MXPA01005463A

MXPA01005463A - Benzamide derivatives and their use as apob-100 secretion inhibitors

Info

Publication number: MXPA01005463A
Application number: MXPA/A/2001/005463A
Authority: MX
Inventors: Alain Claudemarie Daugan
Original assignee: Glaxo Group Limited
Priority date: 1998-12-03
Filing date: 2001-05-31
Publication date: 2002-05-09

Abstract

The invention relates to therapeutic benzamide compounds of formula (I)wherein A represents N or CH;X is selected from the following groups:(i) -C1-6alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6acyl or C1-6acyloxy groups, (ii) oxo, sulfonyl, thioxo, (iii) -C1-6alkylenecarbonyl-, -C1-6alkylenesulfonyl-, -C1-6alkylenethioxo-, (iv) -C2-6alkyleneoxy-, -C2-6alkylenethio-, -C2-6alkylene(N-H or N-C1-6alkyl)amino-, (v) -C1-6alkylenecarboxy-, -C1-6alkylenethioamido-, -C1-6alkylene(N-H or N-C1-6alkyl)carboxamido-, and (vi) -C2-6alkyleneoxycarbonyl-, -C2-6alkylenethiocarbonyl-, -C2-6 alkylene(N-H or N-C1-6alkyl)aminocarbonyl-;Z represents a direct link or -C1-6 alkylene-, optionally containing one double bond and optionally substituted by one or more hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl or C1-6 acyloxy groups;R1 is selected from the following groups:(i) hydrogen, C1-3perfluoroalkyl, (ii) C6-10 aryl, C3-8cycloalkyl and fused benz derivatives thereof, C7-10polycycloalkyl, C4-8cycloalkenyl, C7-10polycycloalkenyl, (iii) a heterocyclyl selected from the group consisting of monocyclic radicals and fused polycylic radicals, and (iv) where either X is C1-6alkylene and Z is a direct link, or Z is C1-6alkylene, R1 additionally may represent a halogen, cyano, nitro or C1-6acyl group, wherein, when R1 contains one or more rings, said rings may each independently bear 0 to 4 substituents. Y represents a direct or oxy link, -C1-6alkylene-, -oxyC1-6alkylene- or a heterocyclyl consisting of monocyclic radicals. R2 represents phenyl, C3-8cycloalkyl, or a heterocyclyl consisting of monocyclic radicals, and where each R2 is optionally substituted by one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C3-8cycloalkyl, C1-3perfluoroalkyl, C1-4perfluoroalkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, cyano, nitro, C1-4alkylaminosulfonyl;R3 represents hydrogen or one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C1-3 perfluoroalkyl or C1-3 perfluoroalkoxy;or a physiologically acceptable salt, solvate or derivative thereof, pharmaceutical compositions, to processes for their preparation and their use in the treatment of conditions mediated by ApoB-100 regulation.

Description

BENZAMIDE DERIVATIVES AND THEIR USE AS INHIBITORS OF ApoB-100 inhibition have been described in WO 96/40640, which is incorporated herein by reference. Brief Description of the Invention The present invention provides a compound of formula (I) where A represents N or CH; X is selected from the following groups: (i) -C? _6 alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy groups, C? _6 alkyl, C? -6 alkoxy, C? Acyl? 6 or C6-6 acyloxy, n-oxo, sulfonyl, thioxo, l6-C6-6 alkylenecarbonyl-, -C6-6 alkylensul fonyl-, -C6-6 alkylenedioxo-, (iv) -C2_6 alkynoxy, -C2 -6 alkylene io-, -C2-6 alkylene (NH or NC? _6 alkyl) amino-, (v) -C? -6 alkylenecarboxy, 6 alkylene, C? -6, acylamino C? -6, and (ix) an aromatic heterocyclyl consisting of monocyclic radicals wherein the radicals contain atoms of 5-6 rings, wherein the radicals contain a total of heteroatoms from 1-4 rings independently selected from oxygen, nitrogen and sulfur, and wherein each one of the heterocyclyl groups is optionally substituted by one or more groups independently selected from halogen, C? _4 alkyl, 1-4 alkoxy, C perf-3 perfluoroalkyl, and perfluor oalkoxy Ci_3; Y represents a direct oxy-bond, C al-C6-alkylene, C?-6 -oxyalkylene or a heterocyclyl radical consisting of monocyclic radicals, where the radicals contain 5-ring atoms and where the radicals contain a total of heteroatoms from 1-4 rings independently selected from oxygen, nitrogen and sulfur and wherein the ring may be independently saturated, partially unsaturated or aromatic; R2 represents phenyl, cycloalkyl or heterocyclyl consisting of monocyclic radicals wherein the radicals contain a total of atoms from 5-6 S. Thus, the polycyclic ring system containing one or more saturated, partially unsaturated or aromatic carbocyclic fused rings. (usually benzo rings) is within the definition of heterocyclyl as long as the system also contains at least one molten ring which contains at least one of the heteroatoms mentioned above. As a substituent, such heterocyclyls can be placed on the remaining molecules of a carbocyclic ring (eg, benzo) or of a heterocyclic ring. With reference to the general formula), the reference to R1 as containing one or more rings is intended to mean any portion or simple or melted cyclic portions placed at Z. The rings may be carbocyclic or heterocyclic, saturated or partially unsaturated and aromatic or non-aromatic. With reference to the polycyclic ring system or radical means that all rings in the system are fused. With reference to the general formula (I), aryl means that the ring or substituyent is - "**" "" * carbocyclic and includes phenyl and naphthyl. With reference to the general formula (I), acyl refers to aliphatic hydrocarbons or cyclohexes placed on a carbonyl group through which the substituent is bonded. With reference to the general formula (I), methylenedioxy refers to the group x, x + 1-methylene-ioxy, where x and x + 1 are integers representing the substitution pattern on the ring, eg, 3, 4- Methylenedioxy With reference to the general formula per fluoroalkyl C? _3, or perfluoroalkoxy Cj, -3 include compounds such as trifluoromethyl tpfluoromethoxy Appropriately, the piperazine or piperidine group in formula (I) is meta or para substituted, more appropriately for substituted Preferably, A represents N. X is appropriately-C6-6 alkylene, optionally containing a double bond, for example, methylene, ethylene, propylene, or but-2-enylene, oxo, sulfonyl, -C2-6 alkyleneoxy-, for example, ethylene-propyleneoxy, -C? _6alkylcarboxboxy-, for example, methylenecarboxy-C? _6alkylene (NH N-Ci-e alkyl) carboxamido-for example, methylene (N-H) carboxamide X is also suitably methylene, oxo or sulfonyl. As a preferred aspect X is a methylene group. Z is suitably a ligature, say: alkylene or C6-6, for example, methylene or ethylene. Z is more appropriately a direct link. R1 is suitably selected from the following groups (i) hydrogen, cyano, C? -3 perfluoroalkyl, for example, trifluoromethyl (ii) optionally substituted phenyl, wherein the optional substitution is effected by one or two groups independently selected from Ci-alkyl 6, for example, methyl, cyano, halogen, for example, fluoro, C6-6 alkoxy, for example, methoxy, perfluoroalkylC? -3, for example, trifluoromethyl, hydroxycarbonyl, alkoxycarbonyl C? _4, for example, methoxycarbonyl, aminocarbonyl , me ti? lioxy, nitro, acyl C? _6, for example, acetyl, phenyl or a heterocyclic aromatic consisting of radicals ...- fc. *. &- polycyclic molten radical radicals, wherein the radicals contain a total of 5-membered atoms, for example, oxadiazole, wherein the optional substitution is effected by C 4 alkyl, eg, methyl or perfluoroalkyl C -3, for example, trifluoromethyl, or an optionally substituted aromatic heterocyclyl consisting of fused polycyclic radical monocyclic radicals, wherein the radicals contain a total of atoms from 5-10 rings, eg, indolyl, pyrrolyl, thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl or pyrazinyl, wherein the optional substitution is effected by C 1 -4 alkyl, for example, methyl or halogen, for example, fluorine. wherein R1 is a substituted phenyl group, the substitution is suitably at the 3-position Where R1 is an optionally substituted aromatic heterocyclyl, is preferably an optionally substituted pyrrolyl, wherein the optional substitution is effected by a methyl group. More preferably, the substitution pattern is 2-pyrrolyl.

Methyl oxadiazole Y is suitably a direct ligation, a 2, 5-sub-tolute oxazolyl group, or - (CH 2) n-0-, wherein n is an integer from 0-3. More appropriately, Y is a direct oxy ligature. Preferably Y is a direct link. Preferably Y is suitably cyclohexyl, a 5-6 membered aromatic heterocyclyl, for example, pyrrolyl or pyridyl, or a phenyl group optionally substituted by one or two groups independently selected from halogen, for example, fluoro or chloro, C? -4 alkyl , for example, methyl, ethyl or isopropyl, C 1 -4 alkoxy, for example, methoxy or trifluoromethyl groups, wherein the substitution is appropriately in one or two of the 2-, 3-or 4- positions on the phenyl ring . Preferably, R 2 is a phenyl group substituted by a trifluoromethyl group, more preferably at the 4-position. Equally preferably, R 2 is a phenyl group substituted by an isopropyl group, more preferably at the 4-position. Preferably Y is a direct ligation and R ' is a phenyl group substituted by a group £ & trifluoromethyl or isopropyl, more preferably in the 4-position. R3 is suitably hydrogen, halogen, for example, chloro, C? _4 alkyl, for example, methyl, C perf _3 perfluoroalkyl, for example trifluoromethyl or C? -4 alco alkoxy, for example , methoxy. R3 is more appropriately hydrogen, halogen, for example, chloro, C alquilo _ alkyl, for example, methyl or C alco alkoxy-for example methoxy. R3 is preferably a hydrogen, methyl, methoxy or chloro group. R3 is also preferably a hydrogen, methoxy or chloro group. The substitution is preferably in the 5 or 6 position. Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the preferred groups for each variable. Even the most preferred compounds of the invention include those in which each variable of Formula (I) is selected from the most preferred or most preferred groups of each variable. An appropriate subgroup of a compound of formula (I) is represented by the formula (la) where A is CH or N; x is appropriately C? -6 alkylene, optionally containing a double bond, oxo, sulfonyl, -C2-6alkyleneoxy, alkylcarboxyiCi -alkylene C6-6alkyl (N-H or NC6-6alkyl) carboxamido; Z represents a direct bond or alkylene C-6 / R1 represents one of the following groups (i) hydrogen, perfluoroalkyl C? _3, (ii) optionally substituted phenyl, wherein the optional substitution is effected by one or two groups independently selected from Ci alkyl. 6, cyano, halogen, C?-D alkoxy, C?-3 perfluoroalkyl, hydroxycarbonyl, C? _4 alkoxycarbonyl, aminocarbonyl, C flu _3 per fluoroaminocarbonyl, methylenedioxy, nitro, C? _6 acyl, phenyl or an optionally substituted aromatic heterocyclyl which consists of monocyclic radicals and fused polycyclic radicals, where the radicals contain a total of 5 ring atoms, where optional substitution is effected by Cl-4 alkyl, or C? _3 perfluoroalkyl, (iii) an aromatic heterocyclyl optionally a consistent substitute of monocyclic radicals and fused polycyclic radicals, wherein the radicals contain a total of atoms from 5-10 rings, wherein the optional substitution is effected by C? _4 alkyl, or C perf _3 perfluoroalkyl; or iv) wherein either X is alkylene C? -6 and Z is a direct bond, or Z is a C? -6 alkylene, R1 can additionally represent a cyano group and represents a direct bond or oxy, an aromatic heterocyclyl group of 5 members, -alkylene C? _6 or -oxyalkylene C? -6-; R2 represents phenyl, C3_8 cycloalkyl, or an aromatic heterocycle containing 5-6 ring atoms and 1-4 hetero rings, wherein each ring is optionally substituted by one or more groups independently selected has ogen, C? _4 alkyl, C4-4alkoxy or perfluoroalkyl C i -3; R represents hydrogen, halogen, C? -4 alkyl or C? _ Alkoxy; or a physiologically acceptable salt, solvate or derivatives thereof. An additional appropriate subgroup of a compound of formula (I) is represented by formula (Ib) wherein X is methylene, oxo or sulfonyl, Z is selected from a direct ligation or NH with the proviso that if X is a methylene group, Z is a direct ligation; R1 is selected from the following groups: (i) hydrogen (ii) C6-6 alkoxy, C6-6 alkylthio, (iii) C6-6 alkylamino, C6-6 dialkylamino, C6-6alkylamino or C6-6alkylamino , with the proviso that Z is not NH, (iv) unsubstituted vinyl, Cß-io aryl / C 3-8 cycloalkyl, C 3-8 cycloalkenyl, AAFA ^^ ^ abi (v) aryloxy C6-? Or (vi) heterocyclyl selected from the group consisting of heterocyclic radicals of 5 and ß members which may be saturated, unsaturated or aromatic Parcia lly, and benzo fused derivatives thereof , wherein the radicals may contain a total of heteroatoms from 1 to 3 independently selected from oxygen, nitrogen and sulfur, with the proviso that if X is CH2, it is selected from groups (iv) and (vi) where when R1 contains one or more rings, the rings may each independently bear 0 to 3 substituents independently selected from halogen, hydroxy, cyano, Ci alquijlo 6 alkoxy C? _6 alkylaminocarbonyl C? -6, dialkylamino C? -6 , dialkylaminocarbonyl? -6, dialkylaminocarbonyl Ci-ealkoxy C? _6, acyl 01-67 perfluoroalkoxy C? -3, acyloxy CX-6, hydroxycarbonyl and alkoxycarbonyl C1-6; Y represents a bond, an oxazolyl group, a C1-6alkylene group or a -OC6- alkylene; R represents phenyl, C3_f cycloalkyl or a heterocycle containing atoms of 5-6 rings and heteroatoms of 1-4 rings, wherein each ring is optionally substituted by one or more groups independently selected from halogen, C? -4 alkyl, C alco alkoxy ? 4, C3_8 cycloalkyl, C? -3 perfluoroalkyl, C? -3 perfluoroalkoxy, C? -6 alkoxycarbonyl, cyano, phenyl, phenoxy, benzyl, benzyloxy; R3 represents hydrogen or one or two groups independently selected from halogen groups, Ci_4 alkyl, or Ci.4 alkoxy; or a physiologically acceptable salt, solvate or derivative thereof A subgroup of the invention still further suitable is represented by a compound of formula (le) wherein X is methylene, oxo or sulfonyl, R1 represents phenyl, or a 5-6 membered aromatic heterocyclic group, the group is optionally substituted by one or two groups independently selected from C1-7alkyl, halogen, alkoxy C ? 6, trifluoromethyl, hydroxycarbonyl and C 6 alkoxycarbonyl; R2 represents phenyl substituted by one or two groups independently selected from halogen, trifluoromethyl, C alquilo _ alkyl, or C i 4 alkoxy groups; R3 represents hydrogen or one or two groups independently selected from ha groups. Oxygen, Ci-4 alkyl, and Ci_4 alkoxy; or a physiologically acceptable salt, solvate or derivative thereof. A subgroup of the invention still ap: opiate is further represented by a compound of: order (Id) wherein R 1 represents phenyl optionally subsided by one or two independently selected groups of C 1 -C 6 alkyl, cyano, hydrogen, C 1 -6 alkoxy, trifluoromethyl, hydroxycarbonyl and alkoxycarbonyl c 1-6; R 2 represents phenyl substituted by one or two groups independently selected from halogen, trifluoromethyl, C? -4 alquiloalkyl and C alco _ alco alkoxy groups, - R3 represents hydrogen or one or two groups independently selected from halogen groups, Ci_4 alkyl and Ci-4 alkoxy; or a physiologically acceptable salt, solvate or derivative thereof. A still suitable subgroup of the invention is further represented by a compound of formula (le) wherein R1 is selected from the following groups (i) aminocarbonyl, (ii) phenyl optionally substituted by l or i. - iJiAR. -jáJ? US? nr.

C? _6, cyano, halogen, C? -6 alkoxy, C? _3 perfluoroa, hydroxycarbonyl, C4-aminocarbonyl alkoxy, methylenedioxy, nitro, acyl Cl-6 and phenyl or an optionally substituted 5-membered aromatic heterocyclyl, wherein the optional substi tution is effected by C 1 -3 perfluoroalkyl alkyl, or (iii) an optionally substituted aromatic heterocyclyl consisting of monocyclic radicals and fused polycyclic radicals, wherein the radicals contain a total of 5 carbon atoms. -10 rings, wherein the optional substitution is effected by Ci-4 alkyl; R2 represents phenyl optionally substituted by one or two groups independently selected from halogen groups, perfluoroalkyl Ci. 3, Ci_4 alkyl and Ci_4 alkoxy; R3 represents hydrogen, halogen, C? -4 alkyl or Ci_4 alkoxy; or a physiologically acceptable salt, solvate derived therefrom. It will be clear that references herein to a compound of formula (I) apply equally to a compound of formula (la) - (le). Particularly preferred compounds of the invention include those in which each variable of formula (I) is selected from the appropriate groups of each variable. Even the most preferred compounds of the invention include those in which each variable in formula (I) is selected from the preferred or most preferred groups of each variable. Appropriate compounds according to the invention include: [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of the 4'-Tr if luorome ti 1 -bi-feni 1 -amide 2-carboxylic; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] phenyl] -amide of 4'-i-sopro-pyl-5-methyl-1-phenyl-2-carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-i-sopropi-6-methoxy-phenyl-2-carboxylic acid; [4- [4- (3-C? Ano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-i-sopropi-1-6-met-1 -bi-phenyl-1-2-carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 6-met il-4'-tri f luoromet-1-biphenyl-2-carboxylic acid; (4-. {3- (3-methyl- [1, 2, 4] oxadiazol-5-yl) -benz 1: 1] -piperazin-1-yl.}. 4 '-i-sopropi-1 • 5-met-il-biphenyl-2-carboxylic acid; 5-Chloro-4'-isopropyl-bi-phenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl-phenyl-amide; [4- [4- (3-Cyano-benzyl) -piperazin-yl] phenyl] -amide of 6-methoxy-4'-trifluoromethyl-2-biphenyl-2-carboxylic acid; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 5-met il-4 '-trif luoromet il-bif nil-2-carboxylic acid; 5-Chloro-4'-1 r i f-lor-t-1-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of bi-phenyl 1-2 -carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 5-met oxy-bi-n-n-2-carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-yl] -amide) of 4-Chloro-4 '-trif luoromet-il-bif! In il-2-carboxylic acid; N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -2-phenoxybenzamide; N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -2- (5-phenyl-oxazol-2-yl) -benzamide; [4 - [4- (4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-isopropyl-biphenyl-2-carboxyl-coamide; 5-methoxy-4'-tri f luoromet il-b? Phenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; [4- [4- (3-C? Ano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4-met il-4 '-trif luoromet il-biphenyl-2-carboxylic acid; 4-methoxy-4'-tri fluoromet i 1 -bi-phenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; 4'-Ethyl-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; [4 - [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-met oxy-bi-phenyl-2-carboxylic acid; [4 - [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl-amide of 4 '-trif luoromet il-bife nil-2-carboxylic acid; [4- (4-thiazol-2-ylmethyl-piperazin-1-yl) -pheni-1] -amide of 4 '-trifluoromethyl-1-phenyl-2-carboxylic acid; 4 '-trifluoromethyl-1-biphenyl-2-carboxylic acid [4- [4- (l-methyl-lH-imidazol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide; (4- (4- (3- (3-methyl- [1,2,4] oxadiazol-5-yl) -benzyl) -piperazin-1-yl) -phenyl) -amide of the acid A ' -isopropyl-6-methyl-biphenyl-2-carboxylic acid; [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) phenyl] -amide of 4 '-tri f-luoromet-1 -bi-phenyl-1-carboxylic acid; [4 (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) phenyl] -amide of 4'-i-sopropi-1, 5-me ti-lb-phenyl-1-2-carboxylic acid; 5-Met i 1 -4 '-tri fluoromethyl-1-biphenyl-2-carboxylic acid [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide; [4- (4-propyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-bi-phenyl-1-2-carboxylic acid; [4- (4- (4-acetyl-benzyl) -piperazin-1-yl) -phenyl] -amide of • tri-fluoromethyl-1-bi-phenyl-2-carboxylic acid; [4 (4-Furan-2-yl-yl-yl-piperazin-1-yl) -phenyl-amide of 4 '-tri fluoromethoxy-1-amino-2-carboxylic acid; [4 (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) phenyl] -amide of 4 '-i-sopropyl-6-methoxy-2-phenyl-2-carboxylic acid; [4- (4- (1-methyl-1H-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide of 4 '-tri fluoromethyl-1-bi-phenyl carboxylic; [4 (4-thiophen-2-ylmethyl) -piperazin-1-yl) -phen-11] -amide of 4 '-tri f-luoromet-il-bi-phenyl-2-carboxylic acid; . { 4- [4- (lH-pyrazol-3-ylmethyl) -piperazin-1-yl-phenyl} -amide of 4 '-tri f luorome t i 1-bi phenyl-2-carboxylic acid amide; [4 (4-thiophen-3-ylmethyl-piperazin-1-yl) -pheni-1] -amide of 4 '-triuromethyl-1-bi-phenyl-yl-2-carboxylic acid; . { 4- [4- (5-fluoro-lH-indol-3-ylmethyl) -piperazln-1-yl] -phenyl} 4'-trifluoromethyl-2-biphenyl-2-carboxylic acid amide; '.I .. * »WfeX.Sr phenyl] -amide of 4' -trifluoromethyl-biphenyl-2-carboxylic acid; [4- (4-Methanesulfonyl-piperazin-1-yl) -phenyl] -amide of 4 '-tri f-luoromet-1-bi-phenyl-1-2-carboxylic acid; [4 - [l- (3-cyano-benzyl) -piperidin-4-yl] -phenyl] -amide of 4 '-tri fluoromet i 1 -bi-phenyl-1-carboxylic acid; N-. { - [-4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl} -2-pyrrole-1-yl-benzamide; N- [4 - [- 4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl} -2-pyridin-2-yl-benzamide; or a physiologically acceptable salt, solvate or derivative thereof. Preferred compounds of the invention include: [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phen-1] -amide of 4 '-isopropyl-5-met i 1 -bi f < nil-2 carboxylic; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-i-sopropyl-6-methoxy-phenyl-2-carboxylic acid; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-i-sopropyl-6-methyl-1-phenyl-2-carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 6-Met il-4'-tri f luoromet-1-bi-phenyl-2-carboxylic acid; (4- {3- (3-methyl- [l, 2,4] oxadiazol-5-yl) -benzyl] -piperazin > -l-yl} -phenyl) -amide of 4 '- isopropyl-5-met i 1-bi-phenyl 1-2 -carboxylic; [4- (4-carbamoylmet-1-piperazin-1-yl) -phenyl] -amide of 4'-tri fluoromethyl-1-bi-phenyl 1-2-carboxylic acid; [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amide of 4 '-isopropyl-1-6-me t-oxy-bi-fem-1-2-carboxylic acid; [4- (4-carbamoylmethyl) l-piperazin-1-yl) -phenyl-4-aminopropyl-6-met-1-b, phenyl-1-carboxylic acid; (4- (4- (3- (3-methyl- [l, 2,4] oxadiazol-5-yl) -benzyl) -piperazin-1-yl) -phenyl) -amide of the acid 'i sopropil -6- met i 1-bi feni 1-2 -carboxylic; [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) m * a * é. && amp; *? - 4-phenyl] -amide of 4 '-tri f luoromet il -bi-phenyl-2-carboxylic acid; [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide of 4'-isopropyl-5-methyl-1-carboxylic acid; 5-Methyl-4'-trifluoromethyl-2-phenyl-2-carboxylic acid [4- (4- (lH-pyrro-1-2-ylmethyl) -p [perazin-1-yl) -phenyl] -amide; or a physiologically acceptable salt, solvate derived therefrom. The term "physiologically functional derivative" as used herein, refers to any physiologically acceptable derivative of a compound of the present invention for example an ester, which when administered to a mammal such as a humane, is capable of providing (direct or indirectly) such compound or an active metabolite thereof Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of the text Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference, The compounds of the invention are inhibitors of hepatic apoB-100 production and are then of use in the treatment of conditions resulting from elevated circulating levels of apoB-100. compounds of the invention to inhibit the production of apoB-100 by human hepatocytes i_n vitro, is determined using human hepatocytes primary as a model system. The specificity of the compounds of the invention is established by comparing the effects of apoB-100, apoprotein A-1 and fibrinogen production. A specificity of at least 100 is preferred. The in vivo profile of the compounds was determined by acute oral administration of the compounds of the invention to DBA / 2 mice and 25 Wistar rats with measurement of plasma levels of apoB-100 as a percentage of the control values. The active compounds were further evaluated in Wistar rats by repeated oral administration (once a day) with measurement of total cholesterol, low-density lipoprotein cholesterol, triglycerides, apob-100 plasma levels and apoA-I as a percentage of the control values. The compounds of the invention are inhibitors ri, potent and specific of apoB-100, which also show good oral bioavailability and duration of action. The compounds of the invention are for use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disorders. The compounds of the invention are also useful in lowering serum levels of lipids, cholesterol and / or triglycerides, and are of use in the treatment of hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and / or hypertriglyceridemia. The invention therefore provides a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof for use in therapy, in particular in human medicine. Also provided as a further aspect of the invention, the use of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof, in the preparation of a medicament for use in the treatment of conditions resulting from levels elevated ba > - *. »Circulation of apoB-100. In an alternative or in a further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions resulting from elevated levels of apoB-100 circulation, comprising the administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof. It will be appreciated that reference to treatment is intended to include prophylaxis as well as relief of established symptoms. The compounds of the formula (I) can be administered as the chemical raw material but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof and formulated for administration by some convenient route. Such compositions are preferably in a form adapted for use -afafc »j in medicine, in particular in human medicine, and may conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus, the compounds of formula (I) are well formulated for oral, buccal, parenteral, transdermal, topical administration (including ophthalmic and nasal by deposit or rectal, or in a form suitable for administration by inhalation or insufflation (either through For oral administration, the pharmaceutical compositions may take the form of for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl). methyl cellulose), fillers (for example, lactose, microcrystalline cellulose or calcium acid phosphate), lubricants (for example, magnesium stearate, talc or silica), disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulfate) The tablets can be coated by the well-known methods in the The liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and conservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, coloring agents and sweeteners as appropriate. Preparations for oral administration may be appropriately formulated to give controlled release of the active compound. For buccal administration, the composition can take the form of tablets or lozenges formulated in a conventional manner. For transdermal administration, the compounds according to the invention can be formulated as creams, gels, ointments or lotions or as a transdermal patch. Such compositions can for example be formulated with an aqueous or oily base with the addition of appropriate thickeners, gelling, emulsification, stabilization, dispersion, suspension and / or coloring. The compounds of the invention can be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with an appropriate vehicle, eg, sterile, pyrogen-free water before its use. The compounds of the invention can be formulated for topical administration in the form of ointments, creams, gels, lotions, weights, aerosols or drops (e.g. eye, ear or nose drops). The ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of appropriate thickeners and / or gelling agents. Ointments for administration to the eye can be manufactured in a sterile manner using sterilized components. The lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. The droplets can be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They can also contain a conservator. The compounds of the invention can be ¿-iB lafa-. formulate in rectal compositions such as suppositories or retention enemas, for example, conventional bases containing suppositories such as cocoa butter or other glycerides. The compounds of the invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (for example subcutaneously or muscularly) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives for example, as a sparingly soluble salt . For intranasal administration, the compounds of the invention can be formulated as solutions for administration by means of an appropriate unit dose device or alternatively measured as a mixture of powders with a suitable carrier for administration, using an er device. appropriate delivery.

Ala The compositions may contain from 0.1% upwards, for example, 0.1-99% of the active material depending on the method of administration. A proposed dose of the compounds of the invention is from 0.25 mg / Kg to about 125 mg / kg of body weight per day for example 20 mg / kg to 100 mg / kg per day. It will be appreciated that it may be necessary to make routine variations to the dose, depending on the age and condition of the patient and the precise dose will ultimately be at the discretion of the attending physician or veterinarian. The dose will also depend on the route of administration and the particular compound selected. The compounds of formula (I) may, if desired, be administered with one or more therapeutic agents and formulated for administration by a convenient route in a conventional manner. The appropriate doses will be readily appreciated by those skilled in the art. For example, the compounds of formula (I) can be administered in combination with a reductase inhibitor HMG CoA. A compound of formula (I), or a physiologically acceptable salt, solvate or derivative thereof, is ^^^ D ^^ íjfck ^ ¡^^^^^^^ can prepare by the general methods described hereafter. In the following description, the groups X, Y, Z, R1, R2 and R3 are as previously defined for the compounds of formula (I), unless otherwise specified. According to a general process (A), a compound of formula (I) can be prepared by reacting a compound of formula (II) with a compound of formula R1-Z-X-L where L represents a suitable leaving group halide, for example, chlorine, under normal conditions of displacement, or where X is an oxo group, L may additionally represent a hydroxy group, the reaction is carried out under normal conditions of acid coupling and amines A compound of formula (II) can be prepared for the reaction of a compound of formula (III) with a compound of formula (IV) (III) (IV) wherein L is defined above and P is an appropriate amine protecting group, for example, tert-butoxycarbonyl (Boc), under normal coupling conditions for an acid and amine coupling, followed by deprotection of a protecting group under appropriate conditions, for example , acid separation of a Boc group. A compound of formula (IV), wherein A represents N, can be prepared by the two step reaction of a compound of formula (V) which comprises the incorporation of a protecting group P, using the standard methodology followed by the reduction of the nitro group, for example, under hydrogenation conditions. A compound of formula (IV) in dolnde A represents CH, can be prepared from the compound of formula (VI) (SAW) by reaction with an appropriate compound of formula H2N-P 'wherein P' is an appropriate protecting group which is unstable under hydrogenation conditions such as a benzyl group, using a coupling agent or agents such as tris (dibenzylidene acetone) dipalladium, 2,2'-bis (diphenylphosphino) -1, 1'-biphenyl (binap) and sodium terbutoxide in an appropriate solvent such as toluene, followed by separation of the protecting group and reduction of the double bond under hydrogenation conditions. According to a second method (B) the compounds of formula (I) can be prepared by the reaction of compounds of formula (III) and the compounds of formula (VII) .. i.

(Vile) where L was defined above, under normal coupling conditions. The compounds of formula (VII) can be prepared by the reaction of a compound of formula (V) with a compound of formula R1-ZXL, where L was defined above, followed by reduction of a nitro group under hydrogenation or reducing conditions of tin chloride. According to a third process (C) a compound of formula (I) wherein Y is -0-C? _4-alkylene-, can be prepared by the reaction of a compound of formula (VIII) with a compound of formula R2 -C? _4 alkylene-L, where L was finished up, The compounds of formula (VIII) can be prepared according to the process detailed in process B. According to a fourth general process (D), a compound of formula (I), wherein at least part of X represents a ligation alkylene for the piperidine or piperazine group can be prepared by reacting a compound of formula (II) with a compound of formula (IX) wherein X 'represents X less a methylene group, under reducing normal amination conditions, for example, using sodium triacetoxyborohydride in a solvent such as dichloroethane. According to a fifth process (E) a compound of formula (I) can be prepared ap art of a different compound of formula (I), or normal techniques well known in the art For example, compounds of formula (I) wherein R 1 comprises a group containing an amide group can be prepared from the compound of formula I), wherein the corresponding position comprises a carboxylic acid group, which in turn can be prepared from the compound of formula (I), wherein the corresponding position comprises a carboxylic ester group. Methods well known in the art can be employed to facilitate the transformation of an ester to an acid and then an amide. A compound of formula (III), wherein Y is a direct bond, is a phenyl or an aromatic heterocycle and L is a hydroxy group, can be prepared first by the coupling of a boronic acid with an appropriate leaving group, represented by a compound of formula (X) and a compound of formula (XI) wherein R represents phenyl or an aromatic heterocyclyl, PG represents a protected carboxylic acid and A and D represent either boronic acid or the appropriate leaving group, such as triflate or bromide, followed by deprotection of a protecting group under normal conditions such as the elimination of the base of an ester group. Where L represents a halide leaving group, the carboxylic acid product can be treated with an appropriate reagent such as thionyl chloride, to give the corresponding chloro leaving group. Where R1 is a phenyl, substituted by an aromatic heterocyclyl, the aromatic heterocyclyl can be introduced by any of the methods well known in the art. For example, wherein the substituent is an oxadiazole substituted by methyl, this can be formed by treating an appropriate benzamide derivative with an appropriate reagent, such as dimethylacetal of dimethylacetamide at elevated temperature, followed by the cyclization of an intermediate compound with hydroxylamine. The various general methods described above may be useful for the introduction of desirable groups at any step in the stepwise formation of the required compound, and it will be appreciated that these general methods may be combined in different ways in such multistage processes. The sequence of the reactions in multistage processes, of course, it must be chosen so that the reaction conditions used do not affect the groups in the desired molecule in the final product. Compounds of formula R1-ZXL, (III), (v; (VI), ( IX), (X) and (XI) are known or can be prepared by normal methods well known in the art and / or described herein Physiologically acceptable salts can be prepared from other salts, including other physiologically acceptable salts compound of formula (I), using conventional methods, The compounds of formula (I) can be easily isolated in association with the solvent molecule. allying or evaporating an appropriate solvent to give the corresponding solvates. When a specific enantiomer of a compound of general formula (I) is required, it can be^^ i obtained, for example, by the resolution of a corresponding enantiomeric mixture of a compound of formula using conventional methods. Thus, in one example an appropriate optically active acid can be used to form salts with the enantiomeric mixture of a compound of general formula (I). The resulting mixture of isomeric salts can be separated, for example, by fractional crystallization from the somatic terephthalate salts from which the required enantiomer of a compound of general formula (I) can be isolated by conversion to the free base. required Alternatively, the enantiomers of a compound of general formula (I) can be synthesized from appropriate optically active intermediates using any of the general processes described herein. The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade. Abbreviations: MS-LCMS mass spectrography, HOBt-1-hydroxybenzotriazole AcOEt-ethyl acetate, EDC1-1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, BINAP-2,2'-bis (diphenylphosphine) - 1 , 1'-hydrophile, THF-tetrahydrofuran, MeOH-me tanol, EtOH-ethanol, Et2Ntriethylamine.

Intermediate 1 5-Methyl oxy-4-trifluoromet-1-bi-phenyl 1-2-carboxylic acid methyl ester To a stirred solution of 4-methoxy-2- (trifluoromethanesulfonyloxy) -benzoic acid methyl ester (6.28) g) in toluene (100 mL), LiCl was added (2.54 g) and Pd (PPh3) 4 (1.15 g). After a few minutes at room temperature, a 2M solution of Na 2 CO 3 (26 mL) was added followed by a solution of 4-tri fluorometho1-phenyl-1-boronic acid (4.17 g) in ETOH (30 mL). The resulting mixture was stirred under reflux for 6 hours. The mixture was cooled to room temperature and the phases were separated. The organic layer was then dried over Na 2 SO 4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / AcOEt (90/10) to give the title compound (5.7 g) as white crystals, m.p .: 93-94 ° C Similarly prepared were: Intermediate 2 Ethyl ester of 4 '-isopropyl 1 - 5-met i 1 -biphenyl-2-carboxylic acid as an oil (10 g), GCMS: m / z 268 (M +) From the methyl ester of 4-methyl-2- (trifluoro-methanesulfonyloxy) -benzoic acid (11.9 g) and 4-isopropyl-1-phenyl boronic acid (7.2 g). Intermediate 3 Methyl ester of 5-metyl-4'-trifluoromethyl-1-bi-phenyl-1-carboxylic acid as a pale yellow oil (4.2 g). GCMS: m / z 294 (M +) From the methyl ester of 4-methyl-2- (tri-fluoro-methansulphonyloxy) -benzoic acid (4.7 g) and 4-trifluoromethoxyphenyl-boronic acid (3.3 g) Intermediary 4 Methyl ester of 6-methoxy-4'-tr if luoromet il-bi-phenyl-2-carboxylic acid as an oil 6. 8 g), GCMS: m / z 310 (M +) from 3-methyxy-2- (tri-fluoro-methylen-fonyloxy) -benzoic acid methyl ester (8.6 g) and 4-trifluoromethoxyphenyl-boronic acid methyl ester (5) g). Intermediate 5 Methyl ester of 4'-isopropyl-1-6-meth oxy-bifeni 1-2 -carboxylic acid as an oil (10 g) 7 GCMS: m / z 284 (M + from the methyl ester of 3-methoxy acid 2- (Trifluoro-methanesulfonyloxy) -benzoic acid (12.2 g) and 4-isopropylgenyl boronic acid (7 g) Intermediate 6 Methyl ester of 4'-isopropyl-6-methyl-1-biphenyl-2-carboxylic acid ico as a colorless oil (15.3g), GCMS: m / z 268 (M +) From the methyl ester of 3-methyl-2- (trifluoro-methanesulfonyloxy) -benzoic acid (15.7 and 4-i-sopro-phenyl-1-boronic acid) (10 g) Intermediate 7 Methacrylic acid 6-methyl-4 '- GCMS: m / z 294 (M +) from methyl ester of 3-me? Ti 1,2- (tri-fluoro-methansul-fonyloxy) -benzoic acid (15.7 and 4-trifluoromethoxyphenyl boronic acid (10 g). 8 2- (41-isopropyl-5-methoxy-biphenyl-2-yl) -4,4 dimet i 1-4,5-dihydro-oxazole To a suspension of magnesium (0.69 g) in Et20 (5 mL) containing a A solution of 1-bromo-4-i-sopropi-l-benzene (5.97 g) in Et20 (50 mL) was added dropwise after the addition of iodine., the mixture was heated under reflux for 1 hour. The resulting solution of Grignard was then carefully added to a solution of 2 (2,4-dimethyloxyfyl) -4,4-dimethyl-4,5-dihydrooxazol (3.52 g) in THF (60 mL) and The mixture was stirred at room temperature for 16 hours. The reaction mixture was then emptied into a saturated aqueous solution of NH4C JJ and the mixture was extracted with Et0, dried over Na2S >F, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / Ac0Et (85/15) to give the title compound (3.52 g) as a pale yellow oil.

MS: m / z 324 (M + 1 Prepared similarly was: Intermediate 9 2- (5-chloro-4'-isopropyl-biphenyl-2-yl) -4, dimethyl-4,5-dihydro-oxazole as a yellow oil ( 7.5 g) MS: m / z 326 (Ml) from 2- (4-chloro-2-methoxy-f-eni-1,4-dimethyl-4,5-dihydro-oxa-zol (10.2 g). and 1-br-orno-isopropyl-benzene (17.3 g) Intermediate 10 -chloro-2'-methyl-trif luoromet i 1 -bi phenyl To a solution of 2-bromo- -chloro-toluene 20.5 g) in toluene ( 100 mL) was added Pd (PPh3) 4 (lg) and the mixture was stirred at room temperature under N2 for 0.25 hours.A 2M solution of Na2CO3 (100 mL) was then added, followed by dropwise addition of acid. 4 -trif luoromet il feni 1 boronic acid (19 g) in MEOH (100 mL) The resulting mixture was heated under reflux for 48 hours.The mixture was then cooled to room temperature and the phases were separated.The organic layer was then dried Na2SO4 was filtered and evaporated under reduced pressure, the residue was purified by r flash chromatography eluting with pet oil ether / AcOEt (90/10) to give the title compound (25.3 g) as a colorless liquid. GCMS: m / z 270 (M +). Intermediate 11 5-Methoxy-1-tri fluoromethyl 1-bi-phenyl 1-2-carboxylic acid The methyl ester of 5-methoxy-4'-tr if luoromet i 1-biphenyl-2-carboxylic acid (5.6 g) is placed in suspension in EtOH (80 mL) and a solution of NAOH (2.9 g) in water (40 mL) was added. The mixture was stirred under reflux for 2 hours and the EtOH was evaporated under reduced pressure. The aqueous layer was then acidified with concentrated HCl and the resulting solid which formed was filtered, washed with water and dried to give the title compound (5.1 g) as white crystals. p. f. : 232-234 ° C.

Similarly prepared were: Intermediate 12 Acid 4'-i sopropil-5-methyl-bi-phenyl 1-2 -carboxylic as white crystals (9g). Mp: 109-111 ° C from the methyl ester of the acid 4 '-i sopropi 1-5-met il-bi-fe-2-carboxylic acid (10 g) Intermediate 13 Acid 5-methyl-4' -trifluoromethyl-biphenyl -2-carboxylic as white crystals (3.7 g). p. F. : 176-178 ° C from methyl 5-methyl-4 '-trif luoromet il-bifeni 1-2 -carboxylic acid ester (4.2 g) Intermediary 14 6-methoxy-4'-tri fluorometi 1-bi acid 1-2-carboxylic pheni as white crystals (2.5 g). mp: 207-209 ° C from the 6-methoxy-4'-tri fluoromethi 1 -bi-phenyl-1-carboxylic acid methyl ester (6.8 g) Intermediate 15 Acid i sopropi l-6-methoxy-bife Nyl-2-carboxylic acid as white crystals 4 g mp: 132-134 ° C from the methyl ester of the acid 4 '-isopropyl-6-methoxy-phenyl-2-carboxylic acid (10 g). Intermediate 16 4'-Isopropyl -6-methyl-1-bi-phenyl 1-2-carboxylic acid as white crystals (10 g), mp: 145-146 ° C from the methyl ester of 4 'isopropyl acid 1-6 -methyl-bi-phenyl 1-2 -carboxylic (15.3 Intermediate 17-6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals 5 g) p. f. : 206-208 ° C from the methyl ester of 6-methyl-4 '-trif luoromethyl-biphenyl-2-carboxylic acid (10 g). Intermediate 18 4'-Isopropyl-5-methoxy-2-carboxylic acid A solution of 2- (4'-i sopropi 1 -5-methoxy-biphenyl-2-yl) -, 4-dimethyl-4, 5- dihydrooxazole (3.4g in 4.5 N HCl (200 mL) was stirred under reflux for 48 hours. The mixture was then cooled to room temperature and extracted with Et20. The organic phase was then washed with brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure to give the title compound (2.5 g) as an imperfect white solid. P. f. : 1 8 8 - 1 9 0 ° C Similarly prepared was: Intermediate 19 5-Chloro-4'-isopropyl-1-bi-phenyl-2-carboxylic acid as white crystals (2.2 g). p. f. : 145-147 ° C from 2 - (5-chloro-4'-isopropy 1 -bi-2-ethylhexyl) -, 4-dimethyl-4,4-dihydrooxazole (7.5 g). Intermediate 20 Acid 5-Chloro-4'-trifluoromethyl-bi-phenyl 1-2-carboxylic acid To a solution of 5'-chloro-2'-methyl-4-tr if luoromet i 1-bi-phenyl (27 g) in one mixture of t-butanol (100 mL) and H20 (200 mL) was added in portions KMn04 (46.9 g). At the end of the addition, the mixture was heated under reflux for 16 hours, cooled to room temperature and filtered over celite. The filtrate was then acidified with concentrated HCl and the aqueous layer was extracted with AcOEt. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure to give the title compound (24 g) as white crystals. . s l r -A p.f .: 174-176 ° C. Intermediate 21 1- (3-cyano-benzyl) - A - (4-nitrophenyl) -piperazine To a stirred solution of l- (4-nitro-phenyl) piperazine (35.9 g) and potassium carbonate (71.6 g) in acetone (500 mL), 3-cyano-benzyl bromide (34 g) was added dropwise at room temperature and the mixture was heated under reflux. After four hours the salts were separated by filtration, washed with acetone and the filtrate was evaporated to dryness. The residue was taken up in CH2C12, and the solution was washed with water, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from the diisopropyl ether / AcOEt to give the title compound (52 g) as orange crystals. p.f .: 120-122 ° C Intermediate 22 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phene amine To a stirred solution of 1- (3-cyano-benz 1) - - 4 -nitro-phenyl) -piperazine (52 g) in EtOH (1.2 L) and THF (300 mL) were added in portions SnC 1? .2H? 0 145. 6 at room temperature and the mixture was - 6 A - heated at 55 ° C for 16 hours. After evaporation of the solvents, the residue was taken up in water, basified with NaOH to a pH of 14 and extracted with CH2C12. The organic layer was then washed with water, dried over Na 2 SO 4 and evaporated. The residue was crystallized from the diisopropyl ether to remove the title compound (40.5g) as light yellow crystals. p. f. : 99-101 ° C. Intermediate 23 N- [4- [3-cyano-benzyl] -piperazin-1-yl] -phenyl] -2-hydroxy-benzamide To a stirred solution of 4 - [4 - (3-cyano-benzyl) -pipe z in-li 1] - phenylamine (2.24 g) 2-hydroxy-benzoic acid (1.08 g), HOBt (1.35 g) and Et3N (1 in CH2C12 (70 mL), EDC1 (1.9 g) was added at room temperature and The mixture was stirred at room temperature for 4 hours, then the organic solution was washed with water, with a saturated solution of NaHCO 3, with brine, and dried over Na 2 SO 4 After filtration and evaporation of the filtrate, the residue was purified. by flash chromatography eluting with CH2Cl / MeOH (98/2) to give the compound ^^ fc ^ dH & ^ i? E ^^^! * ^^ ¡^^ £ 3 - ^^ of the title (1.85 g) as a yellow solid P.f. : 79-81 ° C.

Similarly prepared was: Intermediate 24 N- [4- [3-cyano-benzyl] -piperazin-1-yl] -phenyl] -2-hydroxy-3-methoxy-benzamide as pale yellow crystals (3.4 g) mp: 160- 162 ° C from 4 - [4 - (3-cyano-benzyl) -piperazin-1-yl] phenylamine (4.39 g) and 2-hydr acid < X) 3-methoxybenzoic acid (2.56 g). Intermediate 25 Tert-butyl 4- (4-? Nitrophenyl) piperazine-1-carboxylic acid ester To a solution of 1- (4-nitrophenol) -piperazine (15.5 g) in CH2C12, ( 250 mL) was added Et3N (8 .3 g) The solution was cooled to 0 ° C and di-tert-butyl di-carbonate (17.1 g) was added portionwise After 16 hours at room temperature, the solution was washed with water, with a saturated solution of NaHCO 3 and brine The organic phase was dried over Na 2 SO 4, filtered and evaporated under reduced pressure and the resulting solid was recrystallized from MeOH to give the title compound (21.5 g) as pale yellow crystals. mp: 149-151 ° C. Intermediary 26 Terbutyl ester of 3-nitro-phenyl) pipera zin-1-carboxylic acid To a solution of 1-iodo-3-nor tro-benzene (9g), tert-butyl ester of piperazin-1-carboxylic acid (13.5 g) and sodium tert-butoxide (9.7 g) in d :. Oxane (150 mL) was added t ris (dibenzylidene acetone) dipalladium (2 g) and t r i -o- tol i 1 fos f ina (2.2 g) and the mixture was heated under reflux for 24 hours. The solution was then cooled to room temperature, taken up in Et20 and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized from the diisopropyl ether to give the title compound (6 g) as a yellow solid. p.f .: 126-128 ° C. Intermediate 27 Tert-butyl ester of 4- (4-amino-phenyl) piperazin-1-carboxylic acid. A solution of 4 - (-nit ro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (21.4 g) in EtOH (250 mL) containing 10% Pd / C (0.5 g) was hydrogenated at room temperature . After 16 hours, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The oily residue was crystallized after cyclohexane to give the title compound (17.8g) as pink crystals. p. f. : 95-96 ° C. Similarly prepared was: Intermediate 28 4- (3-Amino-phenyl piperazine-1-carboxylic acid tert-butyl ester as an oil (2.5 g), MS: m / z 278 (M + l) From the tertiary ester Butyl 4- (3-amino-phenyl) -piperaz-1-carboxylic acid (6 g) Intermediate 29 Tert-butyl ester of 4 -. {4 - [(', trif luoromet i 1 -bi-phenyl 1-2 -carbonyl) -amino] -phenyl.} piperazine-l-carboxylic acid Method A: To a stirred solution of 4 - (4-amino-phenyl) tert-bu t -yl ester. -pipe z in-1 -carbohydric acid (1.38g), 4'-t-fluoromethoxy-1-bi-phenyl-1-carboxylic acid (1.33 g), HOBt (0.81 g) and Et2N (0.6 g) ) in CH2C12, (30 mL) EDC1 (1.15 g) was added and the mixture was stirred at room temperature for 6 hours. The organic solution was then washed with water, a saturated solution of NaHCO 3 and dried over Na 2 SO 4.

After evaporation and filtration of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2 / AcOEt (90/10) and the resulting oily compound was crystallized from EtOH to give the title compound (2.3 g) as white crystals. p.f .: 214-215 ° C. Method B: To a stirred solution of tert -butyl ester of the - (4-amino-phenyl) -piperazine-1-carboxylic acid ester (8.1 g) in CH2C12 (150 mL) was added Et20 (3.33 cJ) and the mixture was cooled to 0 ° C. To this solution was added dropwise 4 '-trifor luoromet i lbi feni 1-2 -carbonyl chloride. (8.53 g) in CH2C12 (80 mL) and the mixture was stirred at room temperature for 1 hour.The organic solution was then sequentially washed with water, with a saturated solution of NaHCO:, with brine and then dried over Na2S04, filtered and -^^^ J ^ tj ^ & ^^ j25 ^ evaporated. The oily residue was obtained by triturating the diisopropyl ether of the title compound (13.6 g) as white crystals. p.f .: 213-215 ° C Intermediate 30 Tert-butyl ester of 4- acid. { 4 - [(4'-i-sopropyl-5-met-il-bi-phenyl-1-2-carbonyl) -amino] -phenyl} -pipe razin-1 -carboxylic To a stirred solution of the tert-butyl ester of 4 - (4-amino-phenyl) -piperazin-1 -carboxy-1-yl ester (4.15 g) 4 '-isopropyl-5-met i 1 -bi-phenyl-1-2-carboxylic acid (3.81 g) HOBt' (2.36 g) and Et3N 1.97 g) in CH2C12 (50 mL), EDC1 (3.72 g) was added. g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3, with brine and dried over Na 2 SO 4. After filtration and evaporation of the filtrate, the residue was crystallized from the diisopropyl ester to give the title compound (4 g) as white crystals. p.f .: 173-175 ° C Similarly prepared were: Intermediary 31 Es ter te rt -but í lico de l á c ido 4 -. { 4 H (4'-i-sopropyl-6-methoxy-biphenyl-2-carbonyl) -amino] -phenyl} pipera zin-1 -carboxylic as white crystals (1.9 g) p. f. : 155-157 ° C from 4 '-i-sopropi-1-6-met-oxy-2-phenyl-2-carboxylic acid (1.94 g) and 4 - (4-amino-phenyl) tert-butyl ester ) -pipe z 1 -carboxylic acid (2 g). Intermediary 32 Tert-butyl ester of 4 - acid. { 4 - [(6-met il-4 '-tri fluorometi 1-bi-phenyl-1-2-carbonyl) -amino] -phenyl} piperazine-l-carboxylic like white crystals (1.5 g), mp: 163-165 ° C from 6-met il-4 '-tri f luorome t il-biphenyl-2-carboxylic acid (2 g) and tert-butyl ester of 4 - (4-amino-phenyl) -piperazin-1-carboxylic acid (2 g). Intermediary 33 Tert-butyl ester of 4- acid. { 4 [(4'-isopropyl-6-methyl-biphenyl-2-carbonyl) -amino] -phenyl} -piperazine-1-carboxylic acid as white crystals SHI * A? - 1.8 g), mp: 140-142 ° C from 4 '-i-sopropyl-6-met i 1-bi-enyl-2-carboxylic acid (1.83 g) and tert-butyl ester 4- (4-Amino-phenyl) -piperazine-1-carboxylic acid 2g: Intermediate 34 4- (4-Fluorobenzyloxy) -benzoylamino] -phenyl ester tert-butyl ester} -pipe zin-1 carboxylic as white crystals (6.7 g), mp: 170-171 'C from the acid 2 - (4-f luoro-benzyloxy benzoic acid (3.69 g) and the tert-butyl ester of acid 4 - (4-amino-phenyl) -piperazine-1-carboxylic acid (4.15 g) Intermediate 35 4- {3 - [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino) tert-butyl ester] -phenyl.}. pipera zin-1 -carboxylic as a white solid (3.3 g). mp: 160 ° C from 4-trifluoromethyl-2-phenyl 1-2-carboxylic acid (2.5 g) and 4- (3-amino-phenyl) -piperazine-1-carboxylic acid tert-butyl ester ( 2.5g).

Intermediate 36 (4'-piperazin-1-yl-phenyl) -amide of the 4'-trifluoro-ethyl-bi-phenyl-1-carboxylic acid To a solution of the tert-butyl ester of 4 -. { 4 - [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -piperazine-1-carboxylic acid (11.7 g) in CH2C 12 (50 mL), trifluoroacetic acid (25 mL) was added and the solution was stirred at room temperature for 2 hours. The mixture was then evaporated under reduced pressure and the residue was taken up in water. The resulting precipitate was filtered and washed with water. The resulting solid was then suspended in water, washed with a saturated Na 2 CO 3 solution and extra; or with CH2Cl2. The organic phase was then washed with water, dried over Na 2 SO 4, filtered and evaporated to give the title compound (9 g) as white crystals p. F. 119-124 ° C. Intermediate 37 (4, -piperazin-1-yl-phenyl) -amide of 4 '-i-sopropi-1-5-methyl-1-bi-phenyl-2-carboxylic acid To a solution of the tert-butyl ester of 4 -. { - [(4'-isopropyl-5-methyl-biphenyl-2-carbonyl) -amino] -pheni 1} -pipe zin-1 -carboxylic (4g) in CH2C1; (20 ml) was added trifluoroacetic acid (15 mJ) and the solution was stirred at room temperature for 16 hours. The mixture was then evaporated under reduced pressure and the residue was taken up in water and basified with an aqueous solution of IN NaOH. The resulting precipitate was extracted with CH2C12 and the organic phase was washed with water, dried over Na2S? , filtered and evaporated to give the title compound (3g) as white crystals. p.f .: 131-133 ° C Similarly prepared were Intermediate 38 (4-piperazin-1-yl-phenyl) -amide of 4'-isopropyl-1-6-methoxy-bi-phenyl-2-carboxylic acid as white crystals (1.3 g). mp: 157-159 ° C from the 4- (4 [(4'-i-sopropi-1-6-methoxy-bi-phenyl-2-carbonyl) amino] phenyl-1-tert-butyl ester. -pipera zin - 1-carboxylic acid (1.9 g) Intermediate 39 - 6-methyl-4 '-trifluoromethyl-biphenyl-2-carboxylic acid piper zin-1-yl-phenyl) -amide *. * -.- ,, ": white crystals (0.9 g) p. f. : 155-157 ° C from the 4- (4 [(6-met il-4 '-tri fluoromethyl-biphenyl-2-carbonyl) ami no] -phenyl} -piperaz-1-tert-butyl ester. -carboxy 1 ico (1.5 g) Intermediate 40 (4-piperazin-1-yl-phenyl) -amide of the acid A '-isopropyl-6-meth i 1-bi-phenyl 1-2 -carboxylic acid and white crystals (1.2 g) mp: 130 ° C from the 4- [{4 - [(4'-isopropyl-6-methyl-biphenyl-2-carbonyl) -amino] phenyl] tert-butyl ester. 1-carboxylic acid (1.8 g) Intermediate 41 2- (4-fluoro-benzyloxy) -N- (4-piperazin-1-yl-fem 1) benzamide as white crystals (3.6 g) mp: 143-146 ° C from 4- (4 [2- (4-fluoro-benzyloxy) -benzoylamino] -phenyl} -piperazine-1-carboxylic acid tert-butyl ester (6 g) Intermediary 42 (3) -piperazin-l-yl-phenyl) -amide of the A '-tri fluoromethyl] -bi-phenyl 1-2-carboxylic acid as white crystals (2.5 g) mp: 101-103 ° C from the tert-butyl ester of acid 4. { 3 [('-trifluoromethyl-biphenyl-2-carbonyl) -amino] phenyl} -pipe zin-1-carboxylic (3.3 g). Intermediate 43 4- (4-bromo-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester To a solution of 4- (4-bromo-phenyl) -1, 2 , 3, 6-tet rahydro-pyridine (2.39 g) in CH2C12, (30 mL), Et3N (2 g) was added. The solution was cooled to 0 ° C and di-1rt-butyl dicarbonate (2.29 g) was added.

After 16 hours at room temperature, the solution was washed with water, with a saturated solution of NaHCO 3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure, and the residue was purified by flash chromatography eluting with CH2C12 to give the title compound (2 g) as a white solid. p. f .: 68-70 ° C Intermediate 44 4 - (4-benzylamino-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester To a solution of tert-butyl acid ester 4- (4-bromo-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid (0.34 g), benzylamine (0.12 g) and sodium tert-butoxide (0.13 g) in toluene (8 mL) are they added t ri s (dibenci liden acet ona) dipa ladio (2.2 mg) and Binap (4.6 mg) and the mixture was heated at 80 ° C for 16 hours. The solution was cooled to room temperature, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with petroleum ether / AcOEt (90/10) and the oily residue was crystallized from the diisopropyl ether to give the title compound (0.27 g) as white crystals mp: 120-121 ° C Intermediate 45 4- (4-aminophenyl) piperdin-1 -carboxylic acid tert-butyl ester A solution of tert-butyl acid ester 4- (4-benzylamino-phenyl) -3,6-dihydro-2H-pyridine-l-carboxylic acid (0.27 g) in EtOH (10 mL) containing 10% Pd / C (50 mg) was hydrogenated at room temperature.

After 1 hour, the catalyst was removed by filtration, the filtrate was evaporated under reduced pressure to give the title compound 0.18 g) as a pale pink oil. MS: m / z 277 (M + l) Intermediate 46 Tert-butyl ester of 4 - acid. { 4 - [(4'-tri fluorometi 1-bi-phenyl-1-2-carbonyl) -amino] -phenyl} piperidin-1-carboxylic acid To a stirred solution of the 4- (4-aminophen-1) -piper idin-1 -carboxylic acid tert-butyl ester (0.18 g), 4 '-trif luorome ti 1 -bi phenyl-2-carboxylic acid (0.17 g), HOBt (0.1 g) and Et3N (80 mg) in CH2Cl2 (10 mL), EDC1 (0.15 g) was added at room temperature and The mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na 2 SO 4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with petroleum ether / AcOEt (70/30) to give the title compound (0.25 g) as an orange oil. MS m / z 523 (Ml) Intermediate 47 (4-piperidin-4-yl-phenyl) -amide of the acid A'-tri fluorometi 1-bi-phenyl 1-2 -carboxylic acid trifluoroacetate salt To a solution of the 4- tert-butyl ester. { 4- [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -piperidin-1-carboxylic acid (0.22 in CH2CI2 (5 ml) was added trifluoroacetic acid 1 mL 'and the solution was stirred at room temperature for 1 hour.The mixture was evaporated under reduced pressure and the residue was taken up in water. The resulting product was filtered, washed with water and dried to give the title compound (0.23 g) as white crystals mp: 223-225 ° C Intermediate 48 3- [1, 3] dioxolan-2-yl-benzamide To one solution of 3- (1,3-dioxolan-2-yl) -benzonitrile (5.86 g) in a mixture of EtOH (140 mL) and H20 (60 mL) was added sodium hydroxide (6.46 g) and the mixture was heated under reflux for 2 hours The solvent was evaporated under reduced pressure and the aqueous layer was extracted with CH C 12. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (4.5 g) as a white solid. mp: 92-94 ° C Intermediate 49 3- (3-methyl- [1, 2, 4] oxadiazol-5-yl) -benzaldehyde A mixture of 3- [1,3] dioxolan-2-yl-1-benzamide 2.3 g) and dimethylacetal dimethylacetamide (4 g) were heated under reflux for 1 hour and then evaporated to dryness. The oily residue was dissolved in dioxane (20 mL) and hydroxylamine hydrochloride (1.18 g), acetic acid (20 mL) and a 2N aqueous sodium hydroxide solution (9 mL) was added and the mixture was heated to 90 ° C. for 2 hours. After evaporation, the residue was dissolved in toluene (100 mL) and a solution of IN hydrochloric acid (50 mL) was added and the mixture was stirred at reflux for 2 hours. After cooling to room temperature the organic phase was decanted, washed with water, dried over Na 2 SO 4, filtered and evaporated to give the title compound (2.3 g) as a white solid. p.f. : 114-116 ° C Intermediate 50 [4- (4-bicyclic piperazin-1-yl) -phenyl] -carbamic acid tert-butyl ester «& & fci 0 - To a solution of 4- (4-benzyl-piperazin-1-y1) -phenylamine (32 g) in CH2C12 (500 mL) containing Et2N (18.4 mL) was added dropwise di-tert-dicarbonate. Butyl (28.8 g) at 0 ° C. After 20 hours at room temperature, the solution was washed with water, with a saturated solution of NaHCO 3 and saline. The organic phase was dried over Na 2 SO 4, filtered and evaporated under reduced pressure to give the title compound (43.5 g) as a solid. GCMS: m / z 367 (M +) Intermediate 51 (4-pipera z in 1-yl-phenyl) -carbamic acid tert-butyl ester A solution of tert-butyl acid ester [4- (4-benzyl-piperazin-1-yl) -phenyl] -carbamic acid 43.5 g) in EtOH (1) containing 10% Pd / C (4 g) was hydrogenated at room temperature. After 72 hours, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The oily residue was then purified by flash chromatography eluting with AcOEt / isopropyl (90/10) and the solid obtained was recrystallized from AcOEt to give the title compound (17.5 g as white crystals, mp 155-157). ° C Intermediate 52 (4- {4- [3- (3-Methyl- [1,2,4] oxadiazol-5-yl) -benzyl] -piperazin-1-yl} tert-butyl ester. phenyl) -carbamic acid To a tert-butyl acid ester solution 4 - . 4 -piperazin-1-yl-phenyl) -carbamic acid (2g) in 1,2-dichloroethane (80mL; 3- (3-met-il- [1, 2, 4] oxadiazol-5-yl) -benzaldehyde was added. 1.4 and acetic acid (0.67 g) The solution was cooled to 0 ° C and triacetoxy borohydride sodium 3.15 g was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO 3, with brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (98/2) to give the title compound (2.5 g) as a white solid. P.f .: 159-161 ° C Intermediary 53 4-. { 4- [3- (3-methyl- [1,2,4] oxadiazol-5-yl) -benzyl] -2-piperazin-1-yl} phenylamine To a stirred solution of (4 -. {4 - [3- (3-met i 1- [1, 2, 4] oxadia zol-5 i 1) -benci 11- tert -butyl ester. piperazin-1-yl.} - phenyl) -carbamic acid (2.5 in CH2C1 (4 mL) was added trifluoroacetic acid 6 mL) and the mixture was stirred at room temperature for 16 hours. After evaporation under reduced pressure, the residue was taken up in water, basified with an aqueous solution of IN NaOH and extracted with CH2Cl2. The organic phase was then washed with water, dried over Na 2 SO 4, filtered and evaporated. The oily residue was crystallized from MeOH / H20 to give the title compound (1.35 g) as a solid. p.f .: 106-1080C Intermediate 54 3- (5-t rif luoromet il- [1, 2, 4] oxadiazol-3-yl) benzaldehyde To a stirred solution of 3- (1,3-dioxolan y2-yl) -benzonitrile (4 g) in EtOH (130 mL) was added hydroxylamine hydrochloride (7.9 g) and potassium carbonate (15.7 g) and the mixture was refluxed for 4 hours. The hot mixture was filtered and the remaining solids were washed with EtOH and the filtrate ? f., í. ^ rihás & ¿y¡? evaporated under reduced pressure. The crude amidoxime (4.2 g) was dissolved in trifluoroacetic acid (20 mL and Et3N (2 g) was added and the mixture was stirred at room temperature for 3 hours.The solution was evaporated to dryness and the residue was extracted with CH2C12. The organic was washed with water, dried over Na 2 SO 4, filtered and evaporated, the residue was then dissolved in toluene (100 mL) and IN aqueous hydrochloric acid (30 mL) was added and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature, the organic phase was decanted and washed with brine, dried over a2S0, filtered and evaporated.The residue was purified by flash chromatography eluting with CH C1 to give the title compound (2 g) as a pale yellow oil GCMS: m / z 242 (M +) Example 1 [4 '- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4'-tri fluoromethyl acid 1-bi phenyl-2-carboxylic acid (Method 1 To a stirred solution of 4 - [4 - (3-cyano-benzyl) pipera zi n- 1 -i 1] - phenylamine (0.29g), 4 'acid ^ A & amp; h added room temperature EDC1 (124 mg) the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na 2 SO 4. After filtration and evaporation of the filtrate, the oily residue was crystallized from EtOH to give the title compound (160 mg as white crystals mp: 167-169 ° C.) Analysis for C35H36N40 Calculated: C, 79.51; H, 6.86; N, 10.60; Found: C, 79.41; H, 6.61; N, 10.81% E jmplo 3 [4- [4- (3-cyano-benzyl) -piperazin-1-yl-phenyl] -amide of the acid i sopropi 1 - -met oxy-bi-phenyl-1-carboxylic acid To a stirred solution of 4- [4- (3-cyanobenzyl) -piperazin-1-yl] -phenylamine (400 mg), 4'-i acid Sodipyl-6-methoxybi-1-2-carboxylic acid (444 mg), HOBt (222 mg) and Et3N (166 mg) in CH2C12 (20 mL) was added at room temperature EDC1 (315 mg) i The mixture was stirred at room temperature for 16 hours The organic solution was then washed with water, ^ fes ^ j ^^ yes 6 - with a saturated solution of NaHCO3 and dried over Na2S04. After filtration and evaporation of filtered I, the residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (95/5) to give the title compound (279 mg) as crystals. whites. P. f. : 179 ° C.

Analysis for C35H36N402 (0.5 H20) Calculated: C, 75.92; H, 6.73; N, 10.12; Found: C, 75.65; H, 6.48; N, 10.35% Example 4 [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -pheni-ij -amido of 4 '-i-sopropyl-6-methyl-il-bife-il-2 acid carboxylic acid To a stirred solution of 4 - [4 - (3-cyano-benzyl) -piperazin-1-yl] phenylamine (400 mg) 4'-isopropyl-6-methyl-1-bi-phenyl acid 1-2- carboxylic acid (418 mg), HOBt (222 mg) and Et3N (166 mg) in CH2C12 (20 mL) was added at room temperature EDC1 (315 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na2SO¿ After filtration and evaporation of - * - * - * ~~ - 7 - filtrate, the residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (98/2) and crystallized from AcOEt to give the title compound (304 mg) as crystals whites. p.f .: 137 ° C. Analysis for C 35 H 36 N 40 Calculated: C, 79.51; H, 6.86; N, 10.60; Found: C, 79.31; H, 6.36; N, 10.78% Example 5 [A - (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 6-met il-4 '-tri f-luoromet-il-biphenyl-2-acid carboxylic acid To a stirred solution of 4 - [4 - (3-cyano-benzyl) -piperazin-1-yl] -phenylamine (400 mg), 6-methyl-4'-tri f luoromet i 1 -bi feni acid 1 -2-carboxylic acid (460 mg) HOBt (222 mg) and Et3N (166 mg) in CH2C12 (20 mL) was added EDCl (315 mg) at room temperature and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na 2 SO 4. from AcOEt to give the title compound (122 mg) as white crystals m.p .: 192 ° C. Analysis for C33H29F3N40 Calculated: C, 71.47; H, 5.27; N, 10.10; Found: C, 71.32; H, 5.23; N, 10.17% Example 6 [4 -. { 3- (3-methyl- [1, 2,] oxadi azo l-5 i] 1] -benc 11] -piperazin-1-yl.}. -phenyl) -amide of 4'-isopropyl 1 -5- met il-biphenyl-2-carboxylic acid To a stirred solution of 4-. { 4- [3- (3-met il- [1, 2, 4] -oxadiazol-5-yl) -benzyl] -piperazin-1-yl} phenylamine (175 mg), 4 '-isopropyl-5-methyl-1-biphenyl-2-carboxylic acid (127 mg), HOBt (87 mg) and Et3N (67 mg) in CH2Cl2 (20 mL) were added at room temperature EDCl (124 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na 2 SO 4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (98/2) and crystallized from CH2Cl2 / diisopropyl ether to give the title compound (110 mg) as white crystals. mp: 145-147 ° C. Analysis for C 37 H 39 N 502 Calculated: C, 75.87; H, 6.71; N, 11.96; Found: C, 75.79; H, 7.02; N, 11.81% Similarly prepared were: Example 7 [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -pheni! 5-Chloro-4'-isopropyl-biphenyl-2-carboxylic acid amide as white crystals (280 mg), p. f. : 188-190 ° C from 5-chloro-4'-isopropyl-1-bi-phenyl-2-carboxylic acid (274 mg) and 4 - [4 - (3-cyano-benzyl) -piperazin-1-yl] phenylamine (292 mg) Analysis for C34H33C1N40 Calculated: C, 74.37; H, 6.06; N, 10.20; Found: C, 74.56; H, 6.20; N, 10.05% Example 8 I [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl-amide of 6-methyloxy-4'-tri fluorometi 1-b-phenyl 1-2 -carboxylic acid as white crystals (225 mg), p. f. : 215-217 ° C ^ ¿^ I tmí? í íMáA? from 6-methoxy-4'-trifluoromethyl-biphenyl-2-carboxylic acid (150 mg) and 4- [- (3-cyano-benzyl) -piperazin-1-yl] -phenylamine (150 mg) Analysis for C33H29F3N402 Calculated: C, 68.60; H, 5.20; N, 9.70; Found: C, 68.50; H, 5.19; N, 9.56% Example 9 [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl-amide of 5-methyl-4'-trifluoromet il-biphenyl-2-carboxylic acid as white crystals (240 mg), p. f. : 166-168 ° C from 5-methyl-4'-trifluoromet il-biphenyl-2-carboxylic acid (210 mg) and 4- [4- (3-cyano-benzyl) -piperazin-1-yl] - phenylamine (219 mg) Analysis for C33H29F3N40 Calculated: C, 71.47; H, 5.27; N, 10.10; Found: C, 71.89; H, 5.72; N, 10.18% Example 10 [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 5-chloro-1-trifluoro-ethyl-biphenyl-2-carboxylic acid as white crystals 0.25 g), p. f. : 164-165 ° C from 5-chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (0.19 g) and 4- [4- (3-c-anoenyl) -piperazin-1-yl} phenylamine (0.18 g) Analysis for C 32 H 26 C 1 F 3 N 40 (0.5 H 20) Calculated: C, 65.81; H, 4.66; N, 9.59; Found: C, 65.49; H, 4.79; N, 9.75% To a stirred suspension of N- [4- [3-cyano-benzyl] -piperazin-1-yl] -phenyl] -2-hydroxy-3-methoxy-benzamide (0.33 g) and K2CO3 (0.134 g) in acetone ( 15 mL), 4-trifluoromethyl-benzyl chloride (0.146 g) was added dropwise and the mixture was heated to reflux. After 16 hours, the mixture was cooled to room temperature, the salts were separated by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was then crystallized from EtOH to give the title compound (0.29 g) as pale yellow crystals. p. f. : 118-119.5 ° C. Analysis for C34H31F3N403 Calculated: C, 67.99; H, 5.20; N, 9.33; Found: C, 67.98; H, 5.07; N, 9.32% «». «Ate» «a Example 34 [4- [4- (3-cyano-benzyl) -piperazin-1-yl] phenyl-amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid (Method 2) To a solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -ad ida (0.58 g) in CH2C12 (35 mL) containing Et3N (0.152 g), 3-cyano-benzyl bromide (0.267 g) was added and the mixture was heated to reflux for 2 hours. The solution was washed with water, dried over Na 2 SO 4, filtered and evaporated. The ree was purified by flash chromatography eluting with CH2C12 / MeOH (98/2) and the solid obtained was recrystallized from MeOH / H20 to give the title compound (0.67 g) as white crystals, p. 155 ° C Analysis for C32H27F3N40 Calculated: C, 71.10; H, 5.03; N, 10.36; Found: C, 70.86; H, 4.98; N, 10.27% Example 35 N-4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -2- (4-fluoro-benzyloxy) -benzamide To a solution of 2- (4 -fluoro-benzyloxy) -N- (4-piperazin-1-yl-phenyl) -benzamide (0.31 g) in CH2C1 2 (10 - 8..M.?. i rr? á-i »-U4 ** * m- -.,. *.: ml) containing Et3N (84 mg), 3- cyano-benzyl bromide (0.147 g) was added and the mixture was heated to reflux for 2 hours. The solution was washed with water, dried over Na 2 SO 4, filtered and evaporated. The residue was crystallized from the diisopropyl ether to give the title compound (0.21 g) as white crystals. p. f. : 114-116 ° C. Analysis for C 32 H 29 FN 402 Calculated: C, 73.83; H, 5.61; N, 10.76; Found: C, 74.10; H, 5.89; N, 10.68% Example 36 [3- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl or -amide of 4 '-trifluoromethyl-1-phenyl-2-carboxylic acid. To a solution of 4 '-trifluoromethyl-bi-phenyl-2-carboxylic acid (3-piperazin-1-yl) -phenyl) -amide (0.5 g) in acetone (20 ml) containing K2CO3 (0.19 g), was added 3-cyano-benzyl bromide (0.23 g) and the The mixture was heated to reflux for 2 hours. The solution was cooled to room temperature, the salts were separated by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by crystallization from wu tm? im dto-sjJtt AcOEt to give the title compound (0.17 g) as white crystals. p. f. : 170-172 ° C. Analysis for C 32 H 27 F 3 N 40 Calculated: C, 71.10; H, 5.03; N, 10.36; Found: C, 70.69; H, 5.15; N, 10.18% Example 37 [4- (-carbamoylmethyl-piperazin-1-yl) -phenyl] -amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid To a solution of (4-piperazin-1-yl- 4'-trifluoromethyl-biphenyl-2-carboxylic acid phenyl-amide (0.31 g) in acetone (10 mL) containing K2CO3 (0.31 g), 2-bromoacetamide (0.124 g) was added and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the salts were separated by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (95/5) and the solid obtained was recrystallized from EtOH to give the title compound (0.23 g) as white crystals. p. f. : 226-228 ° C. Analysis for C26H25F3N402 Calculated: C, 64.72; H, 5.22; N, 11.61; .rf ^^^^ MMfcfHÚAMftte ^ MÜd ^ teiMMaMbí Found: C, 64.69; H, 5.45; N, 11.59% Example 38 [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amide of 4"-isopropyl-6-methoxy-bi-phenyl-2-carboxylic acid. 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid 4-piperazin-l-yl-phenyl) -amide (214 mg) in acetone (20 mL) containing K2COB (206 mg), 2-bromoacetamide (100 mg) was added and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the salts were separated by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (92/8) and the solid obtained was crystallized from CH2Cl2 / diisopropyl ether to give the title compound (120 mg) as white crystals. p. f. : 207-209 ° C. Analysis for C29H34N403 Calculated: C, 71.58; H, 7.04; N, 11.51; Found: C, 71.68; H, 6.47; N, 11.44% Example 39 ? M!! L? »S [4- (4-carbamoylmethyl-piperazin-l-yl) -phenyl] -amide of 4" -isopropyl-6-methyl-biphenyl-2-carboxylic acid To a solution of (4-piperazin-l-yl-phenyl) -amide of '-isopropyl-6-methyl-biphenyl-2-carbocyclic acid (206 mg) in acetone (20 L) containing K2C0 | (206 mg), 2- was added bromo-acetamide (100 mg) and the mixture was refluxed for 16 hours, after cooling to room temperature, the salts were filtered off, washed with acetone and the filtrate was evaporated under reduced pressure, the residue was purified by chromatography. Instantaneous eluting with CH2Cl2 / MeOH (93/7) and the solid obtained was recrystallized from CH2Cl2 / diisopropyl ether to give the title compound (190 mg) as white crystals, mp: 181-183 ° C. Analysis for C29H34N402 Calculated : C, 74.01; H, 7.28; N, 11.91; Found: C, 73.87; H, 6.69; N, 11.84% Similarly prepared were: Example 40 [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] < amide of 6-methyl- '-trifluoromethyl-bi-phenyl-2-carboxylic acid as white crystals (100 mg! ? -T -? *. * B «w«. »AÉfc *. i i-a p.f .: 196-198 ° C. from 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (220 mg) and 2-bromoacetamide (100 mg). Analysis for C27H27F3N402 (0.25H20) Calculated: C, 64.73; H, 5.53; N, 11.18; Found: C, 64.44; H, 4.93; N, 10.98% Example 41 [4- (4-Cyanomethyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (1.3 g). p.f .: 244-246 ° C. from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) amide (2.12 g) and chloro-acetonitrile (396 mg). Analysis for C26H23F3N40 (0.25 H20). Calculated: C, 66.59; H, 5.05; N, 11.95; Found: C, 66.51; H, 4.89; N, 11.81% Example 42 [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-bipheni-2-carboxylic acid as white crystals (5.1 g). p. f. : 167-169 ° C. from 4'-trifluoromethyl-bifeni 1-2 -carboxylic acid (4-piperazin-1-phenyl) amide (4.25 g) and bromoacetic acid ethyl ester (1.83 g) • Analysis for C28H28F3N303. Calculated: C, 65.74; H, 5.52; N, 8.21; Found: C, 65.76; H, 5.09; N, 8.16% Example 43 [4- (4- (2-ethoxy-ethyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid 0 as white crystals (210 mg ). p.f .: 176-178 ° C. from 4 '-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) -amide (318 mg) and l-bromo-2-ethoxy-ethane (126 mg). 5 Analysis for C28H30F3N3O2 Calculated: 67.59; H, 6.08; N, 8.45; Found: - C, 67.63; H, 6.05; N, 8.49% Example 44 [4- (4- (3-hydroxy-propyl) -piperazin-1-yl) -phenyl] -0-amide of 4'-trifluoromet il-biphen-2-carboxylic acid as white crystals ( 160 mg). p.f .: 208-210 ° C. ---- * • & * '• from (1-trifluoromethyl-bifeni) -carboxylic acid (4-piperazin-1-phenyl) -amide (318 mg) and 3-bromo-propan-1-ol (125 mg). Analysis for C27H28F3N302 (0.5 H20) Calculated: C, 65.84; H, 5.93; N, 8.53; Found: C, 65.66; H, 6.23; N, 8.40% Example 45 [4- (4,4,4-trifluoro-butyl) -piperazin-1-ylphenyl] -amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (N, 8.40%) 240 mg) .p.f .: 198-200 ° C. from (4-piperazin-1-yl-phenyl) -amide of 4 '-tri fluoromet i 1-bi phenyl-2-carboxylic acid (297 mg) and 4-bromo-1,11-tri-fluoro-butane (143 mg) 15 Analysis for C28H27F6N30 (0.5 H20) Calculated: C, 61.76; H, 5.18; N, 7.72; Found: C, 61.53; H 4.88 N, 7.55% Example 46 [4- (4- (3-Methyl-but-2-ynyl) -piperazin-1-yl] -20-phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (180 mg! p.:203-205 ° C. '' -trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (318 mg) and l-bromo-3-methyl-but-2-ene (122 mg). Analysis for C29H30F3N3O (0.4 H20) Calculated: C, 69.56; H, 6.20; N, 8.39; Found: C, 69.34; H, 5.62; N, 8.55% Example 47 [4- (4- (3-cyano-4-fluoro-benzyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (440 mg). p. f. : 168-170 ° C. from '-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) amide (425 mg) and 3-cyano-4-fluoro-benzyl bromide (214 mg) Analysis for Calculated C32H26F4N40 : C, 68.81; H, 4.69; N, 10.03; Found: C, 68.83; H, 4.55; N, 9.98% Example 48 [4- (4- (3, -methylenedioxy-benzyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (180 mg ) p. f. : 189-191 ° C. ~ * * x * * j * from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) amide (318 mg) and 3,4-methylenedioxy-benzyl chloride (140) mg). Analysis for C32H28F3N303 Calculating: C, 68.68; H, 5.04; N, 7.51; Found: C, 68.44; H, 5.04; N, 7.54% Example 49 [4- (4- (3-nitro-benzyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as light yellow crystals (900 mg ) mp: 152-154 ° C from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) amide (1.06 g) and 3-ni tro-benzyl bromide ( 538 mg). Analysis for C31H27F3N403 Calculated: C, 66.42; H, 4.85; N, 9.99; Found: C, 66.02; H, 5.03; N, 9.95% Example 50 [4- (4- (3-carbamoyl-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-trifluoromethyl-bife-ni-2-carboxylic acid as white crystals 1.5 g) mp: 199-201 ° C. from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) amide (1.7 g) and 3-chloromethyl-benzamide (676 mg). Analysis for C 32 H 29 F 3 N 402 Calculated: C, 68.81; H, 5.23; N, 10.03; Found: C, 68.84; H, 5.52; N, 9.99% Similarly prepared were Example 61 4- (4- (3-methyl- [1,2,4] oxadiazol-5-yl) -benzyl-piperazin-1-yl) -phenyl) -amide of 4-isoprppil-i -methyl-biphenyl-2-carboxylic acid To a solution of 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) -amide (309 mg) in 1,2-dichloroethane (20 mL), 3- (3-methyl- [1, 2, 4] oxadiazol-5-yl) -benzaldehyde (154 mg) and acetic acid (67 mg) were added. . The solution was cooled to 0 ° C and triacetoxy borohydride sodium (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO 3, with brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2C12 / MeOH (98/2) and the solid obtained was recrystallized from CH2Cl2 / hexane to give the title compound (140 mg) as white crystals. p. f. : 74 ° C. Analysis for C37H39N502 (0.5 H20) Calculated: C, 74.72; H, 6.78; N, 11.78; Found: C, 74.39; H, 6.74; N, 11.73% Example 62 HttttMÉtt ^ rtÜÉ * (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl) -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid To a solution of (4- 4'-trifluoromethyl-biphenyl-2-carboxylic acid piperazin-1-phenyl) -amide (310 mg) in 1,2-dichloroethane (20 ml), lH-pyrrole-2-carboxaldehyde (95 mg) and acetic acid were added. (67 mg). The solution was cooled to 0 ° C and triacetoxy borohydride sodium (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO 3, with brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (95/5) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals p. f. : 191-193 ° C. Analysis for C29H27F3N40 Calculated: C, 69.04; H, 5.39; N, 11.10; Found: C, 69.56; H, 5.80; N, 11.06% Example 63 4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) phenyl) -amide of 4'-isopropyl-5-methyl-biphenyl-2-carboxylic acid A solution of 4 '-isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-l-yl-phenyl) -amide (290 mg) in 1,2-dichloroethane (20 ml), lH-pyrrole-2-carboxaldehyde (68 mg) and acetic acid were added. (67 mg). The solution was cooled to 0 ° C and triacetoxy borohydride sodium (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO 3, with brine, dried over Na2SO, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (98/2) and the solid obtained was recrystallized from MeOH to give the title compound (60 mg) as white crystals. p.f .: 185-187 ° C. Analysis for C 32 H 36 N 40 Calculated: C, 78.02; H, 7.36; N, 11.37; Found: C, 78.35; H, 7.11; N, 11.27% Example 64 • * h * rf '& amp' * i &* (*? (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-ylphenyl) -amide of 5-methyl-4 'acid -trifluoromethyl-biphenyl-2-carboxylic acid To a solution of 5-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl-1-amide) (329 mg) in 1, 2 -dichloroethane (20 ml), lH-pyrrole-2-carboxaldehyde (86 mg acetic acid (54 mg) was added.The solution was cooled to 0 ° C and triacetoxy borohydride sodium (238 mg) was added portionwise and the The mixture was stirred at room temperature for 16 hours The solution was then washed with a saturated solution of NaHCO 3, brine, dried over Na 2 SO 4, filtered and evaporated under reduced pressure.The residue was purified by flash chromatography eluting with CH 2 Cl 2 / MeOH (95/5) The oily residue obtained was crystallized from diisopropyl ether to give the title compound (210 mg) as white crystals, p.p .: 196-198 ° C. Analysis for C30H29F3N4O (0.5 H20) Calculated: C 68 30; H, 5.73; N, 10.62; Found: C, 68.05; H, 6.03; N, 10.36% Similarly prepared were: Example 65 [4- (4-propyl-piperazin-1-yl) -phenyl] -amide of trifluoromethyl-bifeni 1-2 -carboxylic acid as white crystals (160 mg). p.f .: 207-209 ° C. from the 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-pheni-1) -amide (0.31 g) and propionaldehyde (64 mg). Analysis for Calculated C27H28F3N30: C, 69.36; H, 6.04; N, 8.99; 10 Found: C, 69.47; H, 6.12; N, 8.86% Example 66 [4- (4- (3-acetyl-benzyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (235 mg) . 15 p. f. : 181-183 ° C from (4-piperazin-1-ylphenyl) -amide a of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid (0.31 g) and 3-acetyl-benzaldehyde (122 mg). Analysis for C33H30F3N3O2 (0.25H20). 20 Calculated: C, 70.51; H, 5.47; N, 7.48; Found: C, 70.41; H, 5.12; N, 7.40% Example 67 [4- (4-furan-2-ylmethyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as pale yellow solid (180 mg) mp: 173-175 ° C a from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) -amide (0.31 g) and furan-2-carboxaldehyde (106 mg). ! Analysis for C29H26F3N302 | Calculated: C, 68.90; H, 5.18; N, 8.31; 10 Found: C, 69.00; H, 5.31; N, 8.17% E emplo 68 [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide of 4 '-isopropyl-6-methoxy-biphenyl-2-carboxylic acid as white crystals (230 mg). 15 pf: 195-197 ° C from the 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl) -amide (0.3 g) and lH-pyrrole-2 -carboxaldehyde (68.5 mg). Analysis for C32H36N402 j 20 Calculated: C, 75.56; H, 7.13; N, 11.01; Found: C, 75.79; H, 7.16; N, 11.03% Example 69 4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4- (4-methyl-1-met-1H-pyrrol-2-ylmethyl) -piperazijn-1-yl) -phenyl] -amide ( 150 mg). mp: 177-179 ° C from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (0.31 g) and 1-methyl-1H-pyrrole-2-amide carboxaldehyde (109 mg) Analysis for C 30 H 29 F 3 N 4 O (1 H 20) Calculated: C, 67.15; H, 5.82; N, 10.44; Found: C, 67.45; H, 5.70; N, 10.51% Example 70 [4- (4-thiophen-2-ylmethyl-piperazin-1-yl) -phenyl] -amide of 4'-trifluoromethyl-biphenyl 1-2-carboxylic acid as a yellow solid (150 mg) . p.f .: 181-183 ° C. from (4-piperazin-1-yl-phenyl) -amide of 4 '-trifluoromethyl-bifeni 1-2 -carboxylic acid (0.31 g) and thiophene-2-carboxaldehyde (126 mg). Analysis for C29H26F3N30S (1.25H20) Calculated: C, 64.01; H, 5.28; N, 7.72; Found: C, 64.05; H, 5.04; N, 7.72% Example 71 already . { 4- [4- (1H-pyrazol-3-ylmethyl-piperazin-1-yl) -i-phenyl] -amide of 4 '-trifluorome ti 1-bi-phenyl-1-carboxylic acid as white crystals (210 mg ). j i p. f. : 194-196 ° C. ! i I from the 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (0.31 g) and lH-pyrazole-3-carboxaldehyde (79 mg). MS: m / z 506 (M + 1). Example 72 [4- (4-thiophen-3-ylmethyl-piperazin-1-yl) -phenyl] -amide of 4"-trifluoromet il-biferyl-2-carboxylic acid as white crystals (170 mg) i p. f .: 187-189 ° C from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (0.31 g) and thiophene-3-carboxaldehyde (112 mg) Analysis for C29H26F3N30S Calculated: C, 66.78; H, 5.02; N, 8.06; Found: C, 67.10; H, 5.40; N, 8.01% i I Example 73 ji { 4- [4- (5-fluoro -lH-indol-3-ylmethyl) -piperazijn-1-yl] -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals (190 mg) p. f.: 168-170 ° C. from 4'-trifluoromethyl-biphenyl-2-carboxylic acid (-piperazin-1-phenyl) -amide (318 mg) and 5-fluoro-1H-indole-3-carboxaldehyde (135 mg Analysis for C33H28F4N40 ( 0.5 H20) Calculated: C, 68.15; H, 5.03; N, 9.63; JI Found: C, 67.97; H, 5.09; N, 9.43% i Example 74 i I (4- (4- (3-methyl- [1, 2,4] oxadiazol-5-yl) -benzyl] -piperazin-1-yl) -phenyl] -amide of 4'-isopropyl-6-methoxy-bipheni-2-carboxylic acid as white crystals (300 mg) .pf: 180-182 ° C. from (4-piperazin-1-yl-phenyl) -amide of the acid 4'-i-sopropi-1-6-methoxy-bi-phenyl 1-2-carboxy lyico (0.32 g) and 3- (3-met il- [1, 2, 4] oxadiazol-5-yl) -benzaldehyde (154 mg) Analysis for C37H39N503 (0.5 H20) Calculated: C, 72.76; H, 6.60; N, 11.47; Found: C, 72.80; H, 6.59; N, 11.31%! Example 75 j (4- { 4- [3- (5-trifluoromethyl- [1,2,4] oxadiazole-3 -trifluoromethyl-biphenyl-2-carb acid-1-yl) -benzyl] -piperazin-1 -i 1.}. oxilic I as white crystals (240 mg). ' [4- [4-. { [biphenyl-3-l-methyl) -carbamoyl] -methyl} 4'-trifluoromethyl-biphenyl-2-carboxylic acid piperazin-1-yl] -phenyl] -amide To a stirred solution of (4- {4 - [(4'-trifluoromethyl-biphenyl) -2- carbonyl) -amino] -phenyl.}. - piperazin-1-yl] -acetic (241 mg), biphenyl, -3-yl-methylamine (95 mg), HOBt (87 mg) and Et3N (202 mg) in CH2C12 (20 mL) were added EDCI (125 mg) and the mixture was stirred at room temperature for 16 hours . The organic solution was then washed with water, with a saturated solution of NaHCO 3 and dried over Na 2 SO 4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (97/3) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals, mp: 165-167 ° C. I Analysis for C39H35F3N402 i Calculated: C, 72.21; H, 5.44; N, 8.64; J i Found: C, 71.94; H, 5.66; N, 8.53%! Example 78: 3- (4- { 4 - [(4'-tri fluoromethyl-2-phenyl-2-iiylcarbonyl) -amino] -phenyl} -piperazin-1-methylmethyl) -i benzoic ( To a solution of 4'-i-trifluoromethyl-biphenyl-2-carboxylic acid [4- [4- (3-carbomethoxy-benzyl) -piperazin-yl-] -phenyl] -amide (1.6 g) in EtOH i (100 mL), IN sodium hydroxide (5.6 ml) was added and the mixture was stirred under reflux for 16 hours. The solution was cooled to room temperature and acidified with IN hydrochloric acid (5.6 mL). The obtained white precipitate was filtered and recrystallized I from EtOH to give the title compound i I (1.4 g) as white crystals. J p.f .: 225-227 ° C. Example 79: 4'-trifluoromethyl-biphenyl-2-carboxylic acid 4- (4- [3- (2,2,2-trifluoro-ethylcarbamoyl) -benzyl] -piperazin-1-yl] -phenyl] -amide The solution is stirred to a stirred solution of 3- (4-. {4-J (4 '-tri fluoromethyl-bifeni-1-2-carboyl) -amino] -phenyl} - piperazin-1-ylmethyl] - Benzoic acid (279 mg), 2,2-trifluoro-ethylamine (74 mg), HOBt (85 mg) and Et3N (63 mg) in CH2C12 (10 mL) were added EDCI (125 mg) and the mixture was stirred at room temperature. The organic solution was washed with water, saturated NaHC03 solution and dried over Na2SO4, after filtration and evaporation.

After being filtered, the residue was purified by chromatography and ins as ant anne with CH2Cl2 / MeOH (97/3) and the solid obtained was recrystallized from the solid.

CH2Cl2 / disopropyl ether to give the title compound (190 mg) as white crystals. P.f .: 205-207 ° C. Analysis for C34H30F6N4O2 Calculated: C, 63.75; H, 4.72; N, 8.75; Found: C, 63.65; H, 4.95; N, 8.63% Example 80 [4- [4- (3-Cyano-benzoyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biferiyl-2-carboxylic acid. To a stirred solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (0.318 g) in CH2C12 (15 mL), containing Et 3 N (79 mg) was added dropwise 3-cyano-benzoyl chloride (0.129 g) and the mixture was stirred at room temperature for 1 hour. The solution was then washed with water, brine, dried over Na 2 SO 3, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2Cl2 / AcOEt (80/20) and the solid obtained was recrystallized from ^ »« RiMMja? Alfe * of AcOEt to give the title compound (0. | 29 g! As white crystals) mp: 178-180 ° C. Analysis for C32H25F3N402 Calculated: C, 69.31; H, 4.54; N, 10.10 Found: C, 69.49; H, 4.63; N, 10.08% i Example 81 II [4- (4-Acetyl-piperazin-1-yl) -phenyl) -amide, 4'-trifluoromethyl-bipheni-2 acid -carboxylic. A solution of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-phenyl) -amide (2.12 mg) in acetic anhydride (10 ml) was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, and the residue was dissolved in CH2C12 and washed with a saturated solution of NaHCO3, brine, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from AcOEt to give the title compound (130 mg) as white crystals. i p.f .: 175-176 ° C. Analysis for C 26 H 24 F 3 N 302 Calculated: C, 66.80; H, 5.17; N, 8.99; Found: C, 66.69; H, 5.15; N, 8.87% I Example 82 j 4 '-trifluoromethyl-2-phenyl-2-carboxylic acid [4- [4- (3-cyano-benzenesul-fonyl) -piperazin-1-yl] -phenyl] -amide. To a stirred solution of 4'-trifluoromethyl-biphenyl-4-piperazyl-1-yl-5-phenyl) -amide. carboxylic acid (0.318 g) in CH2C12 (20 mL), containing Et3N (90 mg) was added dropwise 3 jcyanobenzenesulfonyl chloride (0.179 g) and the mixture was stirred at! I room temperature for 48 hours. The solution is then washed with water, with brine, dried over Na 2 SO, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2C12 to give the title compound (0.39 g) as a white solid. 15 p.f .: 223 ° C. Analysis for C31H25F3N403S (0.5 H20) Calculated: C, 62.10; H, 4.37; N, 9.34; Found: C, 62.03; H, 4.55; N, 9.11% Example 83 [4- (4-methanesulfonyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid. To a solution of 4 '-trifluoromethyl-bifeni 1-2-carbol xi li co (318 mg) (4-piperazin-1-yl-phenyl) -amide in CH2C 12 (10 mL), follow E t 3N (91 mg) was I added methanesulfonyl chloride (70 mL) and mixture I was stirred at room temperature for 1 hour. The solution was washed with water, with brine, dried over Na 2 SO 4, filtered and evaporated. The solid obtained! s re c i s t a l i z a part i of CH3CN to leave the compound of the title (170 mg) as white crystals. I p.f .: 254-256 ° C. j i Analysis for C25H24F3N303S | Calculated: C, 59.63; H, 4.80; N, 8.34; Found: C, 59.58; H, 5.10; N, 8.57% Example 84 | [4 - [1- (3-cyano-benzyl) -piperidin-4-yl] -phenyl] -amide of 4 '-trifluoromet il-bipheniyl-2-carboxylic acid. To a solution of the trifluoroacetate salt of the 4'- (trifluoromethyl-biphenyl-2-carboxylic acid (4-piperidin-4-yl-phenyl) -amide (0.23 g) in acetone (10 mL) containing K2CO3 (0.18 g) g) 3-cyano-benzyl bromide (0.086 g) was added and the mixture heated to reflux. After 16 hours, the mixture was cooled to room temperature, the salts were separated by filtration, washed with acetone and the filtrate I was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2 / MeOH (98/2) and the oily residue was crystallized from the diisopropyl ether to give the title compound (0.13 g) as white crystals. p.f .: 124-126 ° C. Analysis for C33H28F3N30 Calculated: C, 73.45; H, 5.23; N, 7.79; Found: C, 73.43; H, 5.56; N, 7-91% Example 85 N-. { 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl} 2-pyrrol-1-yl-benzamide as a pale yellow solid (426 mg). p.f .: 174 ° C | from 2-pyrrol-1-yl-benzoic acid (538 I mg) and 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenylamine (700 mg) i Analysis for C29H27N50 I Calculated: C, 75.46; H, 5.90; N, 15.17; i Found: C, 75.09; H, 6.07; N, 15.15% I I Example 86 'i N-. { 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl} - 2-pyridin-2-yl-benzamide as white crystals (200 mg). mp: 169-171 ° C from 2-pyridin-2-yl-benzoic acid (199 mg) and 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenylamine (292 mg) . Analysis for C30H27N50 Calculated: C, 76.09; H, 5.75; N, 14.79; Found: C, 76.04; H, 5.94; N, 14.47% Example 87 Citrate salt of the 4- [4- (3-cyano-benzyl-piperazin-1-yl] -phenyl] -amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid to a solution of [4 - [4 - (3-cyano-benzyl] -i-piperazin-1-yl] -phenyl] -amide of 4'- i trifluoromethyl-bi-phenyl-2-carboxylic acid (0.2 g) MeOH I (15 mL) was added with citric acid (71 mg) and the resulting solution was stirred at room temperature, then the solution was evaporated to dryness and the solid was triturated in Et20, filtered and dried to give the compound of the title (0.15 g) as a white powder, mp: 120 ° C. Example 88 I i Hydrochloride salt of [4- [4- (3-cyano-benzyl) -I piperazin-1-yl] -phenyl ] - i 4'-trifluoromethyl-biphenyl-2-carboxylic acid amide. < To a solution of j 4'- i trifluoromethyl-biphenyl-2-carboxylic acid (4-4- cyano-benzyl) -piperazin-1-yl] -phenyl] -amide (0.2 g) in cOEt i (25 mL) was added hydrochloric acid IN (0.9 L) and! The resulting solution was stirred at room temperature for 1.5 hours. The solution was then evaporated to dryness and the solid was recrystallized from AcOEt / hexane to give the title compound (0.18 g) as a white powder. i I p.f .: 165 ° C. i Biological Test 'I Primary human hepatocytes were sown at 50 000 cells / wells in 96-well plates. After I an adhesion phase overnight, the cells were incubated with compounds for 8 hours in a medium RPMI containing 1% FCS, 4 μg / ml insulin, 100 nM dexamethasone and 50 μCi / ml 35 S-methionine. The ! The tests were performed in DMSO and were tested on I cells from 1 μM to 1.6 nM. The production of radiolabelled apoB-100 and apoA-1 (used as a selectivity control) was quantified by analysis of the supernatants using SDS PAGE and exposure of I gels on Phosphorlmager sieves. The inhibition of the secretion of apoB-100 and apoA-1 by compounds is I calculate using controls, and both apoprot were obtained for the invention.

Tablet Compositions j The following compositions A and B can be prepared by wet granulation of ingredients (a) through (c) and (a) through (d) with a solution of povidone, followed by the addition of magnesium stearate and compression .

Composition A mg / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose B.P. 210 26 (c) Sodium Starch Glicolate 20 12 (d) Povidone B.P. 15 9 (e) Magnesium stearate 5 3 500 300 Composition B mg / tablet mg / tabite (a) Active ingredient 250 250 '(b) Lactose 150 150 (c) Avicel PH 1 60 26 (d) Sodium Starch Glycolate 20 12 (e) Povidone B.P. 15 9 (f) Magnesium Stearate 5 3 500 300 Composition C Mg / tablet Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4 359 The following compositions D and E can be prepared directly by direct compression of the mixed ingredients. The lactose used in the I composition E is of the direct compression type.

Composition D Mg / tablet Active Ingredient 250 Magnesium Stearate 4 Pregelatinized Starch NF15 146 400 . «Amari.» *. ».

Composition E Mg / tablet Active Ingredient 250 Magnesium Stearate 5 Lactose 145 Avicel 100 500 Composition F (controlled release composition) Mg / tablet (a) Active Ingredient 500 (b) Hydroxypropylmethylcellulose 112 (Methocel K4M Premium) (c) Lactose B.P. 53 (d) Providone B.P.C. 28 (e) Magnesium Stearate 7 700 The composition can be prepared by wet granulation of the ingredients (a) to (c) with a solution of providone, followed by the addition of magnesium stearate and compression. Composition G (enteric coating tablet) The enteric coating tablets of composition C can be prepared by coating the tablets with 25 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate or anionic polymers of the methacrylic acid and methacrylic acid methyl ester (Eudagrit L). Excluding the Eudagrit L, these polymers should also include 10% (by weight I of the amount of polymer used) of a plasticizer to avoid membrane breakage during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. I Composition H (controlled release enteric coating tablet). The enteric coating tablets of composition F can be prepared by coating the tablets with 50 mg / tablet of an enteric polymer such as phthalate acetate. of cellulose, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate or anionic acid polymers of methacrylic acid and methyl methacrylic acid methyl ester (Eudagrit L). Excluding the Eudagrit L, these polymers should also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent membrane breakage during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citr and triacetin. (ii) Capsule Composition Composition A. Capsules can be prepared by mixing the ingredients of composition D above and filling hard gelatin capsules in two portions with the resulting mixture. Composition B (infra) can be prepared in a similar manner. Composition B Mg / capsule (a) Active Ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycolate 25 (d) Magnesium Stearate 2 420 Composition C Mg / capsule (a) Active Ingredient 250 (b) Macrogol 4000 BP 350 ji 600 I The capsules can be prepared by melting the macrogol 4000 BP, dispersing the active ingredient i 1 in the melt and filling it with hard gelatin capsules in two parts. Composition D! Mg / capsule and Active Ingredient 250 'Lecithin 100 i' i Peanut Oil 100 i I 450, i Capsules can be prepared by dispersing the active ingredient in lecithin and peanut oil and filling the soft gelatine elastic capsules with the dispersion.

Composition E (controlled release capsule) .. .... i. * ...,. . - trrt? fl? riJ Aír f if f.-M ^ M? Mg / capsule (a) Active Ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Ethyl Cellulose 13 513 iii The composition of the controlled release capsule i can be prepared by extruding the mixed ingredients (a) (c) using an extruder, then forming spheres and drying the extrudate. The dry pellets are coated with a release control membrane (d) and filled with hard gelatin capsules. , Composition F (enteric capsule). Mg / capsule (a) Active Ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose B.P. 125 (d) Cellulose Acetate Phthalate 50 (e) Diethyl Phthalate 5 555 The enteric capsule composition can be prepared by extruding the mixed ingredients (a) through I (c) using an extruder, then forming spheres and drying the extrudate. The dried pills are coated with an enteric membrane (d) containing a plasticizer (e) and filled into hard gelatin capsules of two parts. ! Composition G (enteric coating and controlled release capsule). The enteric coating capsules of the composition can be prepared by coating the controlled release pills with 50 mg / capsule of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate or anionic polymers of the methacrylic acid I and methacrylic acid methyl ester (Eudagrit L). Excluding the Eudagrit L, these polymers should also include 10% (by weight of the polymer amount used) of a plasticizer to prevent membrane breakage during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. (iii) Composition of Intravenous Injection. Active Ingredient 0.200 g Pyrogen-free Phosphate Shock Absorber (pH 9.0), sterile up to 10 ml The active ingredient dissolves in most of the buffer at 35-40 ° C, then becomes volume and is filtered through a sterile micropore filter inside 10 ml sterile glass vials (type 1) which are sealed with sterile seals and overlaps. i (iv) Composition of Intramuscular Injection. Active Ingredient 0.20 g Benzyl Alcohol 0.10 g I Glycofurol 75 1.45 g Water for Injection 1 q.s. up to 3.00 ml - The active ingredient dissolves in glycofurol. I The benzyl alcohol is then added and dissolves, and water is added to 3 ml. The mixture is then filtered through the sterile microporous filter and se! seal in sterile 3 ml glass vials (type 1). I (v) Syrup composition. | (saw) Active Ingredient 0.25 g Sorbitol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Taste 0.0125 ml Purified water q.s. to 5.0 ml Sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution is added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and the required volume is then made with the purified water. j (vi) Composition of Suppository. i mg / suppository! Active Ingredient 250 Hard Fat, BP j (Witepsol H15 - Dinamit NoBel) 1770 i 2020 One fifth of the Witepsol H15 is melted in a steam-jacketed container at 45 ° C maximum. The active ingredient is poured through a 2001m mesh and added to the molten base with mixing, using a Silverson coupled with a cutting head, until a disintegration is achieved. uniform. By maintaining the mixture at 45 ° C, the remaining I Witepsol H15 is added to the suspension which is stirred to ensure a homogeneous mixture.1 The complete suspension is then passed through a 2501m stainless steel sieve and, with stirring continuous, it is allowed to cool to 40 ° C. At a temperature of 38-40 ° C, 2.02 g of I aliquots of the mixture are filled into appropriate plastic molds and the suppositories are allowed to cool to room temperature. (vii) Pessary composition Mg / pessary Active Ingredient (631 m) 250 Anhydrous Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000 The above ingredients and pessaries are prepared resulting mixture, (viii) Transdermal composition. Active Ingredient 200 mg Alcohol USP 0.1 ml Hydroxyethyl Cellulose The active ingredient and alcohol USP are gelled with hydroxyethyl cellulose and packaged in a transdermal device with a surface area of 10 cm.

It is noted that in relation to this date, the best method known to the applicant to bring the said invention into practice is that which is clear from the present description of the invention] ^^ «dw« Ma «*

Claims

CLAIMS Having described the foregoing as preceding, the property contained in the following claims is claimed as property:

1. A compound of formula (I) characterized in that: A represents N or CH; X is selected from the following groups: (i) -C? _6 alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy groups, C? _6 alkoxy C? -6 and I acyl, C? -6 or acyloxy C? -6,, i (ii) oxo, sulfonyl, thioxo, i! (iii) -C? -6 alkylenecarbonyl-, i -C? -6 I alkylene sulfonyl-, -C? -6 alkylenethioxo-,! (iv) -C2-6 alkyleneoxy, -C2-6 alkylenethio-, | -C2-β1 alkylene (N-C ?6 alkyl) amino-, 1 * = * ¡* * & k & • AaIT $ .t '^^^ i ^ * 4 gggjfaj i i I (v) -C? -6 alquilencarboxil-, C? -C i _6 alquilentioámido-? -6 alkylene (NH or NC -6 alkyl) carboxamido - (vi) -C2-6 aiquilenoxycarbonyl-, "C2-6 alkylene-iocarbonyl-, -C2_6 alkylene (NH or NC? -6 alkyl) aminocarbonyl-; Z represents a direct bond or -Cl-6 alkylene, optionally containing a double bond and optionally replaced by one or more groups hydroxy, alkyl C? -β, Ci-β alkoxy, Cj? -6 acyl or Ci_6 acyloxy; R1 is selected from the following groups: (i) hydrogen, C? _3 perfluoroalkyl, i (ii) C6-? Aryl, C3-8 cycloalkyl and benzo fusion derivatives thereof, C7-10 polycycloalkyl, C4-8 cycloalkenyl , C7-10 polycycloalkenyl, 1 (iii) a heterocyclyl of the group consisting of monocyclic radicals and molten polyol radicals I, wherein the radicals contain a total of 1 atoms from 5-14 rings, wherein the radicals! I contain a total of heteroatoms from 1-4 adules independently selected from oxygen, nitrogen and sulfur, and wherein the rings Individuals of the radicals can i! I will be independently saturated, partially i I unsaturated or aromatic, and i II (iv) where X is to which C? -6 and Z ex a direct bond, or Z is alkylene C? -6, R p I I additionally represent halogen, cjiano, I nitro or acyl C _6, 'I wherein when R1 contains one or more rings, i I rings may each independently I bear 0 to 4 substituents independently selected from: i (i) halogen, hydroxy, cyano, nitro, formyl, I alkylsulfonylamino C? -6, '(ii) alkyl C? -6 cycloalkyl? 3-8, I perfluoroalkyl C? _3, li (iii) alkoxy C? -6 / methylenedioxy, perfluoroalkoxy C? -3, C? _6 alkyl, (iv) amino, C? _6 alkylamino, dialkylamino C? I? -6, I (v) phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, I (vi) hydroxycarbonyl, C? _6 alkoxycarbonyl,! (vii) aminocarbonyl, alkylaminocarbonyl < ~? -6, dialkylaminocarbonyl C? -6, dialkylaminocarbonyl C? -6 alkoxy C? -6, perfluoroalkylaminocarbonyl Cn3 i i (vi i i) ac i l C? -6, ac i l ox i C? -6 / o C ij yl ox? -6 alkyl C II? -6, acilammo C? _6, yii I (ix) an aromatic heterocyclyl consisting of monocyclic radicals i where I SLEDAI radic containing 5-6 ring atoms , where the R radicals contain a total of 1-4 heteroatoms from I II seleccionadosi rings independently oxygen, nitrogen and sulfur, and wherein each R urio heterocyclyl groups' i is optionally substituted by one or more groups selected I independently of C 1-4 alkyl, C? -4 alkoxy, C? _ 3 perfluoroalkyl, and C? _3 perfluoroalkoxy; Y represents an oxy or direct bond, C6-6- alkylene, C6-6-oXyalkylene or a heterocyclyl! consisting of monocyclic radicals, where] the radicals contain 5-ring atoms and where the radicals contain a total of heteroatoms from 1-4 independently selected rings I of oxygen, nitrogen and sulfur and wherein the ring ": fc -'-" = - Í can be independently saturated, partially unsaturated or aromatic; R2 represents phenyl, heterocyclyl C3 cycloalkyl consisting of monocyclic radicals wherein the radicals contain a total of atoms from 5-6 rings, wherein the radicals contain a total of heteroatoms from 1-4 years independently selected from oxygen, nitrogen and sulfur, wherein the ring can be independently saturated, partially unsaturated or aromatic, and wherein each R2 is optionally substituted by one or more groups independently selected from halogen, C? _4 alkyl, C? -4 alkoxy, C3-8 cycloalkyl, C? -3 perfluoroalkyl, C? -3-hydroxycarbonyl perfluoroalkoxy, and alkoxycarbonyl • Ci-β, cyano, nitro, alkylaminosulfonyl; I i R3 represents hydrogen or one or more groups i independently selected from halogen, I C1-4 alkyl, C1-4 alkoxy, C1-3 perfluoroalkyl, or C3_3 perfluoroalkoxy; or a physiologically acceptable salt, solvate or derivative thereof.

2. The compound according to claim 1, characterized in that A represents N and the piperazine group is substituted.

3. The compound according to claim 1 or 2, characterized in that X is C6-6 alkylene, optionally containing a double bond, oxo, sulfonyl, -alkyleneoxy p2_5_, alkylenecarboxy C1- or alkylene C1- (NH or N-alkyl IC? -6) carboxamido-. 'I

4. The compound in accordance with > claims 1 2, characterized in that X is methylene, oxo or sulfonyl. The compound according to claim 1 or 2, characterized in that X is a methylene group. 6. The compound according to any one of claims 1 to 5, characterized in that I z is a direct ligation or alkylene Ci-β- 7. The compound according to any of claims 1 to 6, characterized in that X it is a methylene group and Z is a direct link! The compound according to any one of the claims 1 to 7, characterized in that Ri is selected from the following groups: 'i! (i) hydrogen, cyano, C? 3- perfluoroalkyl, I (i) phenyl optionally substituted, where I optional substitution is effected by one or two groups independently selected from alkyl C? -6, cyano, halogen, C? -6 alkoxy / perfluoroalkyl and C? -3, hydroxycarbonyl, alkoxycarbonyl? C? -, I aminocarbonyl, methylenedioxy, nitro, acylC? 6, phenyl or an aromatic heterocyclyl optionally substituted i consisting of monocyclic radicals and fused polycyclic radicals, wherein the radicals contain a total of 5-ring atoms, wherein the optional substitution is effected by C1-4 alkyl, or perfluoroalkyl C3-3, (iii) an optionally substituted aromatic heterocyclic consisting of monocyclic radicals and fused polycyclic radicals, wherein the radicals contain a total of atoms of from 5-10 rings, wherein the optional substitution is carried out by C 1 -4 alkyl or perfluoroalkyl C? -3. 9. The compound according to any of claims 1 to 9, characterized in that R1 is an optionally substituted oxadiazolyl or pyrrolyl I, wherein the optional substitution is effected by a methyl group. i | 10. The compound according to any one of claims 1 to 8, characterized in that R1 is selected from the following groups: 'i (i) hydrogen, (ii) substituted phenyl, wherein the substitution is effected by cyano or an oxadiazipyl group substituted by methyl, or | I (iii) a pyrrolyl group. 11. The compound according to any one of claims 1-8, characterized in that XZ is methylene or oxo and R1 is phenyl or a heterocyclyl, wherein each R1 is optionally substituted by one or more groups independently selected from C-alkyl. ? 6, cyano, halogen, C? -6 alkoxy, trifluoromethyl, hydroxycarbonyl and C? _4 alkoxycarbonyl. I ?? in fi t líi ??? í? r ?? liiii ??? ii-?? * r itrii 12. The compound according to any of claims 1-8 characterized in that R1 I is phenyl substituted by 3-cyano. | I 13. The compound according to claim 1, characterized in that -X-Z-RI1 is aminocarbonylmethyl, pyrrolylmethyl or phenylmethyl I substituted by cyano or methyl oxadiazole. 14. The compound according to any one of claims 1-13, characterized in that YI is a direct ligation, a 2,5-substituted oxazolyl group, or - (CH2) n-0-, wherein n is an integer from 0-3. 1

5. The compound according to any of claims 1-14, characterized in that Y is a direct ligation. 1

6. The compound according to any of claims 1-15, characterized in that R2 1 is cyclohexyl, an aromatic heterocyclyl of 5-6 I members or an optionally substituted phenyl group | by one or two groups independently selected from halogen groups, alkyl IC1-4, C1- alkoxy or trifluoromethyl, wherein the • HlHariüAMttiíÉHttaia «jAmm-a-substitution is appropriately in one or two of the I positions 2-, 3-, or 4- on the 1

7. The conformation compound of claims 1-16, ca is a direct ligation and substituted R 2 by an isopropyl group in position 4. i! 1

8. The compound according to any one of claims 1-17, characterized in that Ri I is hydrogen, halogen, C? -4 alkyl or C? _4 J alkoxy 1

9. The compound according to claim 1, characterized in that lestá I represented by the formula (la) where: 'A is CH or N; X 1 is suitably alkylene C? _6, I optionally containing a double bond, oxo, sulfomyl, ^^^ «á == É? -alkylenenoxy C2_6-, -alkylenecarboxyl C? -6 ~ | i C6-C6 alkyl (N-H or N-C6-alkyl) carboxamido; | ! Z represents a direct ligature or C-I 6 alkyl; | R1 represents one of the following groups: I (i) hydrogenoperfluoroalkyl C? -3, I i (ii) optionally substituted phenyl, wherein the optional substitution is effected by one or two groups independently selected from C? -6 cyanoalkyl , halogen, Ci-β alkoxy, perfluoroalkyl and C?-3, hydroxycarbonyl, C alco _4-aminocarbonyl alkoxycarbonyl, C?-3 perfluoroaminocarbonyl, methylenedioxy, nitro, C?-6 acyl, phenyl an optionally substituted aromatic heterocyclyl consisting of radicals monocyclic and fused polycyclic radicals, wherein the radicals contain a total of 5 ring atoms, wherein the optional substitution is effected by alkyl? 4, or perfluoroalkyl C? _3, I (iii) an optionally substituted aromatic heterocyclyl I of monocyclic radicals and / or fused polycyclic radicals, where the radicals contain a total of atoms from 5-

10. | ^ g ^ g ^ | ¿^^^^^ rings, wherein the optional substitution is effected by alkyl C? _4; or perfluoroalkyl C? -3; (iv) wherein each X is alkylene C? -6 and Z is a direct bond, or Z is alkylene Ci-β, R1 can additionally represent a cyano group; Y represents an oxy or direct bond, a 5-membered aromatic heterocyclyl, -U-2 alkylene- or -oxyalkylene Ci-β-; R2 represents phenyl, C3-cycloalkyl, or a 10 aromatic heterocycle containing dd atoms 5-6 rings and heteroatoms of 1-4 rings, wherein each ring is optionally substituted by one or more groups independently selected from the halogen, C? -4 alkyl, C? _4 alkoxy or C perf perf perfluoroalkyl 3. R3 represents hydrogen, halogen, C? -4 alkyl or Ci-4 alkoxy; or a physiologically acceptable salt, solvate or i derived therefrom. I I 20. A compound according to claim 1 represented by the compound of! ! formula (ie) characterized because 'R1 is selected from the following groups i i (i) aminocarbonyl; (ii) phenyl, optionally substituted by C 1 4 4 alkyl, cyano, halogen, C?-6 alkoxy, C?-3 perfluoroalkyl, hydroxycarbonyl, C C -4 alco alkoxycarbonyl, aminocarbonyl, methylenedioxy, nitro, C?-β acyl , phenyl, or an optionally substituted 5-membered aromatic heterocyclic, wherein the subst is effected by C? -4 alquiloalkyl or perfluoroalkyl (iii) an optionally substituted aromatic heterocyclyl consisting of monocyclic radicals and fused monocyclic radicals, wherein the Radicals contain a total of 5-10 atoms, and the optional substratum is bound by alkyl C? _4. R- represents phenyl, optionally substituted by one of two independently selected groups I of halogen, the perfluroalkyl groups C? _3, C? -4 alkyl and C? _4 alkoxy; , I R3 represents hydrogen, halogen, C? _ Alkyl or alkoxy; or a physiologically acceptable salt, solvate or derivative thereof. 21. A compound selected from group i consisting of: 4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] phenyl] -amide of 4 '-isopropyl-5-methyl-1-biphenyl-2-carboxylic acid; , 4 '-isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amido] -α-aa; [4 - [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amidy acid of 4 '-isopropyl-6-methyl-biphenyl-2-carboxylic acid; J [4- [4- (3-cyano-benzyl) -piperazin-1-yl] phenyl] amide (6-methyl-4 '-trifluoromethyl-biphenyl-1-carboxylic acid; ~ - * .. ...... - ** .. (4- ({3- (3-methyl- [1- [1, 2, 4] oxadiazol-5-yl) -benzyl] -piperazin-1-yl] -phenyl) -amide of 4 '-Isopropyl - 5-methyl-biphenyl-2-carboxylic acid; i [5- [4- [3 (cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 5-chloro-4-isopropyl-biphenyl-2-carboxylic acid; [4- [4- (3-cyano-benzyl) -piperazin-yl] phenyl] -amide of 6-methoxy-4'-trifluoromethyl-biphenyl 1-2-carboxylic acid; 5-Methyl-4'-tri fluoromethyl-2-phenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; 5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide I; [4- [4- (3-cyano-benzyl) -piperazin-1-yl] of the bi-phenyl-2-carboxylic acid; I I [4- [4- (3-cyano-benzyl) -piperazin-1-yl] phenyl] amide i of 5-methoxy-bi-phenyl-2-carboxylic acid; [4- [4- (3-Cyano-benzyl) -piperazin-yl] -amide of 4-4 '-trifluoromethyl-biphenyl-2-carboxylic acid; ' N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -2-phenoxy-benzamide; - * • '"& and N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -2- (5-phenyl-oxazol-2-yl) -benzamide; 4- [4- (3-cyano-benzyl) -piperazin-1-yl.}. -phenyl] -ami 1da ! 4-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4 - [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide i; i I [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide I I of 4-methoxy-4'-tri fluoromethyl 1-bi-phenyl-2-carboxylic acid; 4'-ethyl-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; 4 '-Metoxy-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; [4 - [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide i of 3 '-trifluoromethyl-biphenyl-2-carboxylic acid; 4 '-Fluoro-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; I [3 - [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide i of 3 ', 4'-dimethyl-bi-phenyl-2-carboxylic acid; > - * «# fefa¡« H »> TO.. " " . . ÍJ. Í. . r r j'l [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 2 ', 4'-dimethyl-l-biphenyl-2-carboxylic acid; ! 3 ', 4'-Dimethoxy-biphenyl-2-carboxylic acid [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; j! N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -2-! (4-trifluoromethyl-benzyloxy) -benzamide; N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -13-methoxy-2- (4-trifluoromethyl-benzyloxy) -benzamide; j I N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -j2- I (4-fluoro-benzyloxy) -3-methoxy-benzamide; ! N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -3-methoxy-2-phenethi loxy-benzamide; i i N- [4- [4- (3-Cyano-benzyl) -piperazin-1-yl] -phenyl] -2- (2-cyclohexyl-ethoxy) -3-methoxy-benzamide; I N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -2- (2-cyclohexyl-ethoxy) -benzamide; N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -j3-i-methoxy-2- (3-phenylpropoxy) -benzamide; N- [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -'2-I (4-fluoro-benzyloxy) -benzamide; i [3- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; 4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -ami]; [4 - (4-carbamoylmethyl-1-piperazinyl-1-yl) -fenyl] -amide of 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid; 4 '-isopropyl-6-methyl-biphenyl-2-carboxylic acid [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amide; 6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amide; [4- (4-Cyanomethyl-piperazin-1-yl] -phenyl] -amide of 4 '-trifluoromethyl-bifeni 1-2 -carboxylic acid; [4- (4-ethoxycarbonylmethyl-piperazin-1-yl] -phenyl] - 4'-trifluoromethyl-biphenyl-2-carboxylic acid amide: 4 '-trifluoromethyl-bifeni 4- (2-ethoxy-ethyl) piperazin-1-yl] -phenyl-amide carboxyl; [4- (4- (3-hydroxy-propyl) piperazin-1-yl] -phenyl-amide of 4'-tri fluoromethyl-bi-phenyl-2-carboxylic acid;! [4- (4- ( 4,4-trifluoro-butyl) -piperazin-1-yl] -phenyl] -amide of 4'-tri fluoromethyl-bi-phenyl-2-carboxylic acid; [4- (4- (3-Methyl-but-2-enyl) piperazin-1-yl] -phenyl-amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; j II [4- (4- (3 4-fluoro-benzyl) piperazin-1-yl] -phenyl-amide of 4 '-trifluoromet-il-biphenyl-2-carboxylic acid; I i [4- (4- (3,4-methylenedioxy) benzyl) piperazin-1-yl] -i-phenyl-amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; I [4- (4- (3-nitro-benzyl) piperazin-1-yl] -phenyl 4'-trifluoromethyl-biphenyl-2-carboxylic acid; 4'-trifluoromethyl-biphenyl ester 4'-trifluoromethyl-biphenyl-2-carboxylic acid; 4- [4- (4- (3-carbamoyl-benzyl) piperazin-1-yl] -phenyl] -amide; -2-carboxylic acid; 1- [4- (4- (3-methoxy-benzyl) piperazin-1-yl] -phenyl-amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; [4- (4- ( 4-Fluoro-benzyl) piperazin-1-yl] -phenyl-amide I of 4 '-trifluoromet il-biphenyl-2-carboxylic acid; I [4- (4- (3-fluoro-benzyl) piperazin-1- il] -phenyl-amide of 4 '-tri fluoromet il-bi-phenyl-2-carboxylic acid; [4- (4-benzyl) piperazin-1-yl] -phenyl-amide of the acid 4'-trifluoromet il-biphenyl-2-carboxylic; [4- (4- (3-carbomethoxy-benzyl) piperazin-1-yl] -phenyl-1-amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid;! [4- (4-pyridin-4 4'-trifluoromethyl-biphenyl-2-carboxylic acid-4-pyridin-2-yl) -phenyl-ami.da-4-pyridin-2-ylmethyl-piperazin-1-yl) -phenyl-amide 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; 4' - tri fluoromethyl-2-phenyl-2-carboxylic acid [4- (4-pyrazin-4-ylmethyl-piperazin-1-yl) -phenyl-amide; [4- (4-thiazol-4-ylmethyl-piperazin-1-yl) -phenyl-amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; [4- [4- (l-methyl-lH-imidazole] 2'-trifluoromethyl-biphenyl-2-carboxylic acid-2-ylmethyl) -piperazin-1-yl) -phenyl-amide; (4- (4- (3- (3-Methyl- [1,2,4] -oxadiazol-5-yl) -benzyl)! -! I piperazin-1-yl) -phenyl) -amide of the acid! 4'-isopropyl-6-methyl-1-bi-phenyl-2-carboxylic acid; [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -I-amide of the '-tri fluoromethyl-bi-phenyl-2-carboxylic acid; [4 (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -I-amide of 4 '-isopropyl-5-biphenyl-2-carboxylic acid; s' ^ ¡& * arih [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-l-yl) -phenyl-! 5-methyl-4 '-trifluoromethyl-2-phenyl-2-I acid amide! carboxylic; l I I [4- (4-propyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl 1-2-carboxylic acid; 4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4- (3-acetyl-benzyl) -piperazin-1-yl) -phenyl] -amide; [4 (4-furan-2-ylmethyl-piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-biphenyl-2-carboxylic acid; 4 '-isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4- (4- (lH-pyrrol-2-ylmethyl) piperazin-1-yl) -phenyl] -amide; 4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4- (l-methyl-lH-pyrrol-2-ylmethyl) -piperazin-1-yl-] - phenyl] -amide [4- (4- 4 '-trifluoromethyl-biphenyl-2-carboxylic acid (l-methyl-l-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide; I [4- (4-thiophene-2- 4'-tri fluoromethyl-bi-phenyl-2-carboxylic acid ylmethyl-piperazin-1-yl) -phenyl] -amide: II { 4- [4- (lH-pyrazol-3-ylmethyl) -piperazine- 1-yl] -j-phenyl} -amide of '-trifluoromethyl-biphenyl-2-carboxylic acid; . { 4- [4- (5-fluoro-lH-indol-3-ylmethyl) -piperazin-1-yl] phenyl} 4'-trifluoromethyl-bifjenyl-2-carboxylic acid amide; (4- (4- (3-methyl- [1,2,4] -oxadiazol-5-yl) -benzyl) -piperazine-1-yl) -phenyl-amide of 4 '-isopropyl-i 6-methoxy-bi-pheny1-2-carboxylic acid;! (4- { 4- [3- (5-trifluoromethyl- [1,2,4] -oxadiazol-3-yl) -I-benzyl] -piperazin-1 4-trifluoromethyl-bifeni 1-2 -carboxylic acid; 4- ({4- (4 '-trifluoromethyl-biphenyl-2-carbonyl) -yl) -amide. amino] -phenyl.}. -piperazin-1-yl) -acetic;, [4- (4-. {[[(biphenyl-3-ylmethyl) -carbamoyl] -methyl]. piperazin-1-yl) -4-trifluoromethyl-biphenyl-2-carboxylic acid-phenyl] -amide 3- (4-. {4- [(4'-trifluoromethyl-bi-phena 1-2-II carbonyl) -amino] - phenyl.}. -piperazin-1-yl) -benzoic acid; i (4-. {4- [3- (2,2,2-trifluoro-ethylcarbamoyl) -benzyl] -I-piperazin-1-yl) - phenyl) -amide of 4-trifluoromethyl-biphenyl-2-carboxylic acid i'I [4- [4- (3-cyano-benzoyl) -piperazin-1-yl] -phenyl] -amide of 4-trifluoromethyl-2-carboxylic acid; '-trifluoromethyl-biphenyl-2-car boxilicjo; [4- (4-acetyl-piperazin-1-yl) -phenyl] -amide of 4'-tri fluoromethyl-biphenyl 1-2-carboxylic acid; ! 4 '-trifluoromethyl-1-bi-phehyl-2-carboxylic acid [4- [4- (3-cyano-benzenesulfonyl) -piperazin-1-yl] phenyl] -amide; [A- (4-methanesulfonyl-piperazin-l-yl] phenyl] -amidi of 4 '-tri fluoromet il-bi-phenyl-2-carboxylic acid | [4- [1- (3-cyano-benzyl) -piperidine] 4-yl] -phenyl] -amide i of the '-tri fluoromethyl-bi-phenyl-2-carboxylic acid; N- { 4- [4- (3-cyano-benzyl) -piperazin-1-yl] phenyl.} r 2 -pyrrol-1-yl-1-benzamide; N-. {4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl}. 12-I-pyridine -2- 1 -benzamide, or a pharmaceutically acceptable salt, solvate or derivative thereof 22. A compound selected from the group consisting of: [4- [4- (3-cyano-benzyl) -piperazine- 1-yl] -phenyl] -amide of the acid '-tri fluoromethyl-bi-phenyl-2-carboxy lyso; [4- [4- (3-cyano-encyl) -piperazin-1-yl] phenyl] -amide of the acid 4'-Isopropyl 1-5-met il-bi-phenyl-2-carboxylic acid; j! [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -aitiide and 4-carboxylic acid; -i-sopropi 1-6-I-toxi-bi f-i-1 -2-I carboxylic; * ....-.... t «* j < to. ^ -afl [4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] amijda! 4 '-isopropyl-6-methyl-biphenyl-2-carboxylic acid; 6-Methyl-1-4 '-trifluoromethyl-bi-phenyl-2-carboxylic acid 4- [4- (3-cyano-benzyl) -piperazin-1-yl] -phenyl] -amide; (4- ({3- (3-methyl- [1- [1, 2, 4] oxadiazol-5-yl) -benzyl] r-piperazin-1-yl] -phenyl) -amide of 4 '- Isopropyl-5-methyl-1-bi-phenyl 1-2 -carboxylic; 4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amidja; 4 '-isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4- (4-carbamoylmethyl-piperazin-1-yl) -phenyl] -amidja; [4- (4-carbamoylmet-1-piperazin-1-yl) -phenyl] -amide-1-4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid; i I! (4- (4- (3- (3-Methyl- [1,2,4] -ozadiazol-5-yl) -benzyl) - (1-piperazin-1-yl) -phenyl) -amide of 4-acid '-! isopropyl-6-methyl-biphenyl-2-carboxylic acid; | [4 (4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide of 4 '-trifluoromethyl-bi-feriyl-2-carboxylic acid; [4- (4- (lH-pyrrol-2-ylmethyl) -piperazin-1-yl) -phenyl] -amide of '-isopropyl-5-methyl-bi-phenyl-2-carboxylic acid; 5-Methyl-4 '-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4- (lH-pyrrol-2-ylmethyl) piperazin-1-yl) -phene-amide; ! I or a physiologically acceptable salt, solvate or derivative thereof. 23. A compound according to any one of claims 1 to 1; 22 characterized by its use in therapy. 24. A method for the treatment of a mammal, including man, of conditions resulting from elevated circulation levels of apoB-100 characterized in that it comprises! the administration of an effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable derivative thereof. I I 25. The use of a compound according to any one of claims 1 to 22 or? a physiologically acceptable acceptable salt or soljvate thereof in the manufacture of a medicament for M **. .. ^ its use in the treatment of conditions resulting from elevated circulation levels of apoB-100. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable derivative I thereof together with one or more pharmaceutically acceptable carriers. 27. A process for the preparation of a compound of formula (I), characterized in that it comprises: j (A) reacting a compound of formula (II) with a compound of formula R1-Z-X-L wherein L represents a suitable halide leaving group or, where X is an oxo group, L can i additionally represent a hydroxy group; or i (B) the reaction of the compounds of the formula I (III) and the compounds (VII) I ^^^ s (IH) (IV) where L is defined above; or (c) where Y is -O-alkylene C? -4, by the reaction of a compound of formula (VIII) with a compound I of formula R2-alkylene C-L, wherein L was previously defined. [ (D) wherein at least a portion of X represents an alkylene linkage for the piperidine or piperazine group, by reacting a compound of formula (II) with a compound of formula (IX); wherein X 'represents X minus a terminal methylene group; or! (E) reacting a formula (I) I compound to give a different compound of formula! (I) using standard reaction conditions. 10 fifteen The prese of formula (I) where A represents N or CH; X is selected from the following groups: (i) -C? -6 alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy groups, C? -6 alkyl alkoxy CI? _6, I acyl C ? -6 or acyloxy C? -6? I (11) oxo, sulfonyl, thioxo, (iii) -C? -6 alkylenecarbonyl-, -C? -6 I alkylene sulfonyl-, -C? -6 alkylenethioxo-, I (iv) -C2-6 alkyleneoxy, -C2-6 alkylenethio-,, -C2_e alkylene (NH or NC? _6 alky1) amino-, | I (v) -C1-6 alkylenecarboxy, C6-6 alkylenedioamido, -C1-6 alkylene (N-H or N-C6-6 alkyl) carboxamido-, (vi) -C2_6 alkyleneoxycarbonyl-, -C2-6 to the cyclohexane -, -C2-6 to the one in (N-H or -C? -6 I I alkyl) aminocarbonyl-; ! IZ represents a direct bond or -C? -6 alkylene, optionally containing a double bond and optionally substituted by one or more hydroxy groups, C? -6 alkyl, C? _6 alkoxy, C? -6 acyl or Ci_6 acyloxy?; I i R1 is selected from the following groups:! (i) hydrogen, C? -3 perfluoroalkyl, (ii) C3-β cycloalkyl aryl and fusion benzo derivatives thereof, C7-10 polycycloalkyl /! C4-8 cycloalkenyl r C7-10 polycycloalkenyl /! I (iii) a heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, and (iv) wherein each X is C6-6 alkylene and Z is a direct bond, or Z is C1-6 alkylene. 4, R1 may additionally represent a halogen, cyano, nitro or acyl C? -β group; wherein, when R contains one or more rings, the rings can each independently support from 0 to 4 substituents. 1 And represents a direct oxy ligand, alkylene j C? _6-, -oxyalkylene C? _6 or a heterocyclyl consisting of monocyclic radicals. R 2 represents phenyl, cycloalkyl or heterocyclyl consisting of monocyclic radicals and wherein each R 2 is optionally substituted by one or more groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl,! perfluoroalkyl C? -3, perfluoroalkoxy? C? -3, I hydroxycarbonyl, C? -6 alkoxycarbonyl, cyano, nijtro, alkylaminosul fonyl C1-; , R3 represents hydrogen or one or more grits! independently selected from halogeno, C1-4alkyl, C1-4alkoxy, perfluoroalkyl C? -3, or perfluoroalkoxy C? _3; or a physiologically acceptable salt, solvate or derivative thereof, the pharmaceutical compositions, for the processes for their preparation and their use in the treatment of conditions mediated by the regulation of ApoB-10.0. »I.5- ... ¿k, - i * .. * -« «. '.'