaceutical composition according to claim 16, wherein said inhibitors of HIV protease and said inhibitors of HIV reverse transcriptase comprise one or more members selected from the group consisting of indinavir; ritonavir; saquinavir; nelfinavir; amprenavir; nevirapine; delavirdine; efavirenz; zidovudine; didanosine; zalcitabine; stavudine; lamivudine; abacavir; adefovir; dipivoxil; FTC; PMPA; fozivudine todoxil; talviraline; S-1153; MKC-442; MSC-204; MSH-372; DMP450; PNU-140690; ABT-378; and KNI-764.

19. A pharmaceutical composition according to claim 15, further comprising co-administering with said compound of formula (1) as defined in claim 1, one or more supplementary therapeutic agents that provide the auxiliary treatment of diseases or conditions that result directly from HIV infection or that indirectly accompany HIV infection, including AIDS resulting from such infection, wherein said supplemental therapeutic agent is one or more members selected from the group consisting of proliferation inhibitors, immunomodulators; Interferons or derivatives of interferons; fusion inhibitors; integrase inhibitors; RnasaH inhibitors; and inhibitors of viral transcription and RNA replication.

20. A pharmaceutical composition according to claim 19, wherein said proliferation inhibitor is hydroxyurea; said nomomodulator is sargramostim; said fusion inhibitor is AMD3100, T-20, PRO-542, AD-349 or BB-10010, and said integrase inhibitor is AR177.

21. A method of evaluating a putative mutant of the HIV retrovirus with respect to its resistance to therapeutic agents against HIV, which comprises isolating said putative mutant virus from an in vitro culture thereof.; of an in vitro animal infection model thereof; or of samples from a patient, wherein said patient is subjected to an optimal or sub-optimal treatment comprising the administration of a compound as defined in claim 1, alone or together with any combination thereof with one or more agents Therapeutics for the treatment or prevention of HIV infection.

22. - A mutant virus or component part thereof, prepared according to the methods of claim 21.

23. A mutant HIV virus or component thereof according to claim 21, wherein said component is the envelope protein. complete of it, or fragments of infections of it.

24. A method for detecting the presence and / or confirming the activity of a chemokine modulator that has activity against an HIV mutant virus, which comprises using a probe to make said discovery and / or confirmation, a mutant HIV virus or a component of same according to claim 21.

25.- A diagnostic agent for use in the choice of a therapeutic regimen and / or in the prediction of results for a patient who is being treated for infection by a mutant HIV virus , wherein said diagnostic agent comprises a mutant HIV virus or a component thereof according to claim 21.

26.- A pharmaceutical composition for treating or preventing a respiratory disease or condition comprising an amount of a compound according to with any of claims 1 to 3, which is effective to treat said disease or condition, together with a pharmaceutically effective carrier therefor.

27. A compound according to claims 1 to 3 in purified form.

28. - A pharmaceutical composition comprising a compound according to claims 1 to 3 and one or more inert excipients.