MXPA01001331A

MXPA01001331A - 2-substituted-1-piperidyl benzimidazole compounds as orl1-receptor agonists

Info

Publication number: MXPA01001331A
Application number: MXPA/A/2001/001331A
Authority: MX
Inventors: Ito Fumitaka; Kondo Hiroshi; Noguchi Hirohide
Original assignee: Ito Fumitaka; Kondo Hiroshi; Noguchi Hirohide; Pfizer Inc; Pfizer Pharmaceuticals Inc
Priority date: 1998-08-06
Filing date: 2001-02-02
Publication date: 2003-02-17

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is unsubstituted, mono-, di- or tri-substituted (C3-C11)cycloalkyl or (C3-C11)cycloalkenyl or the like, A is unsubstituted (C1-C7)alkyl or (C2-C5)alkenyl, or unsubstituted, mono-, di- or tri-substituted aryl, or aromatic-heterocyclic or the like, Y is hydrogen, halo, amino or mercapto, or unsubstituted, mono-, di- or tri-substituted (C1-C10)alkyl-M-, (C3-C7)cycloalkyl-M-, (C2-C6)alkenyl-M-, (C1-C4)alkyl-NH-((C1-C4)alkyl)-M-, di(C1-C4)alkyl-N-((C1-C4)alkyl)-M-, aryl-M-, aromatic or non-aromatic heterocyclic-M-, aryl-(C1-C5)alkyl-M- or aromatic non-aromatic heterocyclic-(C1-C5)alkyl-M-, wherein M is a covalent bond O, S, NH or the like, or the like;Z1, Z2, Z3 and Z4 are hydrogen or the like, has ORL1-receptor agonist activity, and are useful as analgesics or the like in mammalian subjects.

Description

COMPOUNDS OF 1-PIPERIDIL BENZOIMIDAZOL 2-REPLACED AS AGRONISTS OF ORL1 RECEPTORS TECHNICAL FIELD This invention relates to novel 2-substituted piperidin-4-yl-1-substituted benzoimidazole compounds and their salts, to pharmaceutical compositions containing them, to their medical uses, to processes for preparing these compounds and to intermediates useful in the processes. The compounds of this invention have activity as selective antagonists of the ORL1 receptor and, as such, are useful in the treatment or prevention of disorders or medical conditions selected from pain, inflammatory diseases and the like.

PREVIOUS TECHNIQUE Despite their usefulness as analgesics, the use of opiates such as morphine and heroin is strictly limited. This is because the drugs induce side effects such as euphoria, respiratory depression or constipation. In addition, the multiple dosage of drugs causes addiction. Thus, for a long time there is a need to provide analgesics with fewer side effects.

From the previous point of view, considerable pharmacological and biochemical studies have been carried out to identify opiate receptors and their endogenous ligands in order to prepare peptide and non-peptide opioid ligands for the receptors. In recent years, the amino acid sequences of the opioid receptor subtypes mu (μ), delta (d) and kappa (K) have been identified and published. Subsequently, a new receptor subtype was identified and termed ORL1 receptor, and Meunier, J.C et al. published the isolation and structure of the receptor's endogenous agonist. { Nature, Vol. 377, pgs. 532-535, October 12, 1995). It is suggested that the agonist compounds for the ORL1 receptor are effective in neurogenic inflammation (Tips, Vol. 18, pp. 293-300, August 1997). It is also suggested that agonist compounds are potent analgesics that have fewer physiological side effects and addiction (D. Julius, Nature, Vol. 377, p.476, October 12, 995). It is also suggested, in US 3,318,900, that certain benzoimidazolinylpiperidines have activities similar to morphine. WO 97/40035 describes a 2-piperidyl benzoimidazole compound 2-substituted with a cycloalkyl group at the nitrogen atom of the piperidine group.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the following formula: or a salt thereof, wherein R is selected from the group consisting of cycloalkyl (C3-Cn), bicycloalkyl (C6-C16), tricycloalkyl (C6-C6) and tetracycloalkyl (Cs-C-iß), where said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (Cr C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (CrC7), mono-, di- or tri-halo-alkyl (Ct) -C7), alkenyl (C2-C5), alkynyl (C2-C5), phenyl-C1-C5alkyl, aryl and aromatic or non-aromatic heterocyclic groups comprising from four to ten ring atoms, from one to four ring atoms are independently selected from heteroatoms (i.e., O, S and N), and said phenyl radical being optionally substituted in the phenyl (C1-C5) alkyl, the aryl or the aromatic or non-aromatic heterocyclic, with up to three selected substituents independently from the group consisting of halo, hydroxy, alkyl (CrC4), haloalkyl (CrC), alkoxy (Cr C), haloalkoxy (C? -C4), alkyl (C? -C), -CO-, phenyl, benzyl, -CHO, cyano, alkyl (Ci-GO-CO-, NH2-CO-, NH2-CH2-, amino, alkyl (C4) -NH-, di (alkyl- (C4)) - N -, alkyl (CrC4) -CO-NH-, alkyl (C? -C4) - NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = N-OH; Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (C -? - C? 2) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M-, aryl-M-, heterocyclic-M-aromatic or non-aromatic, aryl-alkyl (C? -C) -M-, heterocycle-alkyl (CrC) -M- aromatic or non-aromatic, said aromatic or non-aromatic heterocyclic radical comprising said groups of four to ten ring atoms, wherein from one to four ring atoms are independently selected from heteroatoms (i.e., O, S, and N), and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO (ie, C (= O)), NQ (ie, N (Q)), NQCO (ie, N (Q) C (= O)) and CONQ (ie, (C (= O) N (Q)), where Q is selected from the group consisting of hydrogen and alkyl (Ci-Cß), said (C1-C12) alkyl, (C3-C7) cycloalkyl radical being optionally substituted, or alkenyl (C2-C6), in such groups, with up to three (preferably from zero to two) substituents selected independently Among the group consisting of halo, hydroxy, amino, alkyl (C? -C4) -NH-, di-alkyl (C? -C4) -N-, hydrazino, azido, ureido, amidino, guanidino, alkoxy (C-) ? -C), alkyl (CrC4) -S-, alkyl (CrC) -SO- and alkyl (C4) -SO2-, and said aryl or aromatic or non-aromatic heterocyclic radical of said groups, with up to three, being optionally substituted (preferably from zero to two) substituents independently selected from the group consisting of halo, hydroxy, alkyl (Cr C4), haloalkyl (C-C4), hydroxy (C? -C), halo-(C1-C4) alkoxy) , alkyl (C.? - C4) -CO-, phenyl, benzyl, -CHO, cyano, alkyl (C? -C4) -CO-, NH2-CO-, -NH2-CH2-, amino, alkyl (CrO- NH-, di- (C 1 -C 4 alkyl) -N-, alkyl (C 1 -C) -CO-NH-, alkyl (C 4) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = N-OH; and each of Z1, Z2, Z3 and Z4 is independently selected from the group consisting of hydrogen, halo, alkyl (C -? - C), haloalkyl (CiC), alkoxy (C -? - C), alkylsulfonyl (CrC4), alkyl (CrC) -CO-, carboxy, alkyl (C4) -COO-, amino, NH2CO-, alkyl (CO -CO-NH-, alkyl (C4) -SO2-NH-, phenyl This invention also relates to processes for preparing compounds of the formula (I) defined as above, which comprise (a) coupling compounds of the formulas wherein R, A, and Z1 to Z4 are defined as indicated above, and L is halo, to give the compound of formula (b) reducing the compound of formula (IX) to the compound of formula (X) by reduction or hydrogenation; and (c) subjecting the resulting compound of formula (X) to benzoimidazole formation to give the compound of formula (I). This invention also relates to an intermediate compound of formula which is useful in the processes mentioned above, for preparing a compound of formula (I) wherein R is selected from the group consisting of cycloalkyl (C3-Cu), bicycloalkyl (C6-Ci6), tricycloalkyl (C6-Ci6) and tetracycloalkyl (C8-C? 6), wherein said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? -C5) and cycloalkyl (C3-C); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and are selected from the group consisting of alkyl (CrC7), mono, di-, or tri-halo-alkyl (C ? -C7), (C2-C5) alkenyl, (C2-C5) alkynyl, phenyl-C1-C5 alkyl, aryl and aromatic or non-aromatic heterocycles comprising from four to ten ring atoms, where from one to four ring atoms are independently selected from heteroatoms, and said phenyl radical being optionally substituted in phenyl (C1-C5) alkyl, aryl or aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (CrC) ), haloalkyl (C C4), alkoxy (C? -C), haloalkoxy (CrC), alkyl (C? -C) -CO-, phenyl, benzyl, -CHO, cyano, alkyl (CrC) -CO- , NH2-CO-, NH2-CH2-, amino, alkyl (C4) -NH-, di (alkyl- (C4)) - N-, alkyl (C? -C) -CO-NH-, alkyl ( C C4) -NH-CO-, hydrazino, azido, ureido, amidino, gua nidino, oxo y = N-OH; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, alkyl (C? -C), alkoxy (C? -C), alkylsulfonyl (C? -C), alkyl (C? -C) -CO-, carboxy, alkyl (C? -C4) -COO-, amino, NH2CO-, alkyl (C? -C4) -CO-NH-, alkyl (C4) -SO2-NH-, phenyl and naphthyl. This invention also relates to an intermediate of the formula which is useful in the aforementioned processes for preparing a compound of the formula (I), wherein R is selected from the group consisting of cycloalkyl (C3-Cn), bicycloalkyl (C6-Ci6), tricycloalkyl (Cede) and tetracycloalkyl (Cs-Ciß), wherein said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (Cr C5) and composed of halo, hydroxy, alkyl (C1-C5) and cycloalkyl (C3-C); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C-C7) alkyl, mono-, di- or tri-halo-alkyl (C1-C7), (C2-C5) alkenyl, (C2-C5) alkynyl, phenyl- (C1-C5) alkyl, aryl and aromatic or non-aromatic heterocyclics comprising from four to ten ring atoms, wherein from one to four ring atoms are independently selected from heteroatoms, and said phenyl radical being optionally substituted in phenyl-(C1-C5) phenyl, aryl or aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? -C4), haloalkyl (C? -C4), alkoxy (C? -C4), haloalkoxy (C? -C), alkyl (C? -C4), -CO-, phenyl, benzyl, -CHO, cyano, (C1-C4) alkyl -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (dC ^ -NH-, d alkyHd-C ^ -N-, alkyl (C? -C4 ) -CO-NH-, alkyl (C4) -NH-CO-, hydrazino, azido, ureido, amidino, g uanidino, oxo y = N-OH; Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, alkyl (CrC), haloalkyl (C? -C4), alkoxy (C1-C4), alkylsulfonyl (C1-C4), alkyl (CrC) -CO-, carboxy, alkyl (Cr C4) -COO-, amino, NH2CO-, alkyl (CC) -CO-NH-, alkyl (C1-C4) -SO2-NH-, phenyl and naphthyl.

DETAILED DESCRIPTION OF THE INVENTION The term "alkyl", as used herein, means a straight or branched saturated monovalent hydrocarbon radical, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and similar. The term "cycloalkyl", as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. The term "C5-C9 alkenyl ring", as used herein, means a carbocyclic radical having at least one double bond including, but not limited to, cyclopentyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and the like. The term "alkenyl", as used herein, means a hydrocarbon radical having at least one double bond, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, and the like. The term "alkynyl", as used herein, means a hydrocarbon radical having at least one triple bond, including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like. The term "alkoxy," as used herein, means an O-alkyl group in which "alkyl" is as defined above.

The term "halo", as used herein, refers to F, Cl, Br, or I, preferably F and Cl. The term "aryl," as used herein, means an aromatic carbocyclic ring system. , monocyclic or bicyclic, of 6 to 11 carbon atoms, including, but not limited to, phenyl, naphthyl, indanyl, (1, 2,3,4) -tetrahydronaphthyl, n-nyl, isoindenyl and the like. The term "aromatic or non-aromatic heterocycle" or "heterocycle", as used herein unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups having from four to ten atoms, comprising from one to four heteroatoms each selected from O, S and N. Such heterocyclic groups include those having a fused benzene ring optionally substituted with an oxo radical.

Examples of the aromatic and non-aromatic heterocycles are azetidinyl, furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, midezolium, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, piperidyl (or piperidinyl). , piperidino, oxazinyl, morpholinyl, morpholino, thiamorpholino, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, piperazino, triazinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzoimidazolyl, chromanyl, sochromanil, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl and quinoxalinyl. Preferred heterocycles are heterocycles of four to six links comprising one to two heteroatoms. Examples of four to six link heterocycles include piperidyl, piperidino, piperazinyl and piperazino. The term "bi-, tri- or tetra-cyclic ring" means cyclic hydrocarbon groups of 6 to 16 carbon atoms, having from two to four rings and including, but not limited to, decahydronaphthalene, bicyclo [2.2.1] heptane , bicyclo [3.2.1] octane, bicyclo [3.3.1] nonane, adamantane and tricyclo [5.2.1.026] decane. The definition "A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring" means the chemical formulation described with the following chemical formula in which the circle represents R.

The term "treat", as used herein, refers to the reversal, alleviation, inhibition of progress or prevention of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" has been defined in the immediately preceding paragraph.

A preferred group of compounds of the present invention includes compounds of the formula (I) wherein R is selected from the group consisting of (C3-Cn) cycloalkyl and (C3-Cn) cycloalkenyl, said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5) alkyl and (C3-C) cycloalkyl; more preferably, R is selected from the group consisting of cycloalkyl (Q3-C11), cycloalkenyl (C3-Cn), mono-, di- or tri-halo-cycloalkyl (C3-Cn), mono-, di- or tri- halo-cycloalkenyl (C3-Cn); more preferably, R is C6-C10 cycloalkyl; and more preferably, R is cycloalkyl (C-C8). A preferred group of compounds of the present invention includes compounds of the formula (I) wherein A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group composed of (C1-C7) alkyl, mono-, di- or tri-halo-alkyl (d-C7), alkenyl (C2C5), alkynyl (C2-Cs) aryl and aromatic or non-aromatic heterocycles comprising from four to six ring atoms, wherein from one to two ring atoms are independently selected from heteroatoms, and aryl, or the aromatic or non-aromatic heterocycle optionally substituted with up to three substituents independently selected from halo, alkyl (CrC4), haloalkyl (C) C4), (C1-C4) alkoxy, -CHO, cyano, (C4) alkyl -CC-, NH2- CO-, NH2-CH2-, amino, alkyl (d-C4) -NH-, di ( (C 4 C) alkyl-N-, (C 1 -C 4) alkyl -CO-NH and (C 1 -C 4) alkyl -NH-CO-, more preferably, A is attached to the carbon atom of R with which R is u nested to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C? -C7) alkyl, (C2-C5) alkenyl, aryl selected from the group consisting of phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, tiinilo, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl being or heterocycle aromatic optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl (CrC4), haloalkyl (C1-C4) and (C4) alkoxy; more preferably, A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (CrC7) and alkenyl (C-C5), phenyl and naphthyl; and more preferably A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of methyl and phenyl. A preferred group of compounds of the present invention includes compounds of formula (I) wherein Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C10) alkyl- M-, (C3-C7) cycloalkyl ) -M-, (C2-C6) alkenyl-M-, aryl-M-, aromatic or non-aromatic heterocycle-M-, aryl (C1-C5) alkyl- and heteroaryl aromatic or non-aromatic-alkyl (C1- C5) -M-, said radical comprising aromatic or nonaromatic heterocyclic groups such four to six ring atoms, where one to two ring atoms are independently selected from heteroatoms, M is selected from the group consisting of a covalent bond , O, S, SO, SO2, CO, NH, N (alkyl (CrC6), CONH and NHCO, said (C1-C10) alkyl, (C3-C7) cycloalkyl and (C2-Ce) alkenyl radical being optionally substituted said groups with one to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4) alkyl -NH-, di-alkyl (d_C) N-, hydrazino, azido, ureido, amidino, guanidino, (C? -C4) -S-, (C C4) alkyl -SO- and (d-C4) SO2-, and said aryl being optionally substituted or aromatic radical or heterocyclic nonaromatic of these groups with substituents independently selected from the group consisting of halo, hydroxy, (C1-C4), halo, (C1-C4) alkoxy (C1-C4) alkyl, (dC) -CO-, phenyl, benzyl, amino, alkyl (C 4) -NH-, di (C 1 -C 4 alkyl) -N-, alkyl (C 1 -C 4) -CO-NH-, NH 2 -CO- , alkyl (C? -C4) -NH- CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = NOH; more preferably, Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (C? -C? 0) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M -, (C 4 C) alkyl - NH - (C 4 alkyl) - NH - (C 1 -C 4) alkyl -, di (alkyl (dC 4) - N - alkyl (C C 4)) - M-, aryl-M-, aromatic or non-aromatic heterocycle-M-, aryl-(C1-C5) alkyl- M- and aromatic or non-aromatic heterocyclic alkyl (C? -C5) -M-, said aryl radical being selected from said groups from the group consisting of phenyl and naphthyl, said aromatic or non-aromatic heterocyclic radical being selected from said groups from the group consisting of azetidinyl, furyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, piperidino, morpholinyl, morforino, pyrimidinyl, pyrazinyl, pyridazinyl , aziridinyl, pyrrolidinyl, piperazinyl and thiamorpholino, M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NH, CONH, N ((C? -C6) alkyl) and NHCO, optionally replaced said radical (C1-C10) alkyl, (C3-C7) cycloalkyl, and (C2-C) alkenyl of said groups with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, alkyl (C? -C4) -NH- , di (C1-C4) alkyl-N-, hydrazino, azido, ureido, amidino, guanidino, alkyl (CrC) -S-, alkyl (C -C) -SO- and alkyl (C1-C4) -SO2- , and said aryl radical or aromatic heterocyclic radical of said groups being optionally substituted with up to three substituents selected from the group consisting of halo, hydroxy, alkyl (C? -C4), halo alkyl (C? -C4), alkoxy (C? -C4), alkyl (C? -C) -CO-, phenyl, benzyl, amino, alkyl (C1-C4) -NH-, di (alkyl (C4)) -N-, alkyl (C4) -CO - NH-, NH 2 -CO-, (C 1 -C 4) alkyl-NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = NOH; more preferably, Y is selected from the group consisting of hydrogen, amino, alkyl (d-Cß) -M-, piperidyl, piperidino and piperazinyl, M is selected from the group consisting of a covalent bond O, SO2, CO, NH, CONH and NHCO, said alkyl radical being Ci-Cß-M being optionally substituted with up to three substituents independently selected from the group consisting of amino and guanidino, and said piperidyl, piperidino or piperazinyl being optionally substituted with up to three substituents independently selected from alkyl (CrC4); and more preferably, Y is selected from the group consisting of amino, alkyl (C? -Ce) -NH-, amino-alkyl (CrC6) -O-, amino-alkyl (C? -Ce) -CONH-, amino-alkyl (CrCe) -SO2- and piperazinyl substituted with alkyl (C1-C4). A preferred group of compounds of the present invention includes compounds of formula (i) wherein Z1, Z2, Z3, and Z4 are independently selected from the group consisting of hydrogen and halo; more preferably, Z1 and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogens; more preferably, Z1, Z2, Z3, and Z4 are hydrogens; and more preferably, Z1, Z2, Z3 and Z4 are hydrogens. A preferred group of the compounds of the present invention includes the compound of formula (I), wherein R is selected from the group consisting of cycloalkyl (C3-Cn) and cycloalkenyl (O3-C11), said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? -C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (dC), mono-, di- or tri-halo-alkyl (C ? -C7), (C2-C5) alkenyl, (C2-Cs) alkynyl, aryl and aromatic or non-aromatic heterocycles comprising four to six ring atoms, wherein from one to two ring atoms are independently selected from heteroatoms, and aryl, or the aromatic and nonaromatic heterocycles being optionally substituted with up to three substituents independently selected from halo, alkyl (CrC4) haloalkyl (C1-C4), (C1-C4) alkoxy, -CHO, cyano, alkyl (C) C4) -CO-, NH2-CO-, NH2-CH2-, amino, (C1-C4) alkyl -NH-, di (C1-C4 alkyl) -N-, alkyl (C? -C4) -CO -NH- and alkyl (d-C4) -NH-CO-; Y is selected from the group consisting of hydrogen, halo, mino, mercapto, (C1-C10) alkyl-, M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-Cß) -M-, aryl-M- , aromatic or non-aromatic heterocycle-M-, aryl-alkyl (C1-C5) -M-, and aromatic or non-aromatic heterocycle-(C1-C5) alkyl- M-, said aromatic or non-aromatic heterocyclic radical comprising said groups from four to six ring atoms, where from one to two atoms are independently selected from heteroatoms, M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NH, N (alkyl (d) Cß)), CONH and NHCO, said alkyl (C C10), (C3-C7) cycloalkyl and (C2-C6) alkenyl radical being optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy , amino, alkyl (C? -C4) -NH-, di-alkyl (dC) -N-, hydrazino, azido, ureido, amidino, guanidino, alkyl (C? -C4) -S-, alkyl (C1-C4) ) -SO- and alkyl (C? -C4) -SO2- , and said aryl or aromatic or non-aromatic heterocyclic radical of said groups being optionally substituted with substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 4) alkyl, haloalkyl (CrC 4), alkoxy (CrC), alkyl (CrC4) -CO-, phenyl, benzyl, amino, alkyl (CC) -NH-, di (alkyl (C? -C)) -N-, (C1-C4) alkyl -CO-NH-, NH2-CO -, alkyl (C1-C) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = NOH; and Z1 ', Z2, Z3, and Z4 are independently selected from the group consisting of hydrogen and halo. The most preferred compounds of this invention are the compounds of formula (I) wherein R is selected from the group consisting of cycloalkyl (C3-Cu) and cycloalkenyl (C3-Cn), mono-, di- or tri-halo- cycloalkyl (C3-Cn), or mono-, di- or tri-halo-cycloalkenyl (C3-Cn); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (CrC), alkenyl (C2-C5), aryl selected from the group consisting of by phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl being optionally substituted or aromatic heterocycles with up to three substituents independently selected from the group consisting of halo, (C? -C4) alkyl, haloalkyl (C? -C4) and alkoxy (C? C); And it is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C10) alkyl-, M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-Ce) -M-, alkyl (d) -C4) -NH- (C 1 -C 4 alkyl) - M-, di (C 4) alkyl-N- (alkyl (d-C 4)) -M-, aryl-M-, aromatic or non-aromatic heterocycle M-, aryl-(C1-C5) alkyl- M-, and aromatic or non-aromatic-alkyl heterocycle (CrC5) -M-, said aryl radical being selected from said groups from the group consisting of phenyl or naphthyl, said heterocyclic radical being selected aromatic or non-aromatic of said groups from the group consisting of azetidinyl, furyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, piperidino, morpholinyl, morforino, pyrimidinyl, pyrazinyl, pyridazinyl, aziridinyl, pyrrolidinyl, piperazinyl and thiamorpholino, M is selected from the group composed of a covalent bond, O, S, SO, SO2, CO, NH, CONH, N (alkyl (d-C6)) and NHCO, said radicals being optionally substituted (Cr C10), cycloalkyl (C3-C7) and alkenyl (C2-Ce) of said groups with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, alkyl (C? -C4) -NH-, di-alkyl (C? -C4) -N-, hydrazino, azido, ureido, amidino, guanidino, alkyl (C? -C4) -S-, alkyl (CrC4) -SO- and alkyl (dd) -SO2-, and said aryl radical or aromatic heterocyclic radical being optionally substituted or not Aromatic of said groups with up to three substituents selected from the group consisting of halo, hydroxy, (C 1 -C 4) alkyl, halo (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, alkyl (C 1 -C) -CO -, phenyl, benzyl, amino, alkyl (d-C4) -NH-, di (alkyl (d-C4)) - N-, alkyl (d-C4) -CO-NH-, NH2-CO-, alkyl ( CrC4) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = NOH; and Z1 and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogens. A more preferred group of the above compounds of this invention are the compounds of formula (I) wherein R is (C6-C10) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C C) and (C2-C5) alkenyl, phenyl and naphthyl; Y is selected from the group consisting of hydrogen, amino, alkyl (d-Cß) -M-, piperidyl, piperidino and piperazinyl, M is selected from the group consisting of a covalent bond, O, SO2, CO, NH, CONH and NHCO, said alkyl radical being optionally substituted (C? -C6) -M- with up to three substituents independently selected from the group consisting of amino and guanidino, and said piperidyl, piperidino or piperazinyl being optionally substituted with up to three independently selected substituents between alkyl (C? -C4); and Z1, Z2, Z3 and Z4 are hydrogens. A particularly preferred group of the above compounds of this invention, called group of compounds B, are the compounds of formula (I) wherein R is (C7-C8) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl; Y is selected from the group consisting of amino, alkyl (Ci-C6) NH-, amino-alkyl (C? -C6) -O-, amino-alkyl (Ci-Ce) -CONH-, amino-alkyl (d-? C6) -SO2- and piperazinyl substituted with alkyl (C? -C4); and Z1, Z2, Z3 and Z4 are hydrogens. A group of preferred individual compounds of this invention is selected from the group consisting of? / -methyl-1 - [1- (1-phenylcycloheptyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-amine; 2- (4-methylpiperazino) -1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazole; 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1 / - / - benzoimidazole; 2- (4-methylpiperazino) -1 - [1 - (1-phenylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazole; 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -2- (4-pyridinyl) -1H-benzoimidazole; ? / - methyl-1 - [1 - (1-methylcytononyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-amine; 1 - [1 - (1-phenylcyclononyl) -4-piperidinyl] -1 H -benzoimidazol-2-amine; ? / -. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} -acetamide; 2- (4-methylpiperazino) -1 - [1 - (1-methylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazole; 3-amino-1 -. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} -1-propanone; ? / - methyl-1 - [1 - (1-methylcyclooctyl) -4-piperidinyl] -1H-benzoimidazol-2-amine; 4-. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} -1-piperidinecarboximidamide; 4-. { 1 - [1 - (1-methylcyclooctyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-yl} -1-piperazinecarboximidamide; 2-amino -? / -. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamide; 2- ( { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl) -1 / - / - benzoimidazol-2-yl} oxy) -1-ethanamide; 3- ( { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-yl.} - sulfonyl) -1-propanamine; 1 - . 1 - [1 - (1-phenylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazol-2-amine; 2-amino-N-. { 1- [1- (1-phenylecyclooctyl) -4-piperidinyl] -1H-benzoimidazol-2-yl} acetamide; and (2S) -2-amino- / V-. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} propanamide or a salt thereof. A group of more preferred individual compounds of this invention are selected from the group consisting of 2- (4-methylpiperazino) -1 - [1- (1-phenylcycloheptyl) -4-piperidinyl] -1H-benzoimidazole; 1- [1- (1-phenylcyclononyl) -4-piperidinyl] -1 - / - benzoimidazol-2-amine; ? / - methyl-1 - [1 - (1-methylcycloalkyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-amine; 2-amino- / V-. { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamide; 2- ( { 1 - [1 - (phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl}. Oxy) -1-ethanamide; 3- ( { 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1- -benzoimidazol-2-yl}. Sulfonyl) -1-propanamine; and 2-amino-N-. { 1 - [1 - (1-phenylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamide, or a salt thereof. This invention also relates to a pharmaceutical composition for the treatment of a disorder or condition mediated by the ORL1 receptor and its endogenous ligands in a mammal, including a human, or to anesthetize a mammal, including a human, comprising a effective amount of the compound of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. More specifically, this invention relates to a pharmaceutical composition for the treatment of a disorder or condition selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, eating disorders (e.g., in obesity), disorders of the arterial blood pressure (i.e., hypertension or hypotension), tolerance to narcotic analgesics such as morphine, dependence on narcotic analgesics such as morphine, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, disease Alzheimer's disease, dementia, epilepsy and seizures, useful as an analgesic (for acute, chronic or neuropathic pain), anesthetic, neuroprotective agent or analgesic enhancer, useful for controlling water balance (for example, in diabetes insipidus and polyurial), regulate hearing, to control the excretion of sodium ions or for improving brain function, comprising an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is effective in the treatment of such disorder or condition in a mammal, including a human, and a vehicle pharmaceutically acceptable. This invention also relates to a method for the treatment of a disorder or condition, or to anesthetize a mammal, including the human being, in which the treatment or anesthesia can be performed or facilitated by activation of the ORL1 receptor in a mammal including a human being, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, this invention relates to a method for the treatment of a disorder or condition in a mammal, including a human being, wherein the disorder or condition is selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, eating disorders (e.g., in obesity), arterial blood pressure disorders ( that is, hypertension or hypotension), tolerance to narcotic analgesics such as morphine, dependence on narcotic analgesics such as morphine, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias , epilepsy and seizures, or to anesthetize a mammal, including humans, or to relieve pain (for example, acute, chronic or neuropathic pain), producing a neuroprotective effect, potentiating analgesics, controlling water balance (for example, in diabetes insipidus and polyuria), regulating hearing, controlling the excretion of sodium ions or improving brain function in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Among the above processes of this invention for preparing a compound of formula (1), the processes comprising in step (a) are preferred, the coupling reaction is carried out in the presence of a base in a reaction inert solvent, a temperature in the range of room temperature to the reflux temperature of the reaction mixture, for a period of 0.5 to 48 hours; in step (b), the reduction is carried out in the presence of a reduction reagent in a solvent inert to the reaction, at a temperature in the range from room temperature to the reflux temperature of the reaction mixture, over a period of time from 0.5 to 48 hours, and the hydrogenation is carried out in the presence of a metal catalyst at a temperature in the range of 0 ° C to 100 ° C, under an atmosphere of hydrogen, in a solvent inert to the hydrogen reaction, during a period from 0.5 to 48 hours; and in step (c), the benzoimidazole formation is carried out with a coupling reagent selected from the group consisting of carboxylic acids, amino carboxylic acids, acid anhydrides, formamides, alkylcarbonyl halides, aryl carbonyl halides, aryl halides alkylcarbon, heteroaryl carboxylic acids, carbon disulfides, cyanogen halides, cyanamide and trialkyl orthoformates, in the presence of a peptide coupling reagent in a solvent inert to the reaction, at a temperature in the range of 0dC to the temperature of reflux of the reaction mixture, for a period of 1 minute to 120 hours. The most preferred method of this invention for preparing a compound of formula (I) comprises in step (a), the base is selected from the group consisting of K2CO3 and amines; in step (b), the reducing reagent is selected from the group consisting of SnCl2, zinc catalysts and iron catalysts, and the metal catalyst used in the hydrogenation is selected from the group consisting of Raney nickel catalysts, palladium catalysts and platinum catalysts; and in step (c), the peptide coupling reagent used in the formation of benzoimidazole is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DI PC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and diphenylphosphorylazide (DPPA). Preferred intermediates of formula (IX) are those in which R is selected from the group consisting of cycloalkyl (C3-Cu) and cycloalkenyl (C3-Cn), said groups being optionally substituted with up to three substituents independently selected from the group composed of halo, hydroxy, (C1-C5) alkyl and (C3-C7) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C1-C7) alkyl, mono-, di- or tri-halo-alkyl (C-C7) alkyl, (C2-C5) -alkenyl, (C2-C5), aryl and heterocyclic aromatic or nonaromatic comprising four to six ring atoms, where one to two ring atoms are independently selected from heteroatoms , and aryl or aromatic or non-aromatic heterocycle, wherein each of said groups mentioned above is optionally substituted with up to three substituents independently selected from halo, alkyl (d-C4), haloalkyl (CC), alkoxy (C4), -CHO, cyano, alkyl (C? -C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (d-C4) -NH-, di (alkyl- (C? -C4)) - N-, alkyl (d-C4) -CO-NH- and alkyl (C? -C4) -NH-CO-; and Z1, Z2, Z3 and Z4 are independently selected from a group consisting of hydrogen and halo. The most preferred intermediate compounds of the formula (IX) are those in which R is selected from the group consisting of cycloalkyl (C3-Cn), cycloalkenyl (C3-C11), mono-, di-, or tri-halo-cycloalkyl (C3-Cn) and mono-, di- or tri-halo-cycloalkenyl (C3-Cn); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (CrC), alkenyl (C2-C5), aryl selected from the group consisting of phenyl or naphthyl, aromatic heterocycles selected from the group consisting of furyl, thienyl, oxazolyl pyrrolyl, isoxazolyl, thiazolyl, sotiazolilo, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, tiinilo, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl , pyrazinyl and triazinyl, said aryl or aromatic heterocycle optionally substituted with up to three substituents independently selected from the group consisting of halo, (C? -C), haloalkyl (dd) and alkoxy (d-C4), and Z1 being and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogen. The most preferred intermediate compounds of formula (IX) are the compounds wherein R is cycloalkyl (C6-C? 0); A is attached to the atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C? -C) and alkenyl (Q2-C5), phenyl and naphthyl; and Z1, Z2, Z3 and Z4 are hydrogens. Among the above intermediate compounds of formula (IX), compounds in which R is (C7-Cg) cycloalkyl are particularly preferred; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl; and Z1, Z2, Z3 and Z4 are hydrogens.

Preferred of formula (X) intermediates are those wherein R is selected from the group consisting of (C3-Cn) and cycloalkenyl (C3-Cn), optionally substituted such groups with up to three substituents independently selected from the group composed of halo, hydroxy, (C1-C5) alkyl and (C3-C7) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C? -C7), mono-di- or tro-halo-alkyl (d-C7) alkyl, (C2-C5) -alkenyl, (C2-C5), aryl and aromatic heterocyclic or nonaromatic comprising four to six ring atoms, wherein one or two ring atoms are independently selected from heteroatoms, and aryl or aromatic or non-aromatic heterocycle, wherein each of said groups mentioned above is optionally substituted with up to three substituents independently selected from halo, alkyl (CrC), haloalkyl (dd), alkoxy (C? -C4), -CHO, cyano, alkyl (C? -C4) -CO-, NH2-CO-, NH2-CH2, amino, alkyl (C4) -NH-, di (alky1- (CrC4)) - N-, alkyl (C C4) -CO-NH-, alkyl (dd) -NH-CO-; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo. The most preferred intermediate compounds of the formula (X) are those in which R is selected from the group consisting of cycloalkyl (C3-Cn), cycloalkenyl (C3-C11), mono-, di- or tri-halo-cycloalkyl ( C3-Cn) and mono-, di- or tri-halo-cycloalkenyl (C3-C11); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C1-C7) alkyl, (C2-C5) alkenyl, aryl selected from the group a group consisting of phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, oxyl, thiyl, pyridyl, pyrimidinyl, pyryl and triyl, said aryl or aromatic heterocycle being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C? -C4) alkyl, haloalkyl (C? -C) and alkoxy (C ? -C4); and Z1 and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogens. Among the above intermediate compounds of formula (X), the most preferred are compounds wherein R is cycloalkyl (Ce-Cio); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C? -C7) and alkenyl (C2-C5), phenyl and naphthyl; and Z1, Z2, Z3 and Z4 are hydrogens.

Particularly preferred intermediate compounds of the formula (X) are the compounds wherein R is (C7-C9) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl; and Z1, Z2, Z3 and Z4 are hydrogens.

General synthesis The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R, A, Y and Z1 through Z4 in the reaction schemes and discussion indicated below are as defined above. The ORL1 agonist compounds of formula (I) of this invention can be prepared according to the following procedures. In the reaction schemes shown below, a substituent represented as A of the compounds of formulas (V), (a), (VI), (VII), (IX), (X), (XIII), (XIV) ) and (XVI) is attached to the carbon atom in R attached to the nitrogen atom of the piperidine ring: In the compounds of formulas (IV), (Xll) and (XVIII), the cyano group is also attached to the atom of carbon in R that is attached to the nitrogen atom of the piperidine ring. In the compounds of formula (XIV), A is attached to the same carbon atom of R where the amino group is attached to the amino group.

In a desired reaction step of the process described below, the amino protections and the removal of the amino protecting groups with the reagents used can be carried out according to known procedures such as those described in Protective Groups in Organic Synthesis, edited by T.W. Greene et al. (John Wiley &Sons, 1991). Typical amino protecting groups include benzyl, C2H5CO2- and t-ButCO2-, represented as t-Boc or Boc. Scheme 1 illustrates one embodiment of the method of preparation for a compound of formula (I) in which Y is a leaving group, represented by L in the scheme, such as halo, hereinafter represented by formula (la).

SCHEME 1 As shown in scheme 1, a compound of formula (la) in which L represents a leaving group such as halo, can be obtained from a known benzoimidazolylpiperidine compound of formula (II), by intermediates of formula (IV) ) and V). First, a compound of formula (II) can be subjected to Strecker synthesis with the stoichiometric amount of a cyclic ketone compound of formula (III), to give the compound of formula (IV). Secondly, the resulting compound of formula (IV) can be reacted with a Grignard reagent of formula AMgX (X is halo) to give the compound of formula (V). Then, the compound of formula (V) can be reacted with a suitable nucleophilic agent to produce the compound of formula (la) by introducing a leaving group into the compound of formula (V) in the presence or absence of a catalyst. Strecker synthesis can be performed using a suitable cyanation agent according to known procedures reported by A. Kalir, et al. (J. Med. Chem. Vol. 12, p.473, 1969). Suitable cyanating agents include cyanide, such as potassium cyanide (KCN). This reaction can be carried out at a pH in the range of about 3 to 11, at about 0 ° C, such as in ice-cold water. The reaction of the compound of formula (IV) with a Grignard reagent can be carried out under anhydrous conditions according to known procedures (for example, OA Al-Deeb, Arzneim-Forsch./Drug Res., Vol. 44 (11), Nr. 10, 1994). More specifically, this reaction can be carried out in a suitable solvent, such as tetrahydrofuran (THF) or ether, at a temperature of 0 ° C at the reflux temperature of the reaction mixture, for from about 30 minutes to about 48 hours. Preferably, the Grignard reagent can be added to the reaction mixture at about 0 ° C and the reaction mixture can be allowed to warm to room temperature to continue reacting.

The compound of formula (V) thus obtained can be heated to reflux with a suitable nucleophilic reagent to give the compound of formula (la). In the case where L is Cl, a suitable chlorination reagent is, for example, phosphoryl chloride. This reaction can be carried out under conditions initiated, for example, by R. lemura et al. J. Med. Chem. Vol. 29, p. 1178-1183, 1986. A compound of formula (la) wherein L is halo (ie, a compound of formula (I) wherein Y is halo) can be subjected to a reaction with a nucleophilic reagent under reaction conditions. known to give a compound of formula (I) wherein Y is other than halo. Nucleophilic reagents include amine and imine compounds such as mono- or di-alkylamines, cycloalkylamines, alkenyl amines and aromatic amines such as aniline, nitrogen-containing heterocyclic compounds such as aminoazetidine, pyrrolidine, piperidine, piperazine, morpholine and azabicyclic compounds, alkoxides and thioalkoxides such as sodium alkoxide and sodium thioalkoxide, alcohols including cyclic alcohols and diols, and the like. This reaction can be carried out in a solvent inert to the reaction at a temperature of from about 0 ° C to about 200 ° C (preferably from 0 ° to 150 ° C) for about 1 to about 24 hours (preferably for about 2 to about 12 hours) . Suitable inert reaction solvents include alcohols such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and N, N-dimethylformamide (DMF) and the like. If appropriate, this reaction can be carried out in a suitable reaction chamber such as an autoclave. A substitution reaction of a compound of formula (I) in which Y is Cl with an imide, can be carried out according to the procedures presented by C. H. Senanayake et al., Tetrahedron Lett., Vol. 38, p. 5607-5610, 1997. In the report, Pd catalyst is used in the presence of a toluene base with heating. In addition, a compound of formula (I) in which Y is linked to the benzoimidazole ring via S, can be oxidized to the corresponding sulfonyl compound, under conventional oxidation conditions with thioethers, using oxidizing reagents such as potassium permanganate. A compound of formula (II) can be prepared by carbonylation of a diamine compound of formula (X).

The carbonylation can be carried out by reacting a compound of formula (X) with a suitable carbonylating agent, such as carbonyldiimidazole, trichloromethyl chloroformate, triphosgene or urea, in a reaction-inert solvent such as THF, benzene, toluene or chloroform, at a temperature in the range of about 0 ° to about 120 ° C, for about 0.5 to about 24 hours. The reaction can be carried out according to the procedures described in WO 98/54168. The compounds of the formula (I) in which Y is other than halo can also be prepared by the procedures illustrated in scheme 2.

SCHEME 2 t (O) As shown in scheme 2, compounds of formula (I) in which Y is other than halo can also be prepared by the process comprising: (a) reductive amination of a piperidine-4-one compound of formula (VI) to give the 4-aminopiperidine compound of formula (VII): (b) the coupling reaction of the compound of formula (VII) with a nitrobenzene compound of formula (VIII) in which L is a group protruding such as halo to give the nitroaniline compound of formula (IX), (c) reducing the resulting nitroaniline compound of formula (IX) to give the diamine compound of formula (X), and (d) forming the benzoimidazole ring with the compound of formula (X) to give the compound of formula (I) Each reaction step is described more specifically below (a) Reductive amination can be performed by an oximation of the piperidine-4- compound one of formula (VI), followed by reduction. Both reactions can be carried out under carbonyl compounds oximation conditions known to those skilled in the art. For example, oximation can be performed by reaction of the piperidine compound with hydroxylamine in the presence or absence of a base, in a reaction-inert solvent such as alcohol, at about room temperature, for about 0.5 to 48 hours. The resulting oxime compound can be extracted and subjected to reduction under known conditions to give the amine compound of formula (VII). The reduction can be carried out in the presence of a reducing agent such as lithium aluminum hydride, in a solvent inert to the reaction such as THF, at a temperature of about 0 ° C at room temperature, for about 0.5 to 48 hours. (b) - (c) Steps (b) and (c) can be performed under conditions known to those skilled in the art (eg, B. de Costa et al., J. Chem. Soc. Perkin. Trans., Vol. 1, pp. 1671-1680, 1992 and NA Meanwell et al., Bioorganic & amp; amp; amp; amp.; Medicinal Chemistry Letters, Vol 6, No 14 pp. 1641-1646, 1996). For example, the coupling reaction (b) can be carried out in the presence of a base such as K2CO3 and triethylamine (NEt) 3, in a reaction-inert solvent such as acetonitrile, at reflux for about 0.5 to 48 hours. Then, the resulting compound of formula (IX) can be extracted and subjected to reduction to give the compound of formula (X). The reduction can be carried out in the presence of a suitable reducing agent such as SnCl 2, zinc catalyst and iron catalyst, in a reaction-inert solvent such as ethanol, at a temperature in the range from room temperature to the reflux temperature of the reaction mixture (preferably at reflux) for from about 0.5 to about 48 hours. The reduction can be carried out under known hydrogenation conditions, such as in the presence of a metal catalyst, such as Raney nickel catalysts, palladium catalysts and platinum catalysts, at a temperature in the range of about 0 ° to 100 ° C ( preferably at about room temperature) under a nitrogen atmosphere in a reaction inert solvent such as ethanol or THF, for a period of about 0.5 hours to 2 days. (d) A compound of formula (X) can be cyclized to form a benzoimidazole ring by reaction with appropriate cyclization agent, to give the compound (I) in a reaction inert solvent, in the presence or absence of a reagent coupling Suitable cyclizing agents include a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride, and the like), a formamidine (e.g., formamidine alkylate such as acetate) of formamidine), an alkyl carbonyl halide (eg, a cycloalkyl carbonyl halide), an aryl or aryl alkyl carbonyl halide (eg, phenylacetyl halide), a heteroaryl carboxylic acid (eg, a piperidinyl acid compound) carboxylic), carbon disulfide, cyanogen halide (e.g., cyanogen bromide), cyanamide, trialkyl orthoformate (e.g., triethyl orthoformate) and the like. Suitable solvents are tetrahydrofuran (THF), xylene, ethoxyethanol and the like. Suitable coupling reagents are those typically used in the synthesis of peptides, including dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazole-1-yloxy-hexafluorophosphate. tris (dimethylamino) phosphonium (BOP), diphenylphosphoryl azide (DPPA) and the like.

This reaction can be carried out at a temperature of about 0 ° C at the reflux temperature of the reaction mixture, preferably from about room temperature to the reflux temperature, for a period of about 1 minute to about 120 hours, preferably for about 10 minutes to approximately 72 hours. An embodiment of the 2-aminobenzoimidazole ring formation is also reported by N. A. Meanwell et al., Bioorganic & Medicinal Chemistry Letters, Vol. 6, No. 14, p. 1641-1646, 1996. These reactions are also presented by A. F. Pozharskü et al, Russ. Chem. Rev. (British translation), vol. 35. P. 122, 1996. Alternatively, a compound of formula (X) can be subjected to a coupling reaction with an isothiocyanate compound and subsequent desulfurization under known conditions, to give a compound of formula (I) wherein And it is connected to the benzoimidazole ring through NH. For example, the first coupling reaction can be carried out in a reaction-inert solvent, such as an alcohol (for example, ethanol), at a temperature from about room temperature to 100 ° C, for a period of 30 minutes to 48 minutes. hours, under agitation. The desulfurization can be carried out in the presence of an alkyl halide at reflux for a period of about 30 minutes to 48 hours. A compound of formula (I) in which Y is connected to the benzoimidazole ring through a carbonyl (C = O), can be prepared according to known procedures. For example, a compound of formula (I) wherein Y is hydrogen can be reacted with a lithiation reagent, such as n-BuLi, under known conditions, followed by reaction with an appropriate amide compound, such as an N, N-alkylalcoxy amide, under known conditions. The first reaction can be carried out at about -78 ° C in a solvent inert to the reaction such as THF, for a period of about 30 minutes to 48 hours. The subsequent reaction can be carried out at a temperature of about -78 ° C at room temperature in THF, for about 30 minutes to 24 hours, according to known procedures presented by G. Bitan et al., J. Chem. Soc. Perkin. Trans Vol. 1, pgs. 1501-1510, 1997. In addition, the compounds of formula (I) thus obtained can be modified in the group Y described as shown below. A compound of formula (I) in which Y has an amino or imino group (eg, piperidinyl, piperazinyl and the like) in its terminal position, can be further reacted with a desired reagent under known conditions to modify Y. For example, these amine or imine compounds can be reacted with an alkylcarbonyl halide at about room temperature, in a basic solvent, to give an amide compound. The amine or imine compounds can be reacted with an amino acid, or sulfone or amino acid sulfoxide in the presence or absence of a coupling reagent known to those skilled in the art in peptide synthesis. Suitable coupling reagents include WSC and the like. The amino or methyl compound may be coupled with an amino acid, a sulfone or amino acid sulphoxide or a phthalimide alkyl sulfonyl halide, under conventional amide formation conditions, in the presence of a coupling reagent, in a reaction-inert solvent as acetonitrile, at about room temperature. These amino acids include isoleucine, alanine, methionine, proline, phenylalanine, valine and the like. Suitable coupling reagents are those typically used in the synthesis of peptides including WSC, dicyclohexylcarbodiimide (DCC), N, N'-carbonyldiimidazole (CDl), POCI3, TiCl, SO2CIF, benzotriazol-1-yl diethyl phosphate, Ti ( Obu) 4, molecular sieves, N, N, N ', N'-tetramethyl (succinimido) uronium tetrafluoroborate, CBMIT, Lawesson's reagent, chlorosulfonyl isocyanate, P2l, pyridinium-Bu3N salts and a mixture of Bu3P and PhCNO. The amine or imine compounds can also be reacted with a guanidine compound under known conditions. A suitable reaction condition comprises the reaction with an amino-protected guanidine compound, in a reaction-inert solvent such as THF, at about room temperature (see M. S. Bernatowicz et al., Tetrahedron Letí., Vol. 34). The intermediate compounds (VI) can be prepared by the procedures illustrated in scheme 3.

SCHEME 3 Route 1 of scheme 3 illustrates a method of preparing a compound of formula (VI) from 4-piperidinol of formula (XI), according to the procedures presented by A. Kalir et al., J. Med. Chem ., Vol. 12, p. 473-477, May 1996. First, a compound of formula (XI) can be condensed with a compound of formula (III) and cyanate to give the compound of formula (Xll). Secondly, the obtained compound of formula (Xll) can be reacted with a Grignard reagent AMgX, where X is halo, to give the compound of formula (XIII). Then, the resulting compound of formula (XIII) can be oxidized to give the compound of formula (VI). The condensation and cyanation can be carried out using HCl salt of 4-piperidinol in water at about room temperature. Route 2 illustrates a method of preparing a compound of formula (VI) from a starting amine (XIV), comprising the condensation of a compound of formula (XIV) with 3,3-ethylenedioxypentane dimethanesulfonate. -1, 5-dioI (XV), followed by deprotection. These reactions can be carried out under known conditions (for example, B. de Costa et al., J. Chem. Soc. Perkin, Trans., Vol. 1, pp. 1671, 1992 and RL McQuin et al., J. Med. Chem. Vol. 24, pp. 1429-1432, 1981). Route 3 illustrates a process for preparing a compound of formula (VI) from a known 4-piperidone ethylene ketal (XVII). This preparation comprises (a) the condensation of a compound of formula (XVII) with a ketone compound of formula (III), (b) cyanation (c) reaction of the compound of formula (XVIII) with a Grignard reagent and (d) deprotection of the compound of formula (XVI). These reactions can be carried out under conditions similar to those described in scheme 1. The starting amine compounds of formula (XIV) can be easily prepared by methods known to an expert (for example, J. Weinstock, et al., OS IV 910 , EJ Cone, et al., J. Med. Chem., Vol. 24, pp. 1429-1432, 1981, and the Ritter Reaction described in Org. React. Vol. 17, pp. 313-325, 1969) . In addition, the compounds of formula (I) wherein Y is substituted or unsubstituted alkylcarbonyl, can be prepared using a procedure similar to that presented in P.D. Edwards et al. J. Med. Chem., Vol. 38, pgs. 76-85, 1995. For example, 2-lithium-benzoimidazole, prepared by the addition of n-butyl lithium to banzoimidazole in tetrahydrofuran, can be added with 3-t-butoxycarbonylamino-N-methoxy-N-methylpropionamide to give the product acylated Then, the protecting group (eg, Boc) can be removed by treatment with hydrochloric acid in methanol. The starting materials (III), (XI), (XIV), (XVII) and the other reagents are known compounds or compounds available in the market, or they can be prepared according to procedures known to a person skilled in the art. In each reaction described above, unless otherwise indicated, the reaction pressure is not critical. Generally, the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). The present invention also includes isotopically-labeled compounds, which are identical to those mentioned in formula (I) except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or Mass number found normally in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 1 C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36CI, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain compounds labeled with isotopes of the present invention, for example those in which radioactive isotopes such as 3H and 14C are incorporated, useful in distribution assays in drug tissues and / or substrates. Particularly preferred are the tritiated isotopes, ie with 3H, and carbon-14, ie, 14C, for their ease of presentation and detectability. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, can produce therapeutic benefits resulting from increased metabolic stability, for example, increase in half-life in vivo or reduction of the required dose and, therefore, can Prefer in some circumstances. The isotope-labeled compounds of formula (I) of this invention and their prodrugs can generally be prepared by carrying out the procedure described in the schemes described above and / or examples and preparations shown below, substituting reagents not labeled with isotopes for isotope-labeled reagents. easily acquirable. The compounds of formula (I) of this invention are basic, therefore they will form acid addition salts. All such salts are within the scope of this invention. However, it is necessary to use acid addition salts that are pharmaceutically acceptable for administration to a mammal. The acid addition salts can be prepared by conventional methods. For example, salts can be prepared by contacting the basic compounds with an acid, in substantially equivalent proportions, in water or in an organic solvent such as methanol or ethanol, or in a mixture thereof. The salts can be isolated by crystallization or evaporation of the solvent. Typical salts that can be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, gluconate, saccharate, banzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate salts and pamoate (1,1'-methylene-bis- (2-hydroxy-3-naphthoate).

The compounds of formula (I) of this invention may contain one or more asymmetric centers and, therefore, may exist as diastereomers. The invention includes both mixtures thereof and individual separated diastereomers. In addition, when the compounds of this invention form hydrates or solvates, they are also within the scope of this invention. It has been found that the compounds of formula (I) possess selective affinity for ORL1 receptors and ORL-1 receptor agonist activity. Thus, these compounds are useful as analgesic, anti-inflammatory, diuretic, anesthetic, neuroprotective, antihypertensive and anxiolytic agents, and the like, in mammals, especially in humans, in need of such agents. The affinity, the agonist activities and the analgesic activity can be demonstrated by the following tests respectively.

Selective affinity for QRL1 receptors Affinity for ORL1 receptor: ORL1 receptor binding affinity of the compounds of this invention is determined by the following procedures. Membranes of transfected HEK-239 cells are combined with the human ORL1 receptor and SPA beads coated with wheat germ agglutinin with [3H] 0.4 nM nociceptin and unlabeled test compounds in 200 μl of 50 mM Hepes buffer, pH 7.4, containing 10 mM MgCl 2 and 1 mM EDTA. This mixture is incubated at room temperature (abbreviated as ta) for a period of 30 to 60 min. The non-specific binding is determined by the addition of 1 μM nociceptin. Radioactivity is counted by using Wallac 1450 MicroBeta.

Affinity for the μ receptor: The binding affinity to the mu opiate receptor (μ) of the compounds of this invention is determined by the following procedures. Membranes of transfected CHO-K1 cells are combined with the human mu opioid receptor and SPA beads coated with wheat germ agglutinin with 1.0 nM [3 H] DAMGO and unlabeled test compounds in 200 μl of 50 mM Hepes buffer, pH 7.4, which contains 10 mM MgCl 2 and 1 mM EDTA. This mixture is incubated at rt for a period of 30 to 60 min. The non-specific binding is determined by the addition of 1 μM DAMGO. Radioactivity is counted by using Wallac 1450 MicroBeta.

Affinity for the k receptor: The binding affinity to the kappa opioid receptor (k) of the compounds of this invention is determined by the following procedures.

Membranes of transfected CHO-K1 cells are combined with the human kappa opioid receptor and SPA beads coated with wheat germ agglutinin with 0.5 nM [3 H] CI-977 and unlabeled test compounds in 200 μl of 50 mM Hepes buffer. , pH 7.4, containing 10 mM MgCl 2 and 1 mM EDTA. This mixture is incubated at rt for a period of 30 to 60 min. The non-specific binding is determined by the addition of 1 μM CI-977. Radioactivity is counted by using Wallac 1450 MicroBeta.

Affinity for the receptor d: The affinity for binding to the opiate receptor delta (d) of the compounds of this invention is determined by the following methods. Membranes of transfected CHO-K1 cells are combined with the human delta opioid receptor and SPA beads coated with wheat germ agglutinin with 2.9 nM [3H] DPDPE and unlabeled test compounds in 200 μl of 50 mM Hepes buffer, pH 7.4, which contains 10 mM MgCl 2 and 1 mM EDTA. This mixture is incubated at rt for a period of 30 to 60 min. The non-specific binding is determined by the addition of 1 μM of each of the unlabeled ligands. Radioactivity is counted by using Wallac 1450 MicroBeta. Each non-specific binding percentage thus obtained is represented in a graph according to the concentration of the compound. A sigmoid curve is used to determine 50% binding (ie, Cl50 values). In this test, most of the compounds prepared in the working examples presented below showed a greater affinity for ORL1 receptors than for mu receptors.

CI5o (ORL1 receptors) nM / CI5o (mu receptors) nM < 1.0 Functional assay: The functional activity of the compounds of this invention in each opioid receptor can be determined in a 35S-GTPγS binding system according to the procedures presented by L.J. Sim. R. Xiao and S. Childers Neuroreort \ lo. 7, pgs. 729-733, 1996. Membranes of CHO-K1 or HEK cells transfected with human ORL1, mu, kappa and delta receptor are used. The membranes are suspended in ice-cold 20 mM HEPES buffer, pH 7.4, containing 100 mM NaCl, 10 mM MgCl 2 and 1 mM EDTA. Before use, 0.17 mg / ml Dithiothreitol (DTT) is added to this buffer. Membranes are incubated at 25 ° C for 30 minutes with the appropriate concentration of test compounds in the presence of 5 μM GDP, 0.4 nM 35S-GTPγS and SPA beads coated with wheat germ agglutinin (WGA) (1.5 mg ) in a total volume of 0.2 ml. The basal junction is evaluated in the absence of agonist and the non-specific binding is determined with 10 μM GTPγS. Radioactivity is counted by using Wallac 1450 MicroBeta. Some compounds of this invention prepared in the examples showed good ORL1 agonist activity in this assay.

Analgesic Test: Tail movement test: Male ICR mice, 4 weeks old and weighing 19-25 g are used. Training sessions are conducted until the mice can move their tails within a period of 4.0 seconds using an Analgesia Meter MK-330a (Muromachi Kikai, Japan). In this experiment the selected mice are used. The latency time is recorded twice 0.5, 1.0 and 2.0 h after the administration of the compound. The beam intensity is set to 80. The time limit is set to 8.0 seconds. A compound of this invention is administered subcutaneously 30 minutes before assay. The DE5o value is defined as the dose of a compound tested that halves the tail movement observed in a control group.

Twist test with acetic acid: Male ICR mice, 4 weeks old and weighing 21-26 g are used. They are fasted the day before use. Acetic acid is diluted with saline at the concentration of 0.7% (v / v) and injected intraperitoneally (0.2 ml / 10 g of body weight) into mice with a 26 gauge needle. A compound of this invention is dissolved in 0.1% of hypromellose (MC) -salt solution and administered subcutaneously to mice 0.5 h before the injection of acetic acid. After the injection of acetic acid, each animal is placed in a 1-l beaker and recorded with a video tape recorder. The number of times the mouse is twisted is counted during a period of 5 to 15 minutes after the injection of acetic acid. The ED 50 value, defined as the dose of the tested compounds that halves the kinking, is observed in the control group. Some compounds of this invention demonstrated good analgesic activity in this assay.

Lysing test with formalin Male SD rats (80-100 g) are injected subcutaneously with a test compound dissolved in 0.1% hypromellose (MC) -salt solution or vehicle. After 30 minutes, 50 μl of 2% formalin is injected into a hind paw. The number of licks of the injected paw per observation period is measured 15 to 30 minutes after the formalin injection and expressed as% inhibition compared to the respective vehicle group. This test procedure is described, for example, in (1) R.L. Follenfant et al., Br. J. Pharmacol. 93, 85-92 (1988); (2) H. Rogers et al., Br. J. Pharmacol. 106, 783-789 (1992); and (3) H. Wheeler-Aceto et al. Psychopharmacology, 104, 35-44 (1991). The compounds of formula (I) of this invention can be administered by conventional pharmaceutical practice by oral, parenteral or topical routes to mammals, for the treatment of the indicated diseases. For administration to a human patient by any means, the dose is in the range of about 0.01 mg / kg to about 3000 mg / kg of body weight of the patient per day, preferably from about 0.01 mg / kg to about 1000 mg / kg of body weight and per day, administered from a single time or in the form of divided doses. However, variations will necessarily occur depending on the weight and disorder of the subject to be treated, the compound used, the disease state being treated and the particular route of administration chosen. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers by any of the above routes indicated above, and such administration can be carried out in a single dose or in multiple doses. Generally, the compounds can be combined with various pharmaceutically acceptable carriers in the form of tablets, powders, capsules, dragees, troches, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, suspensions, solutions , elixirs, syrups or similar. Such pharmaceutical carriers include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizing agents, suspending agents, emulsifying agents, stabilizers, buffering agents, tonicity agents, preservatives, flavoring agents, aromatics, coloring agents and Similar. For example, the tablets may contain various excipients such as starch, lactose, glucose, microcrystalline cellulose, calcium sulfate, calcium carbonate, talc, titanium oxide and the like, coating agents such as gelatin, hydroxypropylcellulose and the like, binding agents such as gelatin. , gum arabic, hypromellose and the like, and disintegrating agents such as starch, agar, gelatin, sodium hydrogencarbonate and the like. In addition, lubricating agents such as magnesium stearate and talc are often very useful for making tablets. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. In general, the therapeutically effective compounds of this invention are present in such oral dosage forms at concentration levels ranging between 5% and 70% by weight, preferably between 10% and 50% by weight. The compounds of the present invention in the form of a solution can be injected parenterally, such as intradermal, subcutaneous, intravenous or intramuscular. For example, the solutions are sterile aqueous solutions, aqueous suspensions and edible oily solutions. The aqueous solutions can be conveniently buffered (preferably at pH> 8) and can contain enough salts or glucose to make the solution isotonic with the blood. The aqueous solutions are suitable for intravenous injection purposes. The aqueous suspensions may contain a suitable dispersing or suspending agent, such as carboxymethylcellulose sodium, hypromellose, polyvinylpyrrolidone or gelatin. Aqueous suspensions can be used for subcutaneous or intramuscular injections. Edible oil such as cottonseed oil, sesame oil, coconut oil or peanut oil can be used for edible oil solutions. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art. It is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin, and this can preferably be done by means of creams, jellies, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice.

EXAMPLES AND PREPARATIONS The present invention is illustrated by the following examples and preparations. However, it should be understood that the invention is not limited to the specific details of these examples and preparations. The melting points were taken with a Buchi micro melting point apparatus and are not corrected. The infrared absorption (IR) spectra were measured by a Shimadzu infrared spectrometer (IR-470). Nuclear magnetic resonance spectra of 1H and 13C (NMR) were measured in CDCI3 by a JEOL NMR spectrometer (JNM-GX270, 270 MHz) unless otherwise indicated, and the positions of the peaks are expressed in parts by million (ppm) downfield of tetramethylsilane. The shapes of the peaks are denoted as follows: s, singlet; d, doublet; t, triplet; m, multiplet; a, wide.

EXAMPLES AND PREPARATIONS EXAMPLE 1 2-Chloro-1H - (1-phenylcycloheptyl) -4-piperidin-p-1-f-benzoimidazole A mixture of 4- (2-keto-1-benzoimidazolinyl) piperidine (5.10 g, 23.5 mmol) and HCl solution in MeOH (20 mL) was stirred at room temperature for 10 minutes. After evaporation of the solvent, the residue was triturated in Et 2 O to give the HCl salt in the form of an off-white powder. To this HCl salt was added cycloheptanone (3.33 ml, 28.2 mmol) followed by the addition of an aqueous solution of KCN (1.92 g, 29.5 mmol) in water (7 ml) at room temperature. After stirring for 128 hours, the resulting solid was collected by filtration, washed with water and dried under vacuum to give 6.81 g (85.7%) of nitrile derivative as a white powder. To a solution of this nitrile derivative (5.12 g, 15.1 mmol) in THF (40 ml) was added a solution of phenylmagnesium bromide in Et 2 O (3.0 M solution, 25 ml) at 0 ° C. Then, the reaction mixture was stirred at room temperature for 18 hours. An aqueous solution of NH 4 Cl was added to the reaction mixture and the resulting appeared solid was collected by filtration, washed with water and Et 2 O and dried under vacuum at 70 ° C to give 4.88 g (82.8%) of 1- [1 - (1-phenylcyclopentyl) -4-piperidinyl] -1,3-dihydro-2H-1,3-benzoimidazol-2-one in the form of a white powder. A mixture of 1- [1- (1-phenolcycloheptyl) -4-piperidinyl] -1,3-dihydro-2H-1,3-benzoimidazol-2-one (2.316 g 5.95 mmol) and phosphoryl chloride (15 ml, 165.5 mmol) was heated to reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into a 25% ammonia solution cooled with ice and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO2), filtered and concentrated. The residue was purified by column chromatography (200 g of silica gel, hexane / ethyl acetate: 4/1) to give 1.42 g (58.7%) of a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.70-7.63 (1H, m), 7.61-7.49 (3H, m), 7.38-7.31 (2H, m), 7.30-7.20 (3H, m), 4.40-4.29 (1 H, m), 3.05-3.00 (2H, m), 2.52-2.22 (4H, m), 2.13-2.09 (4H, m), 1.81-1.72 (5H, m), 1.60-1.49 (5H, m). This free amine was converted to the HCl salt by treating the compound obtained with HCl solution in MeOH. Evaporation of the solvent produced a solid, mp 153-156 ° C. MS (ESI positive) m / z: 408 (M + H) +. Analysis calculated for C25H30N3CI HCI-2.1 H2O: C, 62.26; H, 7.36; N. 8.71. Found: C, 62.06; H, 7.26; N, 8.51.

EXAMPLE 2? / - Methyl-1-f 1 - (1-phenylcycloheptyl) -4-piperidn-p-1 H-benzoimidazole-2-amino A solution of 2-chloro-1- [1- (1-phenylcycloheptyl) -4-piperidinyl-benzoimidazole (example 1.69.3 mg, 0.17 mmol) in a solution of 40% MeNH2 in MeOH (5 ml) was stirred in an autoclave at 110 ° C for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by preparative TLC (0.5 mm x 3 plate, CH 2 Cl 2 / MeOH: 10/1) giving 56.9 mg (83%) of the title compound as an amorphous solid of light brown color.

MS m / z (El): 402 (M +), 345, 317, 230, 173, 147, 91. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.46 (3H, m), 7.38-7.18 (4H, m ), 7.12-6.98 (2H, m), 4.16-4.06 (1H, m), 3.80-3.70 (1H, m), 3.14 (3H, d, J = 4.8 Hz), 3.05-2.96 (2H, m), 2.34-2.05 (8H, m), 1.84-1.44 (10H, m). This free amine (56.9 mg, 0.142 mmol) was converted to the HCl salt by treatment with HCl solution in MeOH (3 mL). Evaporation of the solvent produced a light brown amorphous solid. IR (KBr): 3412, 1660 cm "1. Analysis calculated for C26H34N4-2 HCI-H2O: C, 63.28; H, 7.76; N, 11.35. Found: C, 63.09; H, 7.78; N, 11.50. The free amine was also converted to the salt of ethanesulfonic acid. Analysis calculated for C 26 H 34 N 4-2C 2 H 5 SO 3 -1.1 H2O: C, 56.07; H, 7.86; N, 8.72. Found: C, 56.26; H, 7.96; N, 8.80.

EXAMPLE 3? / - Phenyl-1 - [- (1-phenylcycloheptyl) -4-piperidinip-1-t-benzoimidazole-2-amino This was prepared according to the procedure described in example 2 using aniline (10 equivalents, 120 ° C, 4h) instead of methylamine and MeOH. The yield was 26%.

? NMR (270 MHz, CDCl 3), d 7.60-6.96 (15H, m), 4.10-3.94 (1H, m), 3.05-2.93 (2H, m), 2.45-2.00 (8H, m), 1.90-1.68 ( 4H, m), 1.65-1.40 (6H, m). MS (El) m / z: 464 (M +), 292, 210, 91. This free amine was converted to the hydrochloride salt using a solution of HCl in MeOH to give a light brown amorphous solid. IR (KBr): 3389, 1636, 1589 crt? 1. Analysis calculated for C3? H36N4-2HCI-H20: C, 67.02; H, 7.26; N, 10.08. Found: C, 67.19; H, 7.31; N, 9.96.

EXAMPLE 4 2- (4-Methylpiperazino) -1-f 1 - (1-phenylcycloheptyl) -4-piperidin-p-1 H-benzoimidazole This was prepared according to the procedure described in example 2 using 1-methylpiperazine (2-equivalents, 120 ° C, 10 h) in place of methylamine and MeOH. The yield was 96%. 1 H NMR (270 MHz, CDCl 3) d 7.64-7.44 (4H, m), 7.39-7.30 (2H, m), 7.27-7.10 (3H, m), 4.13-3.98 (1 H, m), 3.28-3.21 ( 4H, m), 3.06-2.95 (2H, m), 2.64-2.58 (4H, m), 2.38 (3H, s), 2.45-1.90 (8H, m), 1.85-1.45 (10H, m). This free amine was converted to the hydrochloride salt using a solution of HCl in MeOH to give a light yellow amorphous solid.

MS (ESI positive) m / z: 472 (M + H) +. IR (KBr): 3410, 1612 cm "1. Analysis calculated for C30H? N5-3 HCI-H2O: C, 60.15; H, 7.74; N, 11.69. Found: C, 59.85; H, 7.86; N, 11.64.

EXAMPLE 5 2-N, N-Dimethyl-1-f 1 - (1-phenylcycloheptyl) -4-piperidin-1 H-benzoimidazol-2-amine This was prepared according to the procedure described in Example 2 using a solution of dimethylamine in MeOH (120CC, 16 h in autoclave) instead of methylamine in MeOH solution. The yield was 97%. 1 H NMR (270 MHz, CDCl 3) d 7.62-7.42 (4H, m), 7.38-7.30 (2H, m), 7.27-7.08 (3H, m), 4.20-4.04 (1H, m), 3.06-2.94 ( 2H, m), 2.88 (6H, s), 2.46-2.00 (8H, m), 1.84-1.40 (10H, m). This free amine was converted to the hydrochloride salt using a solution of HCl in MeOH to give a light yellow amorphous solid. MS (ESI positive) m / z: 417 (M + H) +. IR (KBr): 3400, 1647 cm "1. Analysis calculated for C27H36N4-2 HCI-H2O: C, 63.90; H, 7.94; N, 11.04.

Found: C, 64.03; H, 7.78; N, 10.92.

EXAMPLE 6 2-Methoxy-1 -M - (1-phenylcycloheptyl) -4-piperidinyl-1 H-benzoimidazoles This was prepared according to the procedure described in example 2 using sodium methoxide (10 equivalents, reflux, 10 h) and MeOH instead of methylamine solution in MeOH. The yield was 96%. 1 H NMR (270 MHz, CDCl 3) d 7.57-7.48 (3H, m), 7.38-7.30 (3H, m), 7.27-7.07 (3H, m), 4.17 (3H, s), 4.20-4.00 (1H, m), 3.05-2.90 (2H, m), 2.35-2.00 (8H, m), 1.86-1.42 (10H, m). This free amine was converted to the fumaric acid salt using fumaric acid (1 equivalent) to give a pale yellow amorphous solid. MS (ESI positive) m / z: 404 (M + H) +. IR (KBr): 3400, 1703 cm "1. Analysis calculated for C26H33N3O-C4H4O4-H2O: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.16; H, 6.95; N 7.52.

EXAMPLE 7 2- (Methylsulfanyl) -1H -d-phenylcycloheptyl) -4-p -pepdin-1 H-benzoimidazole This was prepared according to the procedure described in Example 2 using a 15% solution of NaSMe in water and DMF (room temperature, 2 h) in place of methylamine in MeOH solution. The yield was 81%. 1 H NMR (270 MHz, CDCl 3) d 7.70-7.62 (1 H, m), 7.55-7.45 (3H, m), 7.40-7.30 (2H, m), 7.25-7.12 (3H, m), 4.16-4.03 ( 1 H, m), 3.05-2.95 (2H, m), 2.77 (3H, s), 2.43-2.00 (8H, m), 1.90-1.42 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 168-171 ° C. MS (El) m / z: 419 (M +), 372, 362, 183, 149, 73. IR (KBr): 3377 cm "1. Analysis calculated for C26H33N3S-2HCI-2.1 H2O: C, 58.88; H, 7.45.; N, 7.92, Found: C, 58.62; H, 7.16; N, 7.80.

EXAMPLE 8 1 -H - (1-Phenylcycloheptyl) -4-piperidinin-2- (1-pyrrolidinyl) -1 H -benzoimidazole This was prepared according to the procedure described in Example 2 using pyrrolidine instead of methylamine solution in MeOH. The yield was 90%. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.03 (9H, m), 4.17-4.03 (1 H, m), 3.55-3.45 (4H, m), 3.05-2.95 (2H, m), 2.50-2.30 ( 2H, m), 2.30-1.90 (10H, m), 1.85-1.43 (1 OH, m). This free amine was converted to the hydrochloride salt using a solution of HCl in MeOH, mp 178-181 ° C. MS (ES) m / z: 442 (M +), 385, 269, 172, 129, 91. IR (KBr): 3366, 1620 cm "1. Analysis calculated for C29H38N4-2HCl-2H2O: C, 63.15; H, 8.04; N, 10.16. Found: C, 63.31; H, 7.99; N, 9.89.

EXAMPLE 9 2-Morpholino-1-l ~ 1 - (1-phenylcycloheptyl) -4-piperidinip-1 - / - benzoimidazole This was prepared according to the procedure described in Example 2 using morpholine instead of methylamine solution in MeOH. The yield was 44%. ? NMR (270 MHz, CDCl 3) d 7.70-7.58 (1 H, m), 7.56-7.46 (3H, m), 7.40-7.30 (2H, m), 7.25-7.13 (3H, m), 4.16-4.03 (1 H, m), 3.88 (4H, t, J = 4.6 Hz), 3.20 (4H, t, J = 4.6 Hz), 3.06-2.95 (2H, m), 2.47-2.00 (8H, m), 1.90-1.45 (10H, m). This free amine was converted to the HCl salt using HCl solution in MeOH, mp 172-176 ° C. MS (El) m / z: 458 (M +), 402, 373, 181, 124. IR (KBr): 3396, 1612 cm "1. Analysis calculated for C29H38N4O-2HCl-2.1 H2O: C, 63.17; H, 7.71.; N, 10.16, Found: C, 62.80; H, 7.79; N, 9.76.

PREPARED 1? -1-f1 - (1-phenylcycloheptyl) -4-piperidin-1,2-benzenediammine A mixture of 1,4-d-Oxa-8-azaspyrro [4.5] decane HCl salt (this was prepared by mixing 1,4-dioxa-8-azaspiro [4.5] decane (11.41 g, 79,562 mmoles) and solution NH 4N in EtOAc (40 ml), followed by solidification using Et 2 O), cycloheptanone (14.1 ml, 119.5 mmol) and aqueous KCN solution (7.8 g, 119.8 mmol) in water (40 ml), stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated to give 22.11 g of a light yellow oil. To a stirred solution of this crude nitrile derivative (22.11 g) in Et2O (260 ml), 3 M solution in Et2O of phenylmagnesium bromide (133 ml, 397.81 mmol) was added at 0 ° C. Then, the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into aqueous NH 4 Cl solution and extracted with Et 20. The combined extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated to give a yellow oil. A mixture of this oil and 6 N HCl solution was stirred at 60 ° C for 2 hours. The reaction mixture was washed with Et2O. Then, the aqueous layer was basified with 25% NH 4 OH and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated to give a yellow oil. This was purified by column chromatography (80 g of silica gel, EtOAc / n-hexane: 1/7) to give 11.42 g (53%) of the desired ketone derivative as a colorless oil. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.46 (2H, m), 7.35-7.18 (3H, m), 2.74 (4H, t, J = 5.9 Hz), 2.30 (4H, J = 5.9 Hz), 2.11 -2.06 (4H, m), 1.78-1.47 (8H, m), EM m / z: (The direct): 271 (M +). A mixture of the above ketone derivative (11.42 g, 42,078 mmol), NH 2 OH-HCl (3.5 g, 50,494 mmol), NaOAc (5.24 g, 63,117 mmol) and EtOH (150 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with aqueous NaHCOs solution, extracted with EtOAC, washed with water and brine, dried (Na2SO), filtered and concentrated to give 10.41 g of the oxime derivative as a colorless solid. To a stirred solution of this oxime (10.41 g, 36.35 mmol) in THF (300 mL) was added LiAIH (8.3 g, 218.08 mmol) at 0 ° C. After stirring for 10 hours at room temperature, the reaction mixture was quenched with Na 2 SO-10H 2 O and diluted with CH 2 Cl 2. The solid appeared was removed by filtration. The filtrate was concentrated to give 9.94 g (100%) of 4-amino-1- (1-phenycloheptyl) piperidine as a colorless powder. A mixture of 4-amino-1- (1-phenylcycloheptyl) piperidine (446 mg, 1.64 mmol), 2-fluoronitrobenzene (231 mg, 1.64 mmol) and K2CO3 (227 mg, 1. 64 mmole) in MeCN (5 ml) was heated to reflux for 8 hours. After evaporation of the solvent, the residue was diluted with water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a yellow oil, which was purified by column chromatography (30 g of silica gel, hexane / ethyl acetate: 10/1). yielding 557 mg (86%) of a yellow oil. 1 H NMR (270 MHz, CDCl 3) d 8.15 (1 H, dd, J = 1.6, 8.7 Hz), 8.08 (1 H, da, J = 7.1 Hz), 7.48-7.11 (6H, m), 6.81 (1 H , da, J = 8.4 Hz), 6.58 (1 H, ddd, J = 1.3, 6.9, 8.6 Hz), 3.50-3.36 (1 H, m), 2.86-2.76 (2H, m), 2.33-2.22 (2H , m), 2.10-1.90 (6H, m), 1.85-1.68 (2H, m), 1.65-1.40 (8H, m). MS (El) m / z: 393 (M +), 358, 336, 316, 91. A mixture of this oil (827 mg, 2.1 mmol) and SnCl2-2H2O (2.37 g, 10.52 mmol) in EtOH (35 mL) it was heated to reflux for 2.5 hours. After evaporation of the solvent, a saturated solution of NaHCO3 and CH2Cl2 was added to the residue. The yellow solid formed was removed by filtration. The organic layer of the filtrate was separated and washed with brine, dried (Na2SO), filtered and concentrated to give a brown solid, which was purified by column chromatography (40 g of silica gel, CH2Cl2 / MeOH: / 1 to 10/1) to yield 484 mg (63%) of the title compound as a light brown solid. 1 H NMR (270 MHz, CDCl 3) d 7.56-7.42 (2H, m), 7.38-7.15 (3H, m), 6.84-6.58 (4H, m), 3.30-3.08 (1 H, m), 2.90-2.72 ( 2H, m), 2.35-1.90 (9H, m), 1.85-1.65 (2H, m), 1.65-1.25 (1 OH, m).

EXAMPLE 10 1 -H - (1-Phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazole-2-alamine To a solution of BrCN (338 mg, 3.19 mmol) in water (2.9 ml), was added a solution of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] phenylene-1,2-diamine (200 mg, 0.551 mmol) in THF (2.9 ml) at room temperature. After stirring for 18 hours, a 25% solution of NH3 was added to the reaction mixture and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a light brown solid which was purified by preparative TLC (1 mm x 3 plate, CH2Cl2 / MeOH: 10/1, then 0.5 mm x 3 plate, CH2Cl2 / MeOH: 10/1) yielding 77.3 (36%) of a white amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.73-7.07 (11 H, m), 4.62-4.42 (1 H, m), 3.10-2.95 (2 H, m), 2.65-2.40 (4 H, m), 2.30-2.07 (4H, m), 1.90-1.65 (4H, m), 1.65-1.40 (6H, m). This free amine was converted to the HCl salt using HCl solution in MeOH to give an amorphous ivory solid. MS (ESI positive) m / z: 389 (M + H) +. IR (KBr): 3398, 1670 cm "1. Analysis calculated for C25H32N4-2HCI-H2O: C, 62.62; H, 7.57; N, 11. 68. Found: C, 62.66; H, 7.51; N, 11.53.

EXAMPLE 11 2-Methyl-1H - (1-phenylcycloheptyl) -4-piperidin-p-1 / -benzoimidazole A mixture of 1- [1- (phenylcycloheptyl) -4-piperidinyl] -phenylene-1,2-diamine (50 mg, 0.138 mmol) and acetic anhydride (19.6 μl, 0.207 mmol) in xylene (1.5 ml) ) was heated to reflux for 60 hours. After cooling to room temperature, the mixture was basified with 25% NH3 solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated to give a light brown oil, which was purified by preparative TLC (0.5 mm x 3 plate, n-hexane / ethyl acetate: 2/1, revealed 3 times, then 0.5 mm x 2 plate, CH2CI / MeOH: 10/1) producing 18.1 mg (34%) of a light brown amorphous solid. ? NMR (270 MHz, CDCl 3) d 7.60-7.62 (1 H, m), 7.58-7.48 (3H, m), 7.39-7.30 (2H, m), 7.27-7.17 (3H, m), 4.16-3.98 (1 H, m), 3.10-2.98 (2H, m), 2.59 (3H, s), 2.45-2.00 (8H, m), 1.85-1.70 (4H, m), 1.65-1.43 (6H, m). MS (El) m / z: 387 (M +), 330, 215, 172, 129, 91. This free amine was converted to the HCl salt using HCl solution in MeOH to give a light brown amorphous solid. IR (KBr): 3369 cm "1.

EXAMPLE 12 1 -H -f 1 -FenylcycloheptiD-4-piperidinip-1 H-benzoimidazole A mixture of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -phenylene-1,2-diamine (60 mg, 0.165 mmol) and formamidine acetate (35.6 mg, 0.342 mmol) in ethoxyethanol (0.3 ml) it was heated to reflux for 1 hour. After cooling to room temperature, the mixture was basified with 25% NH 3 solution and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a light brown oil, which was purified by preparative TLC (1 mm x 3 plate, CH2Cl2 / MeOH: 10/1 after plate). 0.5 mm x 2, n-hexane / ethyl acetate: 2/1, developed twice) yielding 29.8 mg (48%) of a light brown amorphous solid. H NMR (270 MHz, CDCl 3) d 7.97 (1 H, s), 7.82-7.76 (1 H, m), 7.51-7.45 (2H, m), 7.42-7.19 (6H, m), 4.15-4.01 (1 H, m), 3.06-2.96 (2H, m), 2.37-2.25 (2H, m), 2.17-1.85 (8H, m), 1.85-1.70 (2H, m), 1.65-1.43 (6H, m). MS m / z (El): 373 (M +), 316, 296, 201, 172, 91. This free amine was converted to the HCl salt using HCl solution in MeOH to give a yellow amorphous solid. IR (KBr): 3400 cm "1. Analysis calculated for C25H31N3-HCI-2.5H2O: C, 65.99; H, 8.20; N, 9.23, Found: C, 66.28; H, 8.20; N, 9.22.

EXAMPLE 13 2-lsopropyl-1-ri- (1-phenolcycloheptyl) -4-piperidin-1-benzoimidazole This was prepared according to the procedure described in example 11 using isobutyric anhydride in place of acetic anhydride. The yield was 69%. 1 H NMR (270 MHz, CDCl 3) d 7.76-7.70 (1 H, m), 7.62-7.49 (3H, m), 7.39-7.31 (2H, m), 7.25-7.15 (3H, m), 4.20-4.05 ( 1 H, m), 3.18 (1 H, qq, J = 6.8, 6.9 Hz), 3.09-2.99 (2H, m), 2.53-2.36 (2H, m), 2.32-2.18 (2Hm), 2.16-2.03 (4H m), 1.85-1.45 (10H, m), 1.41 (6H, d, J = 6.8 Hz). MS m / z (El): 415 (M +), 372 (M + -CH (CH 3) 2), 358, 243, 172. This free amine was converted to the HCl salt using HCl solution in MeOH to give an amorphous solid light brown. IR (KBr): 3422 cm'1. Analysis calculated for C28H39N3-2HCI-0.5H2O: C, 67.59; H, 8.10; N, 8.45. Found: C, 67.39; H, 8.30; N, 8.18.

EXAMPLE 14 2-FeniM-F1 - (1-phenylcycloheptyl) -4-piperidin-1 H-benzoimidazole This was prepared according to the procedure described in example 11 using benzoic anhydride in place of acetic anhydride. The yield was 63%. 1 H NMR (270 MHz, CDCl 3) d 7.84-7.77 (1 H, m), 7.75-7.68 (1H, m), 7.64-7.56 (2H, m), 7.54-7.47 (5H, m), 7.38-7.18 ( 5H, m), 4.35-4.19 (1H, m), 3.04-2.90 (2H, m), 2.58-2.40 (2H, m), 2.18-1.98 (6H, m), 1.83-1.66 (4H, m) , 1.64-1.40 (6H, m). MS m / z (El): 449 (M +), 392, 372, 364, 277, 194, 172. This free amine was converted to the HCl salt using HCl solution in MeOH to give a light brown amorphous solid. IR (KBr): 3400 cm "1. Analysis calculated for C3? H35N3-2HCI 0.5H2O: C, 70.05; H, 7.21; N, 7.90. Found: C, 70.45; H, 7.51; N, 7.80.

EXAMPLE 15 2-Benzyl -H - (1-phenylcycloheptyl) -4-piperidin-1 / -benzoimidazole A mixture of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -phenylene-1,2-diamine (50 mg, 0.138 mmol) and phenylacetyl chloride (21.9 μl, 0.165 mmol) in xylene (1.5 ml) was heated to reflux for 15 hours. After cooling to room temperature, the mixture was basified with 25% NH3 solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated to give an oil which was purified by preparative TLC (1 mm x 3 plate, n-hexane / ethyl acetate: 2/1) yielding 62.2 mg (94%) of a white solid in the form of the amide derivative. 1 H NMR (270 MHz, DMSO-d 6) d 9.34 (1 H, s), 7.46-7.15 (10 H, m), 7.12-7.06 (1 H, m), 7.02-6.93 (1 H, m), 6.68- 6.48 (2H, m), 4.33 (1 H, da, J = 7.6 Hz), 3.64 (2H, s), 3.22-3.05 (1 H, m), 2.77-2.60 (2H, m), 2.20-1.10 ( 18H, m). MS (El) m / z: 481 (M +), 424, 390, 308, 279, 218, 172, 91. This amide (62.2 mg, 0.129 mmol) was heated to reflux in xylene (2 mL) for 38 hours. After cooling to room temperature, the mixture was purified by preparative TLC (1 mm x 3 plate)., CH2Cl2 / MeOH: 10/1) yielding 15.4 mg (26%) of a light brown solid. ? NMR (270 MHz, CDCl 3) d 7.80-7.72 (1 H, m), 7.60-7.43 (3H, m), 7.39-7.14 (10H, m), 4.31 (2H, s), 4.08-3.92 (1H, m), 2.92-2.78 (2H, m), 2.40-1.93 (8H, m), 1.80-1.25 (10H, m). MS m / z (El): 463 (M +), 406, 372, 291, 207, 172. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a light brown amorphous solid. IR (KBr): 3356 cm'1.

Analysis calculated for C 32 H 37 N 3 -2 HCl-2.5H 2 O: C, 66.08; H, 7.63; N, 7.22. Found: C, 66.08; H, 7.30; N, 6.93.

EXAMPLE 16 2-Cyclohexyl-1 -H - (1-phenylcycloheptyl) -4-piperidinium-1 H-benzoimidazole This was prepared according to the procedure described in Example 15 using cyclohexanecarbonyl chloride in place of phenylacetyl chloride, and phosphoryl chloride in place of xylene. The yield was 53.9% in two stages. ? NMR (270 MHz, CDCl 3) d 7.76-7.69 (1 H, m), 7.62-7.50 (3H, m), 7.40-7.32 (2H, m), 7.30-7.15 (3H, m), 4.18-4.02 (1 H, m), 3.10-2.98 (2H, m), 2.88-2.72 (1 H, m), 2.53-1.25 (28H, m). MS m / z (The direct): 455 (M +), 398, 370, 283, 201, 172, 91. This free amine was converted to the HCl salt using HCl solution in MeOH to give a brown amorphous solid. IR (KBr): 3414 cm "1. Analysis calculated for C31H41N3-2HCI-H2O: C, 68.12; H, 8.30; N, 7.69, Found: C, 68.29; H, 8.33; N, 7.45.

EXAMPLE 17 1-ri- (1-Phenyl-cycloheptyl) -4-piperidin-p-2-piperidino-1H-benzoimidazole This was prepared according to the procedure described in Example 2 using piperidine instead of methylamine in MeOH. The yield was 81%. H NMR (270 MHz, CDCl 3) d 7.64-7.44 (4H, m), 7.40-7.30 (2H, m), 7.25-7.10 (3H, m), 4.17-4.00 (1 H, m), 3.20-3.10 ( 4H, m), 3.05-2.95 (2H, m), 2.45-2.02 (8H, m), 1.90-1.45 (15H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 177-180 ° C. MS (El) m / z: 456 (M +), 399, 372, 283, 255, 202, 91. IR (KBr): 3383, 1612 cm "1. Analysis calculated for C3oH40N -2HCM .1 H2O: C, 65.58; H, 8.11; N, 10.20. Found: C, 65.23; H, 8.12; N, 9.89.

EXAMPLE 18 2- (4-Benzyl-prosperazino) -1 -H - (1-phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazole This was prepared according to the procedure described in example 2 using 4-benzylpiperazine instead of methylamine in MeOH. The yield was 68%. 1 H NMR (270 MHz, CDCl 3) d 7.64-7.44 (4H, m), 7.40-7.10 (10H, m), 4.13-4.00 (1 H, m), 3.60 (2H, s), 3.30-3.18 (4H, m), 3.05-2.95 (2H, m), 2.70-2.60 (4H, m), 2.45-2.00 (8H, m), 1.90-1.45 (1 OH, m). This free amine was converted to the HCl salt using HCl solution in MeOH, mp 139-143 ° C. MS (El) m / z: 374 (M + -benzylpiperazinyl), 293, 254, 172, 129, 91. IR (KBr): 3387, 1611 cm "1. Analysis calculated for C36H 5N5-3HCM .6H2O: C, 63.03; H, 7.52; N, 10.21. Found: C, 62.74; H, 7.62; N, 10.00 EXAMPLE 19 1 -H - (1-Phenylcycloheptyl) -4-piperidinip-2-piperazin-1 H-benzoimidazole A mixture of 2- (4-benzyl-1-piperazinyl) -1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -benzoimidazole (Example 18, 42.5 mg, 0.07 mmol), palladium black (12 mg), HCl solution in MeOH (0.2 M, 1.5 ml) and MeOH (8.5 ml), was stirred under hydrogen atmosphere at room temperature for 22.5 hours. The mixture was basified with saturated NaHCO3 solution and the catalyst was removed by filtration. The filtrate was extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (0.5 mm x 1 plate, CH 2 Cl 2 / MeOH / NH 4 OH: 90/10/1) to give 29 mg (81.7%) of an amorphous solid. ? NMR (270 MHz, CDCl 3) d 7.65-7.58 (1 H, m), 7.54-7.48 (3H, m), 7.38-7.32 (2H, m), 7.24-7.12 (3H, m), 4.16-4.04 (1 H, m), 3.25-3.13 (4H, m), 3.13-2.95 (6H, m), 2.48-2.03 (4H, m), 1.90-1.40 (10H, m). This free amine was converted to the HCl salt, mp 159-163 ° C. MS m / z (El): 457 (M +), 401, 284, 254, 204, 173, 146, 82. IR (KBr): 3348, 1591 cm "1 Analysis Calculated for C29H39N5-3HCI-3H2O: C, 56.08; H 7.79; N, 11.28, Found: C, 56.07; H, 7.71; N, 10.92.

EXAMPLE 20 N-Pentyl-1H - (1-phenylcycloclopentyl) -4-piperidinin-1-t-benzoimidazole-2-amino This was prepared according to the procedure described in Example 2 using n-amylamine instead of methylamine in MeOH. The yield was 37.3%. ? NMR (270 MHz, CDCl 3) d 7.55-7.43 (3H, m), 7.40-7.30 (2H, m), 7.28-7.18 (2H, m), 7.11-6.96 (2H, m), 4.13-4.00 (1H , m), 3.85-3.70 (1 H, m), 3.60-3.45 (2H, m), 3.10-2.93 (2H, m), 2.35-2.00 (8H, m), 1.90-12.0 (16H, m), 1.00-0.85 (3H, m). This free amine was converted to the HCl salt, mp 156-159 ° C. MS m / z (El): 458 (M +), 401, 286, 204, 172, 129, 91. IR (KBr): 3400, 1655 cm "1 Analysis Calculated for C30H42N4-2HCI-H2O: C, 65.56; H 8.44; N, . 19. Found: C, 65.25; H, 8.35; N, 10.21.

EXAMPLE 21 N-Cyclohexyl-1H - (1-phenylcycloheptyl) -4-piperidin-1 H-benzoimidazol-2-amine This was prepared according to the procedure described in Example 2 using cyclohexylamine instead of methylamine in MeOH. The yield was 23%. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.43 (3H, m), 7.40-7.30 (2H, m), 7.30-7.20 (2H, m), 7.10-6.96 (2H, m), 4.05-3.87 (2H , m), 3.85-3.67 (1 H, m), 3.10-2.95 (2H, m), 2.40-2.00 (8H, m), 1.90-1.10 (20H, m). This free amine was converted to the HCl salt using a solution in HCl in MeOH. MS m / z (El): 470 (M +), 413, 298, 216, 173, 134, 91.

EXAMPLE 22 N-allyl-1-ri- (1-phenylcycloheptyl) -4-piperidinin-1-benzoimidazole-2-amine This was prepared according to the procedure described in Example 2 using allylamine instead of methylamine in MeOH. The yield was 15%. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.43 (3H, m), 7.40-7.20 (4H, m), 7.13-6.98 (2H, m), 6.15-6.00 (1 H, m), 5.29 (1 H , dd, J = 1.1, 17 Hz), 5.20 (1 H, da, J = 10.3 Hz), 4.25-4.10 (3H, m), 3.87-3.72 (1 H, m), 3.10-2.95 (2H, m ), 2.38-1.95 (8H, m), 1.90-1.43 (10H, m). This free amine was converted to the HCl salt using a solution in HCl in MeOH. MS m / z (El): 428 (M +), 371, 351, 343, 256, 200, 173, 144, 118, 82.

EXAMPLE 23 1- (1-ri- (4-Fluorophenyl) cycloheptyp-4-piperidinyl > -2- (4-N-methylpperazino) -1H-benzoimidazole This was prepared according to the procedure described in Examples 1 and 4 using 4-fluorophenylmagnesium bromide in place of phenylmagnesium bromide. The total yield was 27.2%. 1 H NMR (270 MHz, CDCl 3) d 7.64-7.59 (1 H, m), 7.52-7.44 (3 H, m), 7.19-7.12 (2 H, m), 7.02 (2 H, dd, J = 8.7, 8.7 Hz) , 4.13-3.98 (1 H, m), 3.28-3.22 (4H, m), 3.04-2.93 (2H, m), 2.66-2.58 (4H, m), 2.38 (3H, s), 2.40-2.00 (8H , m), 1.85-1.40 (10H, m). This free amine was converted to the HCl salt using HCl solution in MeOH. MS m / z (El): 490 (M +), 404, 299, 272, 218, 191, 160, 134, 109, 84. IR (KBr): 3368, 1609 cm "1 PREPARATION 2 1- (Phenylcyclooctyl) piperidine -4-one This was prepared according to the procedure of B. de Costa et al. (J. Chem. Soc. Perkin Trans 1, 1992, 1671-1680) using 1-phenylcyclooctylamine (RL McQuinn et al., J. Med. Chem., 1981, 24, 1429-1432) instead of 1- (2 -benzo [b] thienyl) cyclohexylamine. The total yield was 39%. 1 H NMR (270 MHz, CDCl 3) d 7.46-7.40 (2H, m), 7.35-7.18 (3H, m), 2.74 (4H, ta, J = 6.0 Hz), 2.32 (4H, ta, J = 6.0 Hz) , 2.27-2.05 (4H, m), 1.80-1.30 (1 OH, m).

PREPARATION 3 N- (2-nitrofeniD -? / - p - (1-phenylcyclononyl) -4-p -peridininamine This was prepared according to the procedure of B. de Costa et al. (J. Chem. Soc. Perkin Trans 1, 1992, 1671-1680) using 1- (1-phenylcyclooctyl) p -peridin-4-one instead of 1- [1- (2-benzo [b] thienyl) cyclohexyl ] -piperidin-4-one and the procedure of NA Meanwell et al. (Bioorg, Med. Chem. Lett., 1996, 6, 1641). The total yield was a yield of 76%. 1 H NMR (270 MHz, CDCl 3) d 8.14 (1 H, dd, J = 1.6, 8.6 Hz), 8.05 (1 H, da, J = 7.3 Hz), 7.44-7.38 (2H, m), 7.38-7.28 ( 3H, m), 7.26-7.18 (1 H, m), 6.78 (1 H, gives J = 8.7 Hz), 6.61-6.53 (1H, m), 3.46-3.30 (1H, m), 2.96 (2H, da , J = 12.2 Hz), 2.30-1.90 (8H, m), 1.70-1.25 (12H, m). MS (El) m / z: 407 (M +), 3.72, 336, 306, 286.

PREPARATION 4 1 -H - (1-Phenylcyclooctyl) -4-piperidinin-1,3-d-hydro-2,3-benzoimidazole-2-one A mixture of? / - (2-nitrophenyl) -? / - [1- (1-phenylcyclooctyl) -4-piperidinyljamine (140 mg, 0.344 mmol), Raney Ni (300 mg) in EtOH (2 ml) and THF (4 ml) was stirred under a hydrogen atmosphere at room temperature for 3 days. After removing the catalyst by filtration, the filtrate was concentrated to give 133 mg of an oil which was dissolved in THF (3 ml). To this solution was added 1, 1'-carbonyldiimidazole (67 mg, 0.413 mmol) and the resulting mixture was stirred at room temperature for 3 days.

Then, the reaction mixture was diluted with saturated NaHCO3 solution and extracted with CH2Cl2. The combined extracts were washed with water and brine, dried (Na2SO), filtered and concentrated. The residue was purified by column chromatography (40 g of silica gel, CH 2 Cl 2 / MeOH: 25/1) to give 74 mg of a light brown powder. The total yield was 53%. 1 H NMR (270 MHz, CDCl 3) d 7.50-7.20 (7H, m), 7.15-7.00 (3H, m), 4.23-4.08 (1 H, m), 3.20-3.10 (2H, m), 2.40-2.00 ( 8H, m), 2.00-1.30 (12H, m). MS m / z (The direct): 403 (M +), 332, 304. 268, 216, 184, 82.

EXAMPLE 24 2- (4-Methylpiperazino) -1-ri- (1-phenylcyclooctyl) -4-piperidinin-1H-benzoimidazole This was prepared according to the procedure described in examples 1 and 4 using 1- [1- (1-phenylcylocloctyl) -4-piperidinyl] -1,3-dihydro-2 - / - 1, 3- benzoimidazol-2-one as starting material. The total yield was 7.8%. ? NMR (270 MHz, CDCl 3) d 7.63-7.59 (1 H, m), 7.54-7.44 (3 H, m), 7.40-7.33 (2 H, m), 7.28-7.21 (1 H, m), 7.19-7.12 ( 2H, m), 4.10-3.94 (1 H, m), 3.28-3.15 (6H, m), 2.64-2.55 (4H, m), 2.50-1.96 (11H, m, including 3H, s, at 2.36 ppm) , 1.85-1.34 (12H, m). This free amine was converted to the HCl salt using HCl solution in MeOH. MS m / z (El): 486 (M +), 415, 400, 299, 268, 217, 184, 160, 134.

EXAMPLE 25 1 -H -d-Phenylhexylcycloheptyl) -4-piperidinin-2- (4-piperidinii) -1 / -benzoimidazole A mixture of 1- [1- (1-phenolcycloheptyl) -4-piperidinyl] -phenylene-1,2-diamine (100 mg, 0.275 mmol), 1-benzylpiperidine-4-carboxylic acid (500 mg, 0.5 mmole, this acid was prepared from 4-piperidinecarboxylic acid according to the procedure of FI Carrol et al., J. Org. Chem., 1996, 31, 2957), and N-ethyl-N'- hydrochloride. 3-dimethylaminopropylcarbodiimide (106 mg, 0.551 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (15 g of silica gel, CH 2 Cl 2 / MeOH: 30/1, 1% NH 4 OH) to give 125 mg (80%) of a light brown amorphous solid in the form of a derivative. of amide. MS (El): m / z: 564 (M +), 507, 473, 362, 310. A mixture of the above amide derivative (125 mg, 0.222 mmol) and phosphoryl chloride (3 ml) was stirred at 100 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into NH 4 OH solution and extracted with CH 2 Cl 2. The combined extract was washed with brine, dried (Na2SO), filtered and concentrated to give a brown oil which was purified by preparative TLC (1 mm x 3 plate, CH CI2 / MeOH: 10/1) to give 68.2 mg (56%) of a light brown wax.

MS m / z (El): 546 (M +), 455, 400, 373, 292, 240, 173, 91. 1 H NMR (270 MHz, CDCl 3) d 7.80-7.15 (14H, m), 4.20-4.00 (1 H, m), 3.60 (2H, sa), 3.20-3.00 (4H, m), 2.95-2.75 (1 H, m), 3.14 (3H, d, J = 4.8 Hz), 2.55-1.45 (24H, m ). A mixture of the above wax (68.2 mg, 0.125 mmol), palladium black (26 mg) and 0.2 M HCl solution in MeOH (0.81 ml) in MeOH (4.5 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hours. After adding 30 mg of palladium black to the mixture and stirring was continued for 20 hours. Then 20 g of palladium black was added to the mixture and the stirring was continued for 14 hours. After removal of the catalyst by filtration with Celite, the filtrate was basified with NH 4 OH and concentrated in vacuo. The residue was purified by preparative TLC (0.5 mm x 4 plate, CH 2 Cl 2 / EtOH: 5/1, 1% NH 4 OH) to give 34 mg (60%) of a pale yellow amorphous solid. MS m / z (El): 456 (M +), 439, 400, 348, 286, 202, 172, 145, 91. 1 H NMR (270 MHz, CDCl 3) d 7.76-7.70 (1H, m), 7.66-7.58 (1H, m), 7.56-7.50 (2H, m), 7.40-7.32 (2H, m), 7.27-7.18 (3H, m), 4.18-4.02 (1H, m), 3.30-3.21 (2H, m ), 3.10-2.90 (3H, m), 2.87-2.75 (2H, m), 2.53-1.67 (17H, m), 1.68-1.45 (6H, m). This free amine was converted to the HCl salt by treatment with a solution of HCl in MeOH. Evaporation of the solvent produced a yellow amorphous solid. IR (KBr): 3400 cm'1 Analysis Calculated for C3oH4oN4-3HCI-5H2O: C, 60.76; H, 7.82; N, 9.45. Found: C, 61.13; H, 8.18; N, 9.33.

EXAMPLE 26 N-methyl-1 -H -f 1 -phenylcyclohexyl) -4-piperidinip-1 H-benzoimidazole-2 -amine This was prepared according to the procedure described in Examples 1 and 2 using cyclohexanone instead of cycloheptanone. The performance of the two stages was 38%. 1 H NMR (270 MHz, CDCl 3) d 7.49-7.18 (7H, m), 7.10-6.95 (2H, m), 4.36-4.18 (1 H, m), 3.08 (3H, d, J = 4.3 Hz), 2.50 -2.00 (6H, m), 1.83-1.60 (6H, m), 1.56-1.20 (4H, m). This free amine was converted to the hydrochloride salt using a solution of HCl in MeOH to give a light yellow amorphous solid. IR (KBr): 3400, 1660 cm "1 Calculated Analysis for C25H32N -2HCI-0.7H2O: C, 63.34; H, 7.53; N, 11.82. Found: C, 63.19; H, 7.77; N, 11.87.

EXAMPLE 27 N-. { 1-f1 - (1-phenylcycloheptyl) -4-piperidinip-1 H-benzoimidazol-2-yl > -1, 2- ethanediamine A mixture of 2-chloro-1- [1- (1-phenylcycloheptyl) -4-piperidinyl-benzoimidazole (Example 1, 202 mg, 0.496 mmol) and t-butyl N- (2-aminoethyl) carbamate (1 mL, 6.34 mmol. ) was stirred at 120 ° C for 16 hours and 140 ° C for 3 h. After cooling to room temperature, water was added to the mixture and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The resulting residue was purified by column chromatography (50 g of silica gel; CH 2 Cl 2 / MeOH: 40/1 to 20/1) to give 194 mg (73.6%) of a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.53-7.41 (2H, m), 7.37-7.19 (5H, m), 7.10-6.97 (2H, m), 5.72-5.61 (1 H, m), 3.86-3.72 ( 1 H, m), 3.62-3.60 (2H, m), 3.49-3.41 (2H, m), 3.00-2.96 (2H, m), 2.35-2.16 (4H, m), 2.11-2.04 (4H, m) , 1.76-1.71 (5H, m), 1.54-1.47 (5H, m), 1.42 (9H, s). MS (El) m / z: 531 (M +). A solution of the above Boc derivative (95.3 mg, 0.179 mmol) in a solution of HCl in MeOH (2 mL) was stirred at room temperature for 16 hours. After evaporation of the solvent, the residue was basified with saturated NaHCO 3 solution, extracted with CH 2 Cl 2, dried (Na 2 SO 4), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 1 plate, CH 2 Cl 2 / MeOH / NH 4 OH: 100/10/1) to give 38 mg (49.1%) of a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.50-7.46 (2H, m), 7.41-7.17 (6H, m), 7.07-6.97 (2H, m), 3.98-3.86 (1 H, m), 3.61-3.56 ( 2H, m), 3.11-3.06 (2H, m), 2.96-2.92 (2H, m), 2.33-2.13 (4H, m), 2.10-2.04 (4H, m), 1.73-1.68 (5H, m), 1.52-1.44 (5H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 228-232 ° C. IR (KBr): 2930, 2860, 1650, 1480 cm "1 Analysis Calculated for C27H37N5-3HCM.5MeOH: C, 58.11; H, 7.87; N, 11.89. Found: C, 57.97; H, 7.68; N, 11.49.

EXAMPLE 28 N-methyl-1 -H -d -methylcyclononyl) -4-piperidinin-1-benzoimidazole-2-amino This was prepared according to the procedure described in Examples 1 and 2 using cyclononanone in place of cycloheptanone and methylmagnesium bromide in place of phenylmagnesium bromide. The total yield was 22.9%. NMR (270 MHz, CDCl 3) d 7.50 (1 H, da, J = 7.9 Hz), 7.35-7.15 (1 H, m), 7.13-6.98 (2H, m), 4.40-4.20 (1 H, m), 3.95-3.70 (1 H, m), 3.3O-3.00 (2H, m), 3.15 (3H, d, J = 4.5 Hz), 2.45-2.10 (4H, m), 2.00-1.30 (18H, m), 0.85 (3H, sa). This free amine was converted to the HCi salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 368 (M +), 354, 338, 283, 222, 147, 82. IR (KBr): 3406, 1661 cm "1 Analysis Calculated for C23H36N4-2 HC. 8H20: C, 58.29; H, 8.85; N, 11.82, Found: C, 58.58; H, 9.00; N, 11.83.

EXAMPLE 29 1-ri- (1-Ethylcyclononyl) -4-piperidinyl) - / V-methyl-1 H-benzoimidazole-2 -amine This was prepared according to the procedure described in Examples 1 and 2 using cyclononanone instead of cycloheptanone and ethylmagnesium bromide in place of phenylmagnesium bromide. The total yield was 17.3%. 1 H NMR (270 MHz, CDCl 3) d 7.50 (1 H, da, J = 7.8 Hz), 7.35-7.25 (1 H, m), 7.14-6.98 (2H, m), 4.42-4.30 (1 H, m) , 3.94-3.80 (1 H, m), 3.35-3.16 (2H, m), 3.15 (3H, d, J = 4.1 Hz), 2.50-2.15 (4H, m), 2.00-1.30 (20H, m), 0.86 (3H, ta). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid.

MS (El) m / z: 382 (M +), 353, 338, 297, 206. IR (KBr): 3416, 1661 cm "1 EXAMPLE 30 1 -H - (1-Phenylcyclononyl) -4-piperidinin-1-f-benzoimidazole-2-amino This was prepared according to the procedure described in Preparations 1, 2, 3 and Example 10 using 1-phenylcyclononylamine as starting material, which was presented by RL McQuinn et al., J. Med. Chem., 1981, 24 , 1429-1432. The total yield was 22.3%. 1 H NMR (270 MHz, CDCl 3) d 7.50-7.20 (7H, m), 7.13-7.01 (2H, m), 3.92-3.74 (1 H, m), 3.30-3.18 (2H, m), 2.40-2.20 ( 2H, m), 2.18-1.93 (6H, m), 1.84-1.73 (2H, m), 1.70-1.24 (12H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 416 (M +), 331, 303, 216, 134, 91. IR (KBr): 3350, 1668 cm "1 Analysis Calculated for C27H36N4-2 HCM .7H2O: C, 62.35; H, 8.02; N, 10.77, Found: C, 62.53; H, 7.94; N, 10.46.

PREPARATION 5 1- (4-Fluorophenyl) cyclononylamine This was prepared according to the procedure of R. L. McQuinn et al., J. Med. Chem., 1981, 24, 1429-1432) using 4-fluorophenylmagnesium bromide in place of phenylmagnesium bromide. The total yield was 28%. ? NMR (270 MHz, CDCl 3) d 7.54-7.46 (2H, m), 7.05-6.95 (2H, m), 2.10-1.72 (4H, m), 1.70-1.35 (14H, m).

EXAMPLE 31 1 -f 1 -H - (4-Fluorophenyl) cyclononip-4-piperidinyl) -1 H -benzoimidazole-2 -amine This was prepared according to the procedure described in Example 30 using 1- (4-fluorophenyl) cyclononol amine as the starting material. The total yield was 29.7%. 1 H NMR (270 MHz, CDCl 3) d 7.48-7.26 (4H, m), 7.15-6.98 (4H, m), 3.92-3.77 (1 H, m), 3.28-3.15 (2H, m), 2.37-2.20 ( 2H, m), 2.18-1.92 (6H, m), 1.86-1.75 (2H, m), 1.66-1.24 (12H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 434 (M +), 348, 321, 216, 134, 109, 82. IR (KBr): 3350, 1670 cm "1 Analysis calculated for C27H35FN4-2HC, 7H2O: C, 60.26; H , 7. 57; N, 10.41. Found C, 60.29; H, 7.62; N, 1019.

EXAMPLE 32? H "1 -H -f 1 -Fenylcycloheptyl) -4-piperidinip-1 • -benzoimidazole-2-ylacetamide A mixture of 2-amino-1- [1- (1-phenylcycloheptyl) -4-piperidinyl-benzoimidazole (Example 10, 85.4 mg, 0.22 mmol) and acetyl chloride (17.2 μ \ 0.242 mmol) in pyridine (1 mL) was stirred at room temperature for 144 h. After evaporation of the solvent, the residue was purified by preparative TLC (1 mm x 2 plate, CH 2 Cl 2 / MeOH: 40/1) to give 20 mg (21%) of a light brown amorphous solid. ? NMR (270 MHz, CDCl 3) d 7.56-7.48 (3H, m), 7.38-7.14 (6H, m), 4.80-4.62 (1 H, m), 3.06-2.90 (2H, m), 2.40-2.25 (4H , m), 2.23 (3H, s), 2.20-2.00 (4H, m), 1.90-1.45 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a light brown amorphous solid. IR (KBr): 3400, 1728 cm "1 Analysis calculated for C27H35N4O-2HCI-3,9H2O: C, 60.56; H, 8. 02; N, 10.46. Found: C, 60.27; H, 7.62; N, 10.48.

EXAMPLE 33? HS-1-H- (1-Fexycycloheptyl) -4-piperidinyl-1-tf-benzoimidazol-2-yl > amino) eth guanidine A mixture of 2-aminoethylamino-1- [1- (1-phenylcycloheptyl) -4-piperidinyl-benzoimidazole (example 27, 85.6 mg, 0.199 mmole) and N, N'-bis Boc guanylpyrazole (117 mg, 0.377 mmole, this was prepared according to the following presented processing: MS Bematowicz, et al., Tetrahedron Lett., 1993, 34, 3389-3392) in THF (3 ml), was stirred at room temperature for 16 h. Water was added to the reaction mixture and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (30 g of silica gel: hexane / acetone: 4/1 to 3/1) to give 95.5 mg (71.4%) of a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 11.46 (1 H, sa), 8.70 (1 H, sa), 7.51-7.45 (2H, m), 7.37-7.19 (5H, m), 7.11-6.99 (2H, m ), 4.71-4.58 (1 H, m), 3.78-3.74 (4H, m), 3.02-2.98 (2H, m), 2.30-2.09 (8H, m), 1.78-1.74 (5H, m), 1.42-1.51 (24H, m). A solution of the above Boc derivative (95.5 mg, 0.144 mmol) in trifluoroacetic acid (1 ml) and CH2Cl2 (1 ml) was stirred at room temperature for 2 h. After evaporation of the solvent, a solution of HCl in MeOH (3 ml) was added to the residue and the resulting mixture was stirred at room temperature for 17 h. After evaporation of the solvent, the residue was solidified by rubbing in ether to give 60 mg (71.4%) of a solid, mp 215-218 ° C. 1 H NMR (270 MHz, DMSO-d 6) d 13.56 (1 H, sa), 10.83 (1 H, sa), 9.24 (1 H, sa), 8.20 (1 H, sa), 7.91 (1 H, sa) , 7.80-7.65 (2H, m), 7.50-7.00 (10H, m), 5.05-4.85 (1H, m), 3.60-2.60 (10H, m), 2.00-1.00 (14H, m). MS (ESI, positive) m / z: 471 (M + H) +. IR (KBr): 3329, 1660 cm "+. Analysis calculated for C28H39N7-3HCI H20: C, 51.34; H, 7.69; N, 14.97. Found: C, 51.58; H, 7.69; N, 15.07.

EXAMPLE 34? H1 -H - (1-Phenylcyclohepti0-4-piperidinip-1 H-benzoimidazol-2-yl) - / V- (4- piperidiniPamine) To a stirred solution of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl) phenylene-1,2-d-amines (253 mg, 0.697 mmol) in EtOH (4 mL) was added a solution of Ethyl 4-isothiocyanato-1-piperidinecarboxylate (478 mg, 2.23 mmole, this was prepared according to the procedure of F. Janssens et al., J. Med. Chem., 1985, 28, 1925-1933) in EtOH (3 ml) and the reaction mixture was stirred at 70 ° C for 2.5 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (100 g of silica gel, hexane / ether: 3/7 to ether alone) to yield 338 mg (84%) of thiourea derivative as a colorless amorphous solid. A solution of the above thiourea derivative (321 mg, 0.556 mmol) and iodomethane (0.346 ml) in EtOH (5 ml) was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, basified with 25% NH 4 OH solution and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated to give a colorless amorphous solid. A mixture of this solid, 2 M KOH (2 ml) and THF (4 ml) was stirred at room temperature for 10 h. The mixture was poured into water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (40 g of silica gel: hexane / acetone: 7/3) to give 156 mg (51.6%) of carbamate derivative as a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.51-7.44 (3H, m), 7.38-7.20 (4H, m), 7.12-6.99 (2H, m), 4.19-4.07 (4H, m), 3.96-3.93 (1 H, m), 3.79-3.69 (1 H, m), 3.09-2.99 (4H, m), 2.32-2.04 (10H, m), 1.80-1.71 (5H, m), 1.55-1.36 (5H, m), 1.31-1.21 (3H, m). A solution of the above carbamate derivative (120 mg, 0.22 mmol) in a 25% solution of HBr in AcOH (2 mL) was stirred at 70 ° C for 14 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by column chromatography (120 g of silica gel: CH 2 Cl 2 / MeOH / NH 4 OH: 100/10/1) to yield 81.2 mg of the desired product as a colorless solid, but still included some impurities. Purification using preparative TLC was not satisfactory. This free amine was converted to the Boc derivative and purified, and then deprotected to give the desired product as indicated below. To a solution of the above amine with impurities (43.7 mg, 0.0928 mmol) in CH2Cl2 (1 mL), a solution of di-t-butyl dicarbonate (24.3 mg, 0.111 mmol) in CH2Cl2 (0.5 mL) was added and the The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was basified with saturated NaHCO3 solution and CH2Cl2 was extracted. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (0.5 mm x 2 plate, CH 2 Cl 2 / MeOH: 9/1) to give 40.4 mg (76.3%) of a colorless amorphous solid. ? NMR (270 MHz, CDCl 3) d 7.51-7.44 (3H, m), 7.38-7.20 (4H, m), 7.11-6.99 (2H, m), 4.17-3.93 (4H, m), 3.80-3.68 (1H, m), 3.04-2.94 (4H, m), 2.28-2.10 (10H, m), 1.78-1.73 (5H, m), 1.48-1.34 (14H, m).

A mixture of the above Boc derivative (40.4 mg, 0.0708 mmol) and HCl solution in MeOH (2 ml) was stirred at room temperature for 17 h. Evaporation of the solvent gave 25 mg of HCl salt of the desired product, mp 231-235 ° C 1 H NMR (270 MHz, CDCl 3) d 10.79 (1 H, sa), 9.25-8.75 (2H, m), 8.21 (1 H , sa), 7.80-7.70 (2H, m), 7.50-7.30 (4H, m), 7.25-7.05 (3H, m), 5.05-4.85 (1H, m), 4.00-3.85 (1H, m) , 3.55-3.20 (4H, m), 3.15-2.60 (8H, m), 2.50-2.30 (2H, m), 2.10-1.70 (9H, m), 1.55-1.05 (6H, m). MS (ESI positive) m / z: 472 (M + H). IR (KBr): 3389, 1645 cm "1 Analysis calculated for C30H4? N5-3HCI-3H2O: C, 57.36; H, 8.07; N, 10.79. Found: C, 57.35; H, 8.30; N, 10.88.

EXAMPLE 35? -Methyl-? T-f-1 -M - (1-FTN-cycloheptyl) -4-piperidinin-1 Af-benzoimidazol-2-yl) - 1,2-ethanediamine This was prepared according to the procedure described in Example 1 and Example 3, using? / -methylethylene diamine (140 ° C, 4.5 h) in place of aniline. The yield was 31%. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.42 (3H, m), 7.37-7.18 (4H, m), 7.11-6.96 (2H, m), 5.23-5.00 (1 H, almost flat), 3.90- 3.75 (1 H, m), 3.65- 3.50 (2H, m), 3.10-2.90 (4H, m), 2.47 (3H, s), 2.35-2.00 (8H, m), 1.85-1.43 (10H, m) . This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 173-177 ° C MS (ESI positive) m / z: 446 (M + H) +. IR (KBr): 3383, 1649 cm "1 Analysis calculated for C28H39N5-3HCI-2.7H2O: C, 55.71; H, 7.91; N, 11.60, Found: C, 56.09; H, 8.22; N, 11.20.

EXAMPLE 36 AZ-Dimethyl-A I-p-fl-Phenyl-cycloheptide-1-piperidinin-1H-benzoimidazole-1-yl-2-ethanediamine This was prepared according to the processing described in Example 1 and Example 3 using? /,? / - dimethylenediamine (120 ° C, 16.5 h) in place of aniline. The yield was 62%. ? NMR (270 MHz, CDCl 3) d 7.55-7.42 (3H, m), 7.40-7.19 (4H, m), 7.13-6.98 (2H, m), 5.39 (1H, sa), 4.00-3.83 (1H, m), 3.59 (2H, t, J = 5.4 Hz), 3.10-2.90 (2H, m), 2.66 (2H, t, J = 5.4 Hz), 2.35 (6H, s), 2.36-2.00 (8H, m ), 1.90-1.43 (10H, m).

This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 188-192 ° C MS (ESI positive) m / z: 460 (M + H) + IR (KBr): 3383, 1649 cm "1 Analysis calculated for C29H41N5-3HCI-2H2O: C, 57.56; H, 8.00; N, 11.57. Found: C, 57.47; H, 8.31; N, 11.18.

EXAMPLE 37 1 - (4- { 1 -F 1 - (1-phenylcycloheptyl) -4-piperidin-p-1 // -benzoimidazol-2-yl.} - piperazine-ethanone A mixture of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -2-piperazinebenzoimidazole (Example 19, 45.8 mg, 0.1 mmol), acetyl chloride (0.03 ml) and pyridine (0.1 ml) in CH2Cl2, stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 1 plate, CH2Cl2 / MeOH: 9/1) to yield 35.3 mg (70.6%) of a colorless solid. ? NMR (270 MHz, CDCl 3) d 7.64-7.57 (1 H, m), 7.53-7.50 (3H, m), 7.38-7.32 (2H, m), 7.27-7.14 (3H, m), 4.16-4.03 (1 H, m), 3.82-3.77 (2H, m), 3.68-3.63 (2H, m), 3.28-3.23 (2H, m), 3.05-2.97 (2H, m), 2.50-2.17 (4H, m), 2.15 (3H, s), 2.13-2.09 (4H, m), 1.79-1.68 (5H, m), 1.57-1.54 (5H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 188-192 ° C MS (ESI positive) m / z: 460 (M + H) +. IR (KBr): 3383, 1649 cm "1 Analysis calculated for C29H4? N5-3HCI-2H2O: C, 57.56; H, 8.00; N, 11.57. Found: C, 57.47; H, 8.31; N, 11.18.

EXAMPLE 38 1-p- (1-Phenylcycloheptyl) -4-piperidinin-2- (4-phenylpiperazino) -1H-benzoimidazole This was prepared according to the procedure described in example 1 and example 4 using 1-phenylpiperazine (140 ° C, 7.5 h) in place of 1-methylpiperazine. The yield was 81%. NMR (270 MHz, CDCl 3) d 7.67-7.60 (1H, m), 7.55-7.48 (3H, m), 7.38-7.13 (7H, m), 7.03-6.87 (3H, m), 4.20-4.06 (1H , m), 3.37 (8H, s), 3.07-2.97 (2H, m), 2.50-2.00 (8H, m), 1.90-1.40 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH, mp 188-192 ° C MS (El) m / z: 533 (M +), 360, 279, 172, 146. IR (KBr): 3396 , 1595 cm "1 Analysis calculated for C35H43N5-3HCM, 5MeOH: C, 63.43; H, 7.58; N, 10.13, Found: C 63.23; H, 7.84; N, 10.20.

EXAMPLE 39 1-ri- (1-Phenylcycloheptyl) -4-piperidinin-2- (4-pyridinyl) -1 / Y-benzoamidazole This was prepared according to the procedure described in preparation 1 and in example 11 using sonicotinic anhydride (120 ° C, 16 h) in place of acetic anhydride. The yield was 82%. 1 H NMR (270 MHz, CDCl 3) d 8.81-8.77 (2H, m), 7.86-7.70 (2H, m), 7.55-7.47 (4H, m), 7.38-7.19 (5H, m), 4.30-4.18 (1 H, m), 3.05-2.94 (2H, m), 2.58-2.42 (2H, m), 2.20-2.03 (5H, m), 1.86-1.42 (11H, m). MS (El) m / z: 450 (M +), 373, 278, 172, 129, 91. This free amine was converted to the HCl salt using a solution of HCl in MeOH. IR (KBr): 3395, 1637 cm "1 Analysis calculated for: C3oH34N4-3HCI-H2O-0.3 MeOH: C, 61.93; H, 6.90; N, 9.53, Found: C, 62.11; H, 7.27; N, 9.33.

EXAMPLE 40 2-MethylsulfoniM -H - (1-phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazole To a stirred solution of 2-methylthio-1- [1- (1-phenylcycloheptyl) -4-p-perpentyl] -1 / - / - benzoimidazole (Example 7, 74.6 mg, 0.178 mmol) in acetic acid (1 ml) was added a solution of potassium permanganate (62.6 mg) in water (2 ml) at room temperature. After stirring 1 h, the reaction mixture was quenched with saturated Na 2 SO 4 solution, basified with 25% NH 4 OH and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO), filtered and concentrated to give 67 mg of colorless solid. This was purified by preparative TLC (1 mm x 1 plate, hexane / acetone: 4/1 developed three times) to give 25.6 mg (32%) of a colorless amorphous solid. ? NMR (270 MHz, CDCl 3) d 7.82-7.72 (2H, m), 7.56-7.50 (2H, m), 7.45-7.31 (3H, m), 7.27-7.20 (2H, m), 5.01-4.90 (1H , m), 3.57 (3H, s), 3.02-2.98 (2H, m), 2.44-2.28 (4H, m), 2.11-1.94 (4H, m), 1.82-1.47 (10H, m). MS (El) m / z: 451 (M +), 394, 372, 332, 254, 200, 172, 129, 91. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a solid, mp 155-158 ° C. IR (KBr): 3381, 1693 cm "1. Analysis calculated for C 26 H 33 N 3 2 2 S-HCM, 7 H 2 O: C, 60.20; H, 7.27; N, 8.10.

Found: C, 60.14; H, 7.38; N, 7.70.

EXAMPLE 41 2- (4-Methylpiperazino) -1 -H - (1-methylcyclooctyl) -4-piperidinin-1H-benzoimidazole This was prepared according to the procedure described in Examples 1 and 4 using cyclooctanone in place of cycloheptanone and methylmagnesium bromide in place of phenylmagnesium bromide. The performance of the four stages was 12.7%. NMR (270 MHz, CDCl 3) d 7.66-7.60 (1H, m), 7.58-7.48 (1H, m), 7.20-7.11 (2H, m), 4.20-4.05 (1H, m), 3.32-3.25 (4H , m), 3.23-3.10 (2H, m), 2.67-2.61 (4H, m), 2.60-2.40 (2H, m), 2.39 (3H, s), 2.28-2.14 (2H, m), 2.05-1.68 (6H, m), 1.67-1.30 (10H, m), 0.90 (3H, sa). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 423 (M +), 353, 338, 298, 217, 206. Analysis Calculated for C20H 1N5-3HCI-4H2O: C, 51.61; H, 8.66; N, 11.57. Found: C, 51.90; H, 8.92; N, 11.37.

EXAMPLE 42 2- (4-Methylpiperazino) -1 -H - (1-methylcyclononyl) -4-piperidin-1-H-benzoimidazole This was prepared according to the procedure described in Examples 1 and 4 using cyclononanone in place of cycloheptanone and methylmagnesium bromide in place of phenylmagnesium bromide. The yield of the four stages was 16.9% 1H NMR (270 MHz, CDCI3) d 7.66-7.60 (1 H, m), 7.58-7.48 (1 H, m), 7.20-7.11 (2H, m), 4.20- 4.04 (1 H, m), 3.32-3.25 (4H, m), 3.24-3.26 (2H, m), 2.67-2.60 (4H, m), 2.55-2.40 (2H, m) 2.38 (3H, s), 2.25-2.13 (2H, m), 1.85-1.35 (18H, m), 0.85 (3H, s). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 437 (M +), 367, 352, 298, 220. lR (KBr): cm "1. Analysis calculated for C27H43H5-3HCI-5H2O: C, 50, 90, H, 8, 86; N, 10, 99. Found: C, 51.28; H, 9.01; N, 11.23.

EXAMPLE 43 3-Amino-1 - (1 -M - (1-phenylcycloheptyl) -4-piperidinip-1 H-benzoimidazol-2-yl-1 • propanone To a stirred solution of 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1 - / - benzoimidazole (example 12, 66.3 mg, 0.178 mmol) in THF (4 mL), n-butyllithium was added (solution 1.54 M in hexane, 0.923 ml, 1.42 mmol) at -78 ° C. After stirring for 1 h at -78 ° C, a solution of 3-f-butoxycarbonylamino-N-methoxy-N-methylpropionamide (140 mg, 0.604 mmol) was added, this was prepared according to the procedure presented by G. Bitan and col., J. Chem. Soc, Perkin Trans. 1, 1997, 1501-1510) in THF (1.5 ml) to the reaction mixture at -78 ° C. After stirring for 0.5 hours at -78 ° C and stirring 15 hours at room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 3 plate, n-hexane / acetone: 5/1, developed 6 times) to give 71.7 mg (74%) of a light brown amorphous solid. This solid (70 mg, 0.131 mmol) was dissolved in a solution of HCl in MeOH (10 mL). After evaporation of the solvent, the residue was dried under vacuum at 45 ° C for 18 hours to yield 60 mg (89%) of a light brown amorphous solid. IR (KBr): 3395, 2931, 1692, 1611, 1477 cm "1.

Analysis calculated for C 28 H 36 N 4 O-2 HCl-2 H 2 O: C, 60.75; H, 7.65; N, 10.12. Found: C, 60.90; H, 7.98; N, 9.95. A small amount of this solid HCl was basified to give the free amine. 1 H NMR (270 MHz, CDCl 3) d 7.90-7.74 (2H, m), 7.56-7.50 (2H, m), 7.42-7.19 (5H, m), 5.51-5.30 (1 H, m), 3.48 (2H, t, J = 6.1 Hz), 3.15 (2H, t, J = 6.1 Hz), 3.02-2.94 (2H, m), 2.50-2.25 (4H, m), 2.24-2.00 (5H, m), 1.95-1.40 (11H, m).

EXAMPLE 44 1-f 1 -H - (4-Fluorophenyl) cycloheptin-4-piperidinyl > -? / - methyl-1 H-benzoimidazol-2-amine This was prepared according to the procedure described in examples 23 and 2. The yield of the two stages was 58.4%. ? NMR (270 MHz, CDCl 3) d 7.52-7.40 (3H, m), 7.29-7.23 (1H, m), 7.13-6.97 (4H, m), 4.24 (1H, sa), 3.84-3.68 (1H, m), 3.13 (3H, da, J = 3.0 Hz), 3.02-291 (2H, m), 2.32-1.90 (9H, m), 1.84-1.40 (9H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 420 (M +), 363, 335, 274, 231, 191, 174, 148, 123. IR (KBr): 3400, 1661 cm "1.

Analysis calculated for C26H33FN4-2HCM .6H2O: C, 60.46; H, 7.55; N, 10.45. Found: C, 60.21; H, 7.34; N, 10.20.

PREPARATION 6 4-Fluoro-1-ri-f1-phenylcycloheptyp-4-piper8dinin-1,3-dihydro-2H-1,3-benzoimidazol-2-one A mixture of 3-fIuoro-N-1- [1- (1-phenylcyanoheptyl) -4-piperidinyl] -1,2-benzenediamine (this was prepared according to the procedure described in Preparation 1 using 2.6 -difluoronitrobenzene in place of 2-fluoronitrobenzene, 178.5 mg, 0.468 mmol) and triphosgene (180 mg, 0.608 mmol) in benzene (8 ml), was stirred at room temperature. The reaction mixture was then heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, basified by the addition of aqueous NaHC 3 solution and extracted with CH 2 Cl 2. The combined extracts were dried (Na2SO4), filtered and concentrated to give 76.3 mg (40%) of the title compound as a white solid. ? NMR (270 MHz, CDCl 3) d 8.99 (1 H, sa), 755-7.47 (2H, m), 7.37-7.17 (3H, m), 7.05-6.96 (2H, m), 6.87-6.76 (1H, m), 4.30-4.18 (1H, m), 3.00-2.88 (2H, m), 2.32-2.00 (8H, m), 1.88-1.40 (10H, m) EXAMPLE 45 4-Fluoro-2- (4-methyl) -1-piperazine-1-H -d-phenylcycloheptyl) -4-piperidin-1H-benzoimidazole This was prepared according to the procedure described in Examples 1 and 4 using 4-fluoro-1- [1- (1-phenolcycloheptyl) -4-pperidinyl] -1,3-dihydro- 2H-1, 3-benzoimidazol-2-one as starting material. The yield of the two stages was 49.3%. ? NMR (270 MHz, CDCl 3) d 7.55-7.48 (2H, m), 7.39-7.31 (2H, m), 7.28-7.19 (2H, m), 7.05 (1 H, dt, J = 4.9, 8.1 Hz), 6.86 (1 H, dd, J = 8.2, 10.4 Hz), 4.13-3.80 (1 H, m), 3.32-3.24 (4H, m), 3.06-2.96 (2H, m), 2.66-2-57 (4H , m), 2.37 (3H, s), 2.34-2.00 (8H, m), 1.90-1.42 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (ESI positive) m / z: 490 (M + H) +. IR (KBr): 3369, 1618 cm "1. Analysis calculated for C3oH4oFN5-3HCI-2H2O: C, 56.74; H, 7.46; N, 11.03. Found: C, 57.04; H, 7.52; N, 11.07.

PREPARATION 7 5-Fluoro-1 -M -d-phenylcycloheptyl-4-piperidinin-1,3-dihydro-2H-1, 3-benzoimidazol-2-one This was prepared according to the procedure described in Preparation 4 using 2,5-difiuoronitrobenzene instead of 2,6-difluoronitrobenzene. The yield of the three stages of 2,5-difluoronitrobenzene was 9.7%. 1 H NMR (270 MHz, CDCl 3) d 9.45 (1 H, sa), 7.55-7.45 (2 H, m), 7.37-7.18 (3 H, m), 7.12 (1 H, dd, J = 4.5, 8.6 Hz), 6.87-6.73 (2H, m), 4.28-4.15 (1H, m), 3.05-2.88 (2H, m), 2.35-2.00 (8H, m), 1.90-1.40 (10H, m).

EXAMPLE 46 5-Fluoro-2- (4-methyl-1-piperazinylH- (1-phenylcycloheptyl) -4-piperidinip-1H-benzoimidazole This was prepared according to the procedure described in Example 45 using 5-fluoro-1- [1- (1-phenyl-cycloheptyl) -4-piperidinyl] -1,3-dihydro-2H-1,3-benzoimidazole-2- ona as starting material. The performance of the two stages was 40.9%. 1 H NMR (270 MHz, CDCI3) d 7.54-7.48 (2H, m), 7.40-7.20 (5H, m), 6.88 (1 H, dt, J = 2.5, 6.2 Hz), 4.10-3.94 (1 H, m), 3.28-3.21 (4H, m), 3.05- 2.95 (2H, m), 2.66-2.57 (4H, m), 2.37 (3H, s), 2.35-2.00 (8H, m), 1.92-1.42 (101-1, m) . This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS m / z (ESI positive): 490 (M + H) +. IR (KBr): 3395, 2932, 1622 cm "1. Analysis calculated for C3oH40FN5-3HCI-2.5H2O: C, 55.94; H, 7.51; N, 10.87. Found: C, 56.12; H, 7.60; N, 10.96.

PREPARATION 8 6-Fluoro-1 -H - (1-phenylcycloheptm-4-piperidinip-1,3-dihydro-2rt-1,3-benzoimidazol-2-one) This was prepared according to the procedure described in Preparation 4 using 2,4-difluoronitrobenzene in place of 2,6-difluoronitrobenzene. The yield of the three stages of 2,4-difluoronitrobenzene was 45.6%. 1 H NMR (270 MHz, CDCl 3) d 9.41 (1 H, sa), 7.55-7.45 (2 H, m), 7.38-7.18 (3 H, m), 7.03-6.93 (2 H, m), 6.75 (1 H, dd , J = 2.0, 8.8, 11.2 Hz), 4.27-4.15 (1 H, m), 3.00-2.93 (2H, m), 2.33-2.00 (8H, m), 1.85-1.43 (10H, m). MS m / z (The direct): 407 (M +), 350, 321, 234, 91.

EXAMPLE 47 6-Fluoro-2- (4-methyl-1-piperaziniD-1 -H - (1-phenylcycloheptyl-4-piperidin-1H-benzoimidazole This was prepared according to the procedure described in Example 45 using 6-fluoro-1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1,3-dihydro-2 - / - 1,3-benzoimidazole- 2-one as starting material. The performance of the two stages was 15.2%. 1 H NMR (270 MHz, CDCl 3) d 7.56-7.47 (3H, m), 7.40-7.16 (4H, m), 6.94-6.84 (1 H, m), 4.10-3.96 (1 H, m), 3.26-3.18 (4H, m), 3.05-2.96 (2H, m), 2.63-2.57 (4H, m), 2.37 (3H, s), 2.43-2.00 (8H, m), 1.83-1.42 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS m / z (ESI positive): 490 (M + H) +. IR (KBr): 3402, 2932, 1616, 1458 cm "1. Analysis calculated for C3oH40FN5-3HCI-3H2O: C, 55.17; H, 7.56; N, 10.72. Found: C, 55.47; H, 7.66; N, 10.93.

EXAMPLE 48 2- (4-Methylpiperazino) -1-f1- (1-phenylcyclohexyl) -4-piperidinin-1f-benzoimidazole This was prepared according to the procedure described in examples 26 and 4. The yield of the two stages was 29%. 1 H NMR (270 MHz, CDCl 3) d 7.64-7.58 (1 H, m), 7.56-7.48 (1 H, m), 7.43-7.26 (5H, m), 7.18-7.11 (2H, m), 4.02-3.87 (1 H, m), 3.32-3.23 (2H, m), 3.23-3.17 (4H, m), 2.60-2.40 (6H, m), 2.33 (3H, s), 2.25-2.00 (4H, m), 1.90-1.35 (1 OH, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give an amorphous solid. IR (KBr): 3387, 2937, 1612 cm "1. Analysis calculated for C29H3gN5-3HCM.5H2O: C, 58.63; H, 7.63; N, 11.79. Found: C, 58.90; H, 8.00; N, 11.53.

EXAMPLE 49? / - Methyl-1-ri- (1-methylcyclooctyl) -4-piperidinin-1 Y-benzoimidazole-2 -amine This was prepared according to the procedure described in examples 41 and 2. The yield of the four stages was 11.2%. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.45 (1 H, m), 7.30-7.20 (1 H, m), 7.13-6.98 (2 H, m), 4.05-3.80 (1 H, m), 3.30- 3.00 (2H, m), 3.15 (3H, s), 2.60-1.95 (4H, m), 1.95-1.20 (16H, m); 0.92 (3H, s a). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a white amorphous solid. IR (KBr): 3400, 2930, 1661 cm "1. Analysis calculated for C22H34N4-2HCl-3H2O: C, 55.75: H, 8.95; N, 11.31, Found: C, 55.62; H, 9.11; N, 11.25.

EXAMPLE 50 1- (1-F 1 - (4-Fluorophenyl) cyclononin-4-piperidinyl > -1 H-benzoimidazole This was prepared according to the procedure described in Example 12 using N-1-. { 1- [1- (4-fluorophenyl) cyclononyl] -4-piperidinyl} -1,2-benzenediamine which was prepared in Example 31. The yield was 88%. ? NMR (270 MHz, CDCl 3) d 7.99 (1 H, s), 7.85-7.77 (1 H, m), 7.48-7.24 (5H, m), 7.02 (2H, t, J = 8.6 Hz), 4.12-3.98 (1 H, m), 3.28-3.12 (2H, m), 2.30-1.90 (8H, m), 1.85-1.24 (14H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: unknown IR (KBr): 3385, 2930, 1605, 1516 cm "1 'Analysis calculated for C27H34FN3-2HCL-2.35H2? -0.05CH2Cl2: C, 60.16; H, 7.80; N, 7.78 Found: C, 60.53; H, 7.72; N, 7.38.

EXAMPLE 51 1- (1-f1- (1-Phenylcycloheptyl) -4-piperidinin-1 Y-benzoimidazole-2-yl> -4- piperidinone This was prepared according to the procedure described in Example 27 using 1,4-dioxa-8-azaspiro [4.5] decane in place of t-butyl? / - (2-aminoethyl) carbamate. The yield was 79.9%. 1 H NMR (270 MHz, CDCl 3) d 7.65-7.58 (1H, m), 7.57-7.49 (3H, m), 7.40-7.30 (2H, m), 7.28-7.15 (3H, m), 4.20-4.05 (1 H, m), 3.53 (4H, t, J = 5.9 Hz), 3.10-2.98 (2H, m), 2.68 (4H, t, J = 5.9 Hz), 2.50-2.00 (8H, m), 1.90-1.40 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 168-172 ° C. MS (El) m / z: 470 (M +), 413, 385, 297, 256, 172, 129, 91. IR (KBr): 3373, 2932, 1717, 1612, 1450 cm'1 Analysis calculated for C30H38N4O-2HCI -3.2H2O: C, 59.93; H, 7.78; N, 9.32. Found: C, 59.53; H, 7.91; N, 9.34.

EXAMPLE 52 1-f 1 -f 1 - (1-Phenylcycloheptyl) -4-piperidinyl-1 f / -benzoimidazol-2-yl} -4- piperidinol To a stirred solution of 1-. { 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1H-benzoimidazol-2-yl} -4-piperidonone (example 51, 162 mg, 0.345 mmol) in MeOH (3 ml) was added NaBH 4 (19.7 mg, 0.521 mmol) at 0 ° C. After stirring for 45 minutes, the reaction mixture was poured into a saturated solution of NH CI and extracted with CH CI. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 1 plate, CH 2 Cl 2 / MeOH: 95/5) to give 157 mg (96.5%) of a colorless solid. 1 H NMR (270 MHz, CCI 3) d 7.63-7.45 (4H, m), 7.40-7.30 (2H, m), 7.26-7.11 (3H, m), 4.13-4.00 (1 H, m), 3.95-3.85 ( 1 H, m), 3428-3.30 (2H, m), 3.10-2.95 (4H, m), 2.45-2.00 (10H, m), 1.90-1.40 (13H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 208-212 ° C. MS (El) m / z: 472 (M +), 415, 387, 299, 255, 2184, 172, 91. IR (KBr): 3400, 2932, 1616, 1447 cm "1. Analysis calculated for C3oH4oN4O-2HCI- 2H2O: C, 61.95; H, 7.97; N, 9.63. Found: C, 61.57; H, 8.31; N, 9.85.

EXAMPLE 53 1-f 1 -H - (1-Phenylcycloheptyl) -4-picperidin-1 H-benzoimidazol-2-yl} -4- piperidinone oxime A mixture in suspension of 1-. { 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1 / - / - benzoimidazol-2-yl} -4-piperidinone (example 51, 136 mg, 0.289 mmol), hydroxylamine hydrochloride (35.1 mg, 0.505 mmol) and sodium acetate (35.9 mg, 0.438 mmol) in EtOH (3 mL) was stirred at room temperature for 0.5 h. The reaction mixture was basified with a saturated solution of NaHCO 3 at 0 ° C and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 1 plate, hexane / acetone: 3/2, then 0.5 mm x 3 plate, CH 2 Cl 2 / MeOH: 95/5) to give 104 mg (74.1%) of a solid colorless. 1 H NMR (270 MHz, CDCl 3) d 7.65-7.48 (4H, m), 7.40-7.30 (2H, m), 7.26-7.13 (3H, m), 4.18-4.04 (1 H, m), 3.40-3.25 ( 4H, m), 3.10-2.98 (2H, m), 2.85 (2H, t, J = 5.9 Hz), 2.54 (2H, t, J = 5.9 Hz), 2.50-2.00 (8H, m), 1.90-1.40 (10H, m). This free amine was converted to the fumaric acid salt to give a colorless solid, mp 201-204 ° C. MS (El) m / z: 485 (M +), 428, 312, 231, 91. IR (KBr): 3232, 2932, 1713, 1464 cm "1.

Analysis calculated for C3oH39N5? -C4H4O4l-CH2Cl2: C, 61.22; H, 6.61; N, 10.20. Found: C, 61.62; H, 6.94; N, 10.23.

EXAMPLE 54 1-f 1 -H - (1-Phenylcycloheptyl) -4-piperidin-1 H-benzoimidazol-2-yl > -4- piperidinylamine To a stirred solution of 1-. { 1- [1- (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} -4-piperidinol (example 52, 106 mg, 0.225 mmol) and triethylamine (0.0623 ml, 0.449 mmol) in CH2Cl2 mesyl chloride was added at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with saturated NaHC 3 solution and extracted with CH 2 Cl 2.

The combined extracts were washed with brine, dried (Na 2 SO 4), filtered and concentrated. The residue was dissolved in DMF (1 ml) and THF (1 ml).

To this solution was added NaN3 (30.7 mg, 0.472 mmol) at room temperature. Then, the reaction mixture was heated to reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with Et2O. The combined extracts were washed with water, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, C2Ci2 / MeOH: 9/1) to give 90 mg (80.6%) of a colorless oil. To a stirred suspension of LiAIH (35.7 mg, 0.941 mmol) in Et2O (1 mL) was added a solution of this azide derivative (90 mg, 0.181 mmol) in Et2O (5 mL) at 0 ° C. After stirring for 3 hours at room temperature, the reaction mixture was quenched with Na2SO4-10H2O. After filtration, the filtrate was concentrated to give 73.5 mg (86.2%) of a colorless foam. 1 H NMR (270 MHz, CDCl 3) d 7.63-7.45 (4H, m), 7.38-7.31 (2H, m), 7.26-7.11 (3H, m), 4.15-4.00 (1 H, m), 3.37-3.31 ( 2H, m), 3.06-2.88 (5H, m), 2.50-1.40 (24H, m). In order to purify this compound, this crude amine was converted to a Boc derivative by treatment with (Boc) 2 O and DMAP in CH 2 Cl 2 to produce the Boc derivative with a yield of 60.6% after purification by preparative TLC. 1 H NMR (270 MHz, CDCl 3) d 7.63-7.45 (4H, m), 7.38-7.31 (2H; m), 7.25-7.11 (3H, m); 4.57 (1 H, s a), 4.10-3.96 (1 H, m), 3.75-3.61 (1 H, m); 3.48 (4H, s), 3.36-3.29 (2H, m), 3.11-2.99 (4H, m), 2.44-2.03 (8H, m), 1.80-1.54 (1 OH, m), 1.46 (9H, s) . This Boc derivative (54 mg, 0.0946 mmol) was treated with HCl solution in MeOH (2 mL) at room temperature for 17 h. Evaporation of the solvent gave a white solid which was washed with Et 2 O and dried under vacuum to yield 25 mg of the HCl salt, mp 225-228 ° C. MS (ESI positive) m / z: 472 (M + H) +. IR (KBr): 3406, 2932, 1618, 1450 cm "1.

Analysis calculated for C3oH? N5-3HCI-3.5H20: C, 55.94; H, 7.98; N, 10.87. Found: C, 55.70; H, 8.202; N, 10.62.

EXAMPLE 55 N-Methyl-1H - (1-methylcycloheptyl) -4-piperidinip-1 H-benzoimidazole-2-amino This was prepared according to the procedure described in Example 28 using cycloheptanone instead of cyclononanone. The total yield was 19.1%. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.46 (1 H, m), 7.29-7.22 (1 H, m), 7.12-6.98 (2 H, m), 4.60-4.42 (1 H, m), 4.00-3.80 (1H, m), 3.26-3.16 (2H, m), 3.15 (3H, da, J = 3.5 Hz), 2.50-1.35 (18H, m), 0.99 (3H, s). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 340 (M +), 326, 309, 194, 82. IR (KBr): 3406, 2934, 1660 cm "1. Analysis calculated for C21H32N4-2HCM .5H2O: C, 57.27; H, 8.47; N, 12.72, Found: C, 57.26; H, 8.84; N, 12.65.

EXAMPLE 56 1 -1 ~ 1 - (1-Ethylcycloheptyl) -4-piperidinin-N-methyl-1 H-benzoimidazole-2-amino This was prepared according to the procedure of Example 29 using cycloheptanone instead of cyclononanone. The total yield was 36%. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.47 (1 H, m), 7.30-7.25 (1 H, m), 7.12-6.98 (2H, m), 4.46-4.30 (1 H, m), 3.94- 3.76 (1 H, m), 3.15 (3 H, da, J = 4.1 Hz), 3.15-3.06 (2H, m) 2.44-2.16 (4H, m), 2.00-1.40 (16H, m), 0.88 (3H, t, J = 7.4 Hz). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 354 (M +), 325, 178. IR (KBr): 3410, 2934, 1661 cm "1. Analysis calculated for C22H34N4-2HCl-MeOH 0.5H2O: C, 58.56; H, 8.74; N, 12.14. Found: C, 58.94; H, 9.08; N, 12.51.

EXAMPLE 57 N-Methyl-1H - (1-propylcycloheptyl) -4-piperidinin-1 H-benzoimidazole-2-amino This was prepared according to the procedure of Example 28 using cycloheptanone instead of cyclononanone and propylmagnesium bromide instead of methylmagnesium bromide. The total yield was 10.6%. ? NMR (270 MHz, CDCl 3) d 7.55-7.47 (1 H, m), 7.23-7.25 (1 H, m), 7.14-6.98 (2H, m), 4.30-4.19 (1 H, m), 3.90-3.77 (1 H, m), 3.20-3.06 (2H, m) 3.15 (3H, da, J = 4.1 Hz), 2.42-2.20 (4H, m) 1.90-1.28 (18H, m), 0.91 (3H, t, J = 6.4 Hz). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 368 (M +), 325, 178. IR (KBr): 3377, 2932, 1661 cm "1. Analysis calculated for C23H36N4-2HCI-2.5H2O-0.5CH2Cl2: C, 53.36; H, 8.38; N, 10.59, Found: C, 53.52; H, 8.34; N, 10.71.

EXAMPLE 58 N-Methyl-1 -fi - (1-propylcyclooctyl) -4-piperidinin-1 H-benzoimidazole-2-amino This was prepared according to the procedure described in Example 57 using cyclooctanone instead of cycloheptanone. The total yield was 8.9%. H NMR (270 MHz, CDCl 3) d 7.53-7.47 (1 H, m), 7.31-7.25 (1 H, m), 7.13-6.98 (2H, m), 4.25-4.15 (1 H, m), 3.87- 3.77 (1 H, m), 3.18-3.105 (5H, m) 2.36-2.20 (4H, m), 1.88-1.20 (20H, m), 0.90 (3H, ta).

This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 382 (M +), 339, 192. IR (KBr): 3389, 2934, 1661, 1479 cm "1. Analysis calculated for C24H38N4-2HCI-2.5H2O: C, 57.59; H, 9.06; N, 11.19, Found: C, 57.45; H, 8.90; N, 10.99.

EXAMPLE 59 3-. { 1 -M - (1-Phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazole-2-iD-propylamine This was prepared according to the procedure described in Example 25 using 2-nitropopionic acid in place of 1-benzylpiperidine-4-carboxylic acid, and Fe, NH CI, and aqueous EtOH in place of H2, palladium black, HCl and MeOH. The total yield was 30.7%. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give an amorphous ivory solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.98 (1 H, sa), 8.81-8.73 (1 H, m), 8.22 (3 H, s), 7.91-7.74 (3 H, m), 7.57-7.40 (5 H , m), 5.15-5.00 (1 H, m), 3.56-3.10 (8H, m), 3.02-2.74 (4H, m), 2.60-2.50 (2H, m), 2.20-1.20 (12H, m). IR (KBr): 3406, 2934, 1612, 1466 cm "1.

Analysis calculated for C28H38N4-2HCI .5H2O: C, 57.53; H, 8.45; N, 9.58. Found: C, 57.71; H, 8.49; N, 9.48.

EXAMPLE 60 1 -fi - (1-methylcyclooctyl) -4-piperidinip-2- (1-piperaziniD-1 H -benzoimidazole This was prepared according to the procedure described in examples 18, 19 and 41. The total yield was 19.7%. 1 H NMR (270 MHz, CDCl 3) d 7.66-7.60 (1 H, m), 7.56-7.50 (1 H, m), 7.20-7.12 (2 H, m), 4.23-4.08 (1 H, m), 3.22- 3.04 (10H, m), 2.56-2.38 (2H, m), 2.25-1.30 (19H, m), 0.88 (3H, s). This free amine was converted to the sai HCl using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 409 (M +), 394, 353, 284, 203, 123, 82. IR (KBr): 3387, 2928, 1630, 1458 cm "1. Analysis calculated for C25H39N5-3HCI-2H2O- MeOH: C, 53.19; H, 8.58; N, 11.93, Found: C, 53.35; H, 8.95; N, 12.07.

EXAMPLE 61 4-f1-ri- (1-Phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazol-2-yl-1-piperidinecarboximidamide This was prepared according to the procedure described in Example 33 using Example 25 as a starting material. The total yield was 68.2%. 1 H NMR (270 MHz, CDCl 3 + CD 3 OD) d 7.68-7.63 (2H, m), 7.55-7.50 (2H, m), 7.40-7.20 (5H, m), 4.18-3.96 (3H, m), 3.28-2.90 (6H, m), 2.55-1.95 (14H, m), 1.85-1.45 (10H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give an amorphous ivory solid. IR (KBr): 3346, 3213, 2932, 1653, 1612, 1465 cm. "1 Analysis calculated for C3? H42N6-2HCI-3H2O: C, 59.51; H, 8.05; N, 13.43. Found: C, 59.16; 8.40; N, 13.18.

EXAMPLE 62 4-. { 1-f1 - (1-methylcyclooctyl) -4-piperidinyl-1 H-benzoimidazol-2-yl > -1 • Piperazinecarboximidamine This was prepared according to the procedure of Example 33 using Example 60 as a starting material. The total yield was 75%. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.75 (2H, sa), 8.76-8.62 (1 H, m), 7.65-7.60 (1 H, m), 7.44-7.29 (2H, m), 4.76-4.60 (1 H, m), 4.00-3.20 (12H, m), 2.30-2.06 (4H, m), 1.96-1.42 (17H, m), 1.39 (3H, s). MS (ESI positive) m / z: 452 (M + H) +. IR (KBr): 3356, 2928, 1609, 1452 cm "1. Analysis calculated for C 26 H 4 N7-2HCl4.5H2O: C, 51.56; H, 8.65; N, 16.19. Found: C, 51.30; H, 8.74; N , 15.98.

EXAMPLE 63 1-ri- (1-Phenylcycloheptyl) -4-piperidin-1H-benzoimidazol-2-yl 4-piperidinyl ether To NaH (60% dispersion in oil, 42.7 mg, 1.08 mmol, washed twice with heptane) was added a solution of 1-benzyl-4-hydroxypiperidine (108 mg, 0.565 mmol) in DMF (1 ml) at 0 °. C and the resulting mixture was stirred at room temperature for 30 minutes. Then, a solid of Example 1 (76.9 mg, 0.189 mmol) was added to the reaction mixture at 0 ° C and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined extracts were washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (30 g of silica gel: hexane / acetone: 3/1) to give 86.4 mg (81.4%) of a colorless solid. H NMR (270 MHz, CDCl 3) d 7.54-7.48 (3H, m), 7.36-7.19 (9H, m), 7.15-7.06 (2H, m), 5.27-5.19 (1 H, m), 4.10-3.98 ( 1 H, m), 3.57 (2H, s), 3.01-2.96 (2H, m), 2.75-2.63 (2H, m), 2.52-2.44 (2H, m), 2.37-2.07 (10H, m), 2.03 -1.92 (2H, m), 1.82-1.69 (5H, m), 1.58-1.50 (5H, m). A mixture of this benzylamine derivative (86.4 mg, 0.154 mmol), palladium black (36.4 mg) and a 0.2 M solution of HCl in MeOH (1 ml) was stirred under an atmosphere of hydrogen at room temperature for 16.5 h. After filtration, the filtrate was basified with a NaHCO 3 solution and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a yellow syrup, which was dissolved in CH2Cl2 (1 ml). To this solution was added a solution of (Boc) 2 O (65.7 mg, 0.301 mmol) and a catalytic amount of DMAP at room temperature. After stirring for 21 hoursThe reaction mixture was poured into a NaHCO3 solution and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, CH 2 Cl 2 / MeOH: 95/5) to give 29.3 mg (33.3% in 2 steps) of a colorless syrup. ? NMR (270 MHz, CDCl 3) d 7.55-7.48 (3H, m), 7.36-7.18 (4H, m), 7.17-7.08 (2H, m), 5.40-5.33 (1H, m), 4.12-4.01 (1H , m), 3.71-3.61 (2H, m), 3.56-3.46 (2H, m), 3.00-2.96 (2H, m), 2.36-2.18 (4H, m), 2.09-2.01 (4H, m), 1.93 -1.46 (14H, m), 1.50 (9H, s). A mixture of this Boc derivative (29.3 mg) and HCl solution in MeOH (1 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was dried at 45 ° C to give 15 mg of the title compound as an HCl salt, mp 114-118 ° C. MS (ESI positive) m / z: 473 (M + H) +. IR (KBr): 3400, 2934, 1684, 1601, 1474 cm'1. Analysis calculated for C3oH4oN4-2HCI4H2O: C, 58.34; H, 8.16; N, 9.07.

Found. C, 58.34; H, 8.19; N, 8.02.

EXAMPLE 64 N-1-1-f 1 - (1-Phenylcycloheptyl) -4-piperidinyl-1 H-benzoimidazol-2-yl > -1, 6-hexanediamine This was prepared according to the procedure of Example 20 using 1,6-hexanediamine instead of amylamine. The total yield was 80.4%. 1 H NMR (270 MHz, CDCl 3) d 7.51-7.44 (2H, m), 7.37-7.20 (5H, m), 7.10-6.97 (2H, m), 4.25-4.19 (1H, m), 3.82-3.70 (1H , m), 3.55-3.47 (2H, m), 3.03-2.99 (2H, m), 2.72-2.66 (2H, m), 2.33-2.09 (8H, m), 1.81-1.64 (10H, m), 1.58 -1.39 (1 OH, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 165-168 ° C. MS (ESI positive) m / z: 488 (M + H) +. IR (KBr): 3385, 2935, 2860, 1650, 1480, 1635 cm "1. Analysis calculated for C3iH45N5-3HCI-2.5H2O: C, 57.98; H, 8.32; N, 10.91 Found: C, 58.14; H, 8.67; N, 10.88.

EXAMPLE 65 1 -1 -. { 1 -H -fi-phenylcycloheptyl) -4-piperidinyl) -1 H -benzoimidazol-2-yl-3-azetidinylamine This was prepared according to the procedure described in example 27 using 4-t-butoxycarbonylaminoazetidine (which was presented in EP106489) in place of t-butyl N- (2-aminoethyl) carbamate. The yield was 47.3%. MS (ESI positive) m / z: 448 (M + H) +. IR (KBr): 3402, 2932, 1647, 1466 cm "1. Analysis calculated for C28H37N5-3HCI-3H2O: C, 55.40; H, 7.64; N, 11.54, Found: C, 55.49; H, 7.92; N, 11.40 .

EXAMPLE 66 N-1 -. { 1 - (1-Phenylcycloheptyl) -4-piperidin-1 H-benzoimidazol-2-yl) -1,4-butanediamine This was prepared according to the procedure described in example 20 using 1,4-butanediamine instead of amylamine. The yield was 43.7%.

? NMR (270 MHz, CDCl 3) d 7.50-7.42 (3H, m), 7.37-7.19 (4H, m), 7.09-6.96 (2H, m), 3.87-3.76 (1H, m), 3.54-3.48 (2H , m), 3.00-2.96 (2H, m), 2.83-2.77 (2H, m), 2.33-2.02 (12H, m) 1.82-1.47 (12H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 213-217 ° C. MS (ESI positive) m / z: 460 (M + H) +. IR (KBr): 3404, 2934, 1655, 1479 cm "1. Analysis calculated for C29H4? N5-3HCI-3H2O: C, 59.90; H, 8.09; N, 11.24.

Found: C, 55.96; H, 8.40; N, 11.03.

EXAMPLE 67 1-. { 1-ri- (1-Methylcycloheptyl) -4-piperidin-p-1 H-benzoimidazol-2-yl > -4- piperidinylamine This was prepared according to the procedure described in Example 27 using 4-t-butoxycarbonylaminopiperidine in place of t-butyl N- (2-aminoethyl) carbamate and 2-chloro-1- [1- (1-methylcycloheptyl) - 4-piperidinyl-benzoimidazole as a starting material which was prepared in example 55. The total yield was 26.6%.

? NMR (270 MHz, CDCl 3) d 7.64-7.48 (2H, m), 7.19-7.10 (2H, m), 4.21-4.06 (1 H, m), 3.44-3.34 (2H, m), 3.22-2.84 (5H , m), 2.58-2.35 (2H, m), 2.27-2.15 (2H, m), 2.05-1.35 (20H, m) 0.97 (3H, s). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a yellow amorphous solid. IR (KBr): 3387, 2934, 1612, 1477 cm "1. Analysis calculated for C25H39N5-2HCl-3H2O-MeOH: C, 54.92; H, 9.04; N, 12.32. Found: C, 54.85; H, 9.30; N , 12.27.

PREPARATION 9 N-1 -M - (1-Metilcicioheptíl) -4-piperidin¡n-1,2-benzenediamine This was prepared according to the procedure described in Preparation 1 using methylmagnesium bromide in place of phenylmagnesium bromide and Zn, NH4CI and aqueous MeOH in place of SnCl2-2H2O and EtOH. The total yield was 22.6%. ? NMR (270 MHz, DMSO-d6) d 6.83-6.61 (4H, m), 3.30 (3H, sa), 3.28-3.14 (1 H, m), 2.98-2.87 (2H, m), 2.30-2.18 (2H , m), 2.11-2.00 (2H, m), 1.90-1.78 (2H, m), 1.70-1.28 (12H, m) 0.93 (3H, s). MS (ESI) m / z: 301 (M +), 286, 244, 194, 161, 119, 82.

EXAMPLE 68 1 -M - (1-methylcycloheptyl) -4-piperidinin-2- (4-piperidinyl) -1 H -benzoimidazole This was prepared according to the procedure of Example 25 using N-1- [1- (1-methylcycloheptyl) -4-p-peridinyl] -1,2-benzenediamine as a starting material. The total yield was 11.8%. NMR (270 MHz, CDCl 3) d 7.79-7.72 (1 H, m), 7.65-7.59 (1 H, m), 7.24-7.17 (2H, m), 4.26-4.11 (1 H, m), 3.33-3.15 (4H, m), 3.08-2.95 (1 H, m), 2.90-2.76 (2H, m), 2.63-2.47 (2H, m), 2.33-2.20 (2H, m), 2.07-1.35 (19H, m) ), 0.98 (3H, s).

This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a pale yellow amorphous solid. MS (El) m / z: 394 (M +), 338, 283, 202, 84. IR (KBr): 3318, 2934, 1626, 1477 cm "1. Analysis calculated for C25H38N4-2HCI4.5H2O: C, 54.74; H, 9.00; N, 10.21. Found: C, 54.84; H, 9.34; N, 10.14.

EXAMPLE 69 1 -fi- (1-lsopropylcycloheptyl) -4-piperidim'p-2- (1-piperazin-1 H-benzoimidazole This was prepared according to the procedure described in Example 60 using isopropylmagnesium bromide in place of methylmagnesium bromide and cycloheptanone instead of cyclooctanone. The total yield from 2-chloro-1- [1- (1-isopropylcycloheptyl) -4-piperidinyl] benzoimidazole was 26.5%. 1 H NMR (270 MHz, CDCl 3) d 7.66-7.60 (1H, m), 7.52-7.44 (1H, m), 7.20-7.10 (2H, m), 4.26-4.11 (1 H, m), 3.32-3.16 ( 6H, m), 3.12-3.05 (4H,), 2.56-2.32 (4H, m), 2.02-1.44 (17H, m), 0.90 (6H, d, J = 6.9 Hz). This free amine became the sa! HCl using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 423 (M +), 380, 178. IR (KBr): 3387, 2930, 1593, 1458 cm "1. Analysis calculated for C26H41N5-3HCI-H2OO.4CH2Cl2: C, 54.20; H, 8.06; N, 11.97, Found: C, 60.29; H, 7.62; N, 10.19.

EXAMPLE 70 2-Amino-N- (1-ri- (1-phenylcycloheptyl) -4-piperidinip-1H-benzoimidazol-2-yl-acetamide A mixture of Example 10 (1470 mg, 3.79 mmol), Boc-glycine (1330 mg, 7.58 mmol), and WSC (1450 mg, 7.58 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 16 h. A 25% solution of NH 4 OH was added to the reaction mixture and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a brown amorphous solid, which was purified by column chromatography (100 g of silica gel, hexane / acetone: 1/4 and then CH2Cl2 / MeOH: 50/1) to give 1.59 g (77%) of a light brown solid. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.48 (4H, m), 7.38-7.30 (2H, m), 7.27 - 7.17 (3H, m), 5.37 (1H, sa), 4.76-4.54 (2H, m), 4.01 (2H, d, J = 5.1 Hz), 3.03-2.90 (2H, m) 2.40-2.00 (8H, m), 1.86-1.40 (1 OH, m), 1.48 (9H, s). A mixture of this Boc derivative (1590 mg, 2.92 mmol) and a solution of HCl in MeOH (50 ml) was stirred at room temperature for 16 h. After evaporation of the solvent, the residue was dissolved in CH2Cl2 and basified with a 25% solution of NH4OH. The organic layer was separated, washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by column chromatography (65 g of silica gel, CH2Cl2 / MeOH: 30/1) to give 990 mg (76%) of an amorphous ivory solid. 1 H NMR (270 MHz, CDCl 3) d 7.54-7.48 (4H, m), 7.38-7.19 (6H, m), 4.75-4.60 (1 H, m), 3.55 (2H, s), 3.02-2.93 (2H, m), 2.38-2.00 (8H, m), 1.84-1.44 (12H, m). MS (El) m / z: 445 (M +), 401, 273, 229, 191, 146, 118, 91. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a yellow amorphous solid. IR (KBr): 3389, 2932, 1744, 1626, 1585, 1475 cm "1. Analysis calculated for C27H35H5O-2HCM.5H2O: C, 59.44; H, 7.39; N, 12.84 Found: C, 59.44; H, 7.33; N, 12.62.

EXAMPLE 71 2- ( { 1-Ri- (1-Phenyl-cycloheptyl) -4-piperidin-1 H-benzoim-8-azozol-2-yl-oxy) -1-ethanamide To a stirred suspension of NaH (60% suspension in oil, 168 mg, 4.2 mmol, washed with heptane) in DMF (0.5 ml) was added ethylene glycol at 0 ° C. After stirring for 20 minutes at room temperature, a solid of example 1 (290 mg, 0.713 mmol) was added to the reaction mixture and the resulting mixture was stirred at 70 ° C for 4.5 hours. After cooling to 0 ° C, water was added and extracted with EtOAc. The combined extracts were washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (40 g of silica gel, hexane / acetone: 3/1) followed by preparative TLC (1 mm x 3 plate, hexane / acetone: 3/2) to give 123 mg (39.9 %) of a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.45 (2H, m), 7.38-7.08 (7H, m), 4.65 (2H, t, J = 4.1 Hz), 4.20-4.05 (1 H, m), 4.01 (2H, t, J = 4.1 Hz), 3.01-2.94 (2H, m), 2.30-2.00 (8H, m), 1.90-1.40 (10H, m).

A mixture of this alcohol derivative (123 mg, 0.284 mmol), MsCl (0.044 ml, 0.568 mmol) and NEt3 (0.0788 ml, 0.568 mmol) in CH2Cl2 (2.5 ml) was stirred at room temperature for 45 minutes. The reaction mixture was diluted with NaHCO3 solution and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated to give 153 mg of a colorless syrup. To a solution of this mesylate derivative (153 mg) in DMF (2 ml) and water (0.5 ml) was added NaN3 (40.9 mg, 0.629 mmol) and the reaction mixture was stirred at 60 ° C for 18.5 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with Et2O. The combined extracts were washed with water, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, hexane / acetone: 7/3) to give 107 mg (82.2% over 2 steps) of a colorless syrup. NMR (270 MHz, CDCl 3) d 7.60-7.45 (2H, m), 7.45-7.00 (7H, m), 4.3-4.10 (1 H, m), 4.01 (2H, t, J = 5.9 Hz), 3.46 ( 2H, t, J = 5.9 Hz), 3.10-2.85 (2H, m), 2.40-1.95 (8H, m) 2.90-1.40 (10H, m).

A mixture of this azide derivative (83.2 mg, 0.182 mmol) and palladium black (31 mg) in MeOH (2 ml) and THF (0.5 ml) was stirred under an atmosphere of hydrogen at room temperature for 3 hours. After filtration, the filtrate was concentrated to give 85.3 mg of a colorless foam, which was dissolved in CH2Cl2 (2 ml). To this solution was added (Boc) 2 O (103 mg, 0.472 mmol) and a catalytic amount of DMAP at room temperature. After stirring for 1 hour, the reaction mixture was poured into a solution of NaHC 3 and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, CH2Cl2 / MeOH: 95: 5 in 2 developed) to 46.6 mg (44.4%) of a colorless foam. 1 H NMR (270 MHz, CDCl 3) d 7.53-7.49 (3H, m), 7.37-7.29 (2H, m), 7.26-7.05 (4H, m), 4.97-4-90 (1H, m), 4.61- 4.56 (1 H, m), 4.28-4.19 (1 H, m), 4.02-3.96 (1 H, m), 3.65-3.59 (1 H, m), 3.48-3.43 (1 H, m), 2.99- 2.93 (2H, m), 2.29-2.17 (4H, m), 2.10-2.05 (4H, m), 1.83-1.70 (5H, m), 1.57-1.48 (5H, m), 1.45-1.41 (9H, m ). A mixture of this Boc derivative (46.6 mg) and a solution of HCl in MeOH (1 ml) was stirred at room temperature for 11 h. The reaction mixture was concentrated in vacuo and the residue was dried at 45 ° C to give 40 mg of the title compound as an HCl salt, mp 180-184 ° C. MS (ESI positive) m / z: 433 (M + H) +. IR (KBr): 3400, 2930, 2860, 1690, 1605, 1490 cm "1.

Analysis calculated for C 27 H 36 N 4 O-2 HCl-2 H 2 O: C, 59.88; H, 7.82; H, 10.35. Found: C, 59.64; H, 7.98; N, 10.09.

PREPARATION 10 2-Chloro-1-f1 - (1-phenyl-4-cyclohepten-1-yl-piperidinyl-benzoimidazole This was prepared according to the procedure described in example 1 using 4-cycloheptenone instead of cycloheptanone. The total yield was 21.2%. 1 H NMR (270 MHz, CDCl 3) d 7.69-7.65 (1 H, m), 7.59-7.55 (1 H, m), 7.46-7.34 (4H, m), 7.27-7.20 (3H, m), 5.74 (2H , t, J = 3.0 Hz), 4.35-4.25 (1 H, m), 3.35-3.20 (2H, m) 2.50-2.22 (8H, m), 2.15-1.80 (6H, m).

EXAMPLE 72 1 - (1-f1 - (1-Phenyl-4-cyclohepten-1-yl) -4-piperidin-p-1 H-benzoimidazol-2-yl.} -4- piperidinamine This was prepared according to the procedure described in Example 67 using 2-chloro-1- [1- (1-phenyl-4-cyclohepten-1-yl) -4-piperidinyl-benzoimidazole as the starting material. The total yield was 49%. The HCi salt was an amorphous solid.

? NMR (270 MHz, DMSO-d6) d 8.68 (1 H, sa), 8.65 (1 H, sa), 8.34 (3H, sa), 7.90-7.75 (2H, m), 7.60-7.45 (5H, m) , 7.40-7.20 (2H, m), 5.78-5.70 (2H, m), 4.45-4.30 (1 H, m), 3.80-2.80 (13H, m), 2.65-2.40 (4H, m), 2.15-1.70 (8H, m). MS (El) m / z: 469 (M +), 392, 370, 299, 253, 217, 170, 142. IR (KBr): 3400, 2939, 1618, 1499 cm "1. Analysis calculated for C3oH39H5-3HCI- 6H2O: C, 52.44; H, 7.92; N, 10.19, Found: C, 52.71; H, 7.66; N, 10.06.

EXAMPLE 73 N-1 -11-n- (1-Phenylcycloheptin-4-piperidnip-1 H -benzolamdazol-2-yl) -1, 8-octanediamine This was prepared according to the procedure described in Example 20 using 1,8-octanediamine instead of amylamine. The yield was 57%. 1 H NMR (270 MHz, CDCl 3) d 7.51-7.44 (3H, m), 7.37-7.19 (4H, m), 7.10-6.97 (2H, m), 4.284.22 (1 H, m), 3.82-3.70 ( 1 H, m), 3.51-3.46 (2H, m), 3.02-2.98 (2H, m), 2.71-2.65 (2H, m), 2.33-1.96 (12H, m), 1.74-1.63 (4H, m) , 1.54-1.25 (16H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 179-182 ° C. MS (ESI positive) m / z: 516 (M + H) +. IR (KBr): 3400, 2934, 1653, 1479 cm "1. Analysis calculated for C33H49H5-3HCI-2H2O: C, 59.95: H, 8.54; N, 10.59.Finding: C, 59.55; H, 8.89; N, 10.39 .

EXAMPLE 74 N-1 -. { 1-f 1 -d-Phenylcycloheptyl) -4-piperidin-1 H-benzoimidazol-2-yl} -1, 10- decanodiamine This was prepared according to the procedure described in example 20 using 1, 10-decanodiamine in place of amylamine. The yield was 61.5%. 1 H NMR (270 MHz, CDCl 3) d 7.51-7.44 (3H, m), 7.37-7.30 (2H, m), 7.28-7.19 (2H, m), 7.10-6.97 (2H, m), 4.184.14 (1 H, m), 3.82-3.71 (1 H, m), 3.55-3.46 (2H, m), 3.03-2.98 (2H, m), 2.70-2.64 (2H, m), 2.32-2.09 (8H, m) , 1.77-1.26 (28H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 165-168 ° C. MS (ESI positive) m / z: 544 (M + H) +. IR (KBr): 3416, 2930, 1653, 1468 cm "1.

Analysis calculated for C35H53N5-3HCI-2.4H2O: C, 60.36; H, 8.80; N, 10.06. Found: C, 60.66; H, 9.22; N. 9.92.

EXAMPLE 75 1-. { 1-f1- (1-lsopropylcycloheptyl) -4-piperidinyl-1 H-benzoimidazol-2-yl} -4- piperidinamine This was prepared according to the procedure described in Example 67 using 2-chloro-1- [1- (1-isopropylcycloheptyl) -4-piperidinyl] -benzoimidazole as starting material which was prepared in Example 69 The total yield from 2-chloro-1- [1- (1-isopropyl-cycloheptyl) -4-piperidinyl-benzoimidazole was 72%. This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 8.78 (1 H, sa), 8.65 (1 H, sa), 8.40 (3 H, sa), 8.35-8.25 (1 H, m), 7.63-7.55 (1 H, m ), 7.45-7.28 (2H, m), 4.574.42 (1H, m), 3.33-3.10 (10H, m), 2.40-1.80 (14H, m), 1.65-1.42 (6H, m), 1.10 ( 6H, d, J = 6.8 Hz). MS (ESI positive) m / z: 438 (M + H) +. IR (KBr): 3364, 2934, 1634, 1616, 1475 cm "1. Analysis calculated for C27H43N5-3HCI-5H2O: C, 50.90; H, 8.86; N, 10.99 Found: C, 50.71; H, 8.79; N, 10.85.

EXAMPLE 76 N-N-11 -fi - (1-Pheneicycloheptyl) -4-piperidinin-1 H-benzoimidazol-2-yl} -1, 4-cyclohexanediamine This was prepared according to the procedure of Example 34 using 4- (t-butoxycarbonylamino) cyclohexyl isothiocyanate (this was presented by J. Smith et al., J. Org. Chem., 1996, 61, 8811-8818) in place of ethyl 4-isothiocyanato-1-piperidinacarboxylate. The total yield from N-1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1,2-benzenediamine was 5.4%. The NMR data of the Boc derivative were as shown below. 1 H NMR (270 MHz, CDCl 3) d 7.52-7.22 (7H, m), 7.11-6.99 (2H, m), 4.48-4.43 (1 H, m), 4.094.01 (1 H, m), 3.93-3.78 (2H, m), 3.69-3.61 (1H, m), 3.49-3.39 (1H, m), 3.06-3.02 (2H, m), 2.29-1.99 (11H, m), 1.78-1.73 (5H , m), 1.62-1.53 (5H, m), 1.47-1.44 (9H, m), 1.37-1.20 (4H, m). HCl salt, mp 242-246 ° C. MS (ESI positive) m / z: 486 (M + H) +. IR (KBr): 3400, 2937, 1647, 1479 cm "1. Analysis calculated for C31H43N5-3HCM.2CH2Cl2: C, 55.49; H, 7.00; N, 10.05. Found; C, 55.07; H, 7.06; N, 10.41 .

PREPARATION 11 2-Chloro-1-f1 - (1-vinylcycloheptyl) -4-piperidinylbenzoimidazole This was prepared according to the procedure described in example 1 using magnesium-magnesium bromide instead of phenylmagnesium bromide. The total yield was 15.3%. 1 H NMR (270 MHz, CDCl 3) d 7.72-7.56 (2H, m), 7.30-7.20 (2H, m), 5.78 (1 H, dd, J = 10.9, 17.6 Hz), 5.13 (1 H, d, J = 10.9 Hz), 5.05 (1 H, d, J = 17.6 Hz), 4.484.32 (1 H, m), 3.24-3.14 (2H, m), 2.55-2.36 (2H, m), 2.32-2.18 ( 2H, m), 2.00-1.80 (4H, m), 1.74-1.40 (1 OH, m).

EXAMPLE 77 1-. { 1-f1- (1-Vinylcycloheptyl) 4-piperidinin-1H-benzoimidazol-2-yl > -4- piperidinylamine This was prepared according to the procedure described in Example 67 using 2-chloro-1- [1- (1-vinylcycloheptyl) 4-piperidinyl] benzoimidazole as a starting material. The total yield from 2-chloro-1- [1- (1-vinylocycloheptyl) 4-piperidinyl] benzoimidazole was 36.1% This free amine was converted to the HCl salt using a solution of HCl in MeOH to give an colorless amorphous solid. 1 H NMR (270 MHz, CDCl 3) d 11.10 (1 H, sa), 8.60-8.50 (1 H, m), 8.35 (3 H, sa), 7.62-7.55 (1 H, m), 7.40-725 (2H, m), 6.10 (1 H, dd, J = 11, 2, 17.5 Hz), 5.61 (1 H, d, J = 11.2 Hz), 5.51 (1 H, d, J = 17.5 Hz), 4.554.40 ( 1 H, m), 3.75-3.00 (9H, m), 2.28-1.35 (20H, m). MS (ESI positive) m / z: 422 (M + H) + IR (KBr): 3400, 2926, 1633, 1616, 1456 cm "1. Analysis calculated for C26H39N5-3HCI-3H2O-0.9CH2Cl2: C, 48. 84; H, 7.59; N, 10.59. Found: C, 48.61; H, 7.95; N, 10.74.

EXAMPLE 78 2-Methyl-N-1-y1-ri-f1-phenycloheptyl) -4-piperidinin-1 H -benzoimidazol-2-yl > - 1, 2-propanediamine This was prepared according to the procedure described in Example 20 using 1,2-diamino-2-methylpropane in place of amylamine. The yield was 26.2%. ? NMR (270 MHz, CDCl 3) d 7.52-7.41 (3H, m), 7.35-7.18 (4H, m), 7.09-6.97 (2H, m), 3.98-3.87 (1H, m), 3.47 (1H, s), 3.43 (1 H, s), 3.02-2.98 (2H, m), 2.34-2.20 (4H, m), 2.11-2.01 (4H, m), 1.81-1.71 (5H, m), 1.59-1.45 (5H, m), 12.4 (6H, s). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, 230-234 ° C. MS (ESI positives) m / z: 460 (M + H) + IR (KBr): 3406, 2934, 1649, 1479 cm "1.

Analysis calculated for C29H41N5-3HCI-2.5H2O. C, 56.72; H, 8.04; N, 11.40. Found: C, 56.43; H, 8.35; N, 11.26.

EXAMPLE 79 1 -ii- (1-Phenylcyclohepten-1-l) -4-piperidin-p-2- (1-piperazin-1 H-benzoimidazole This was prepared according to the procedure described in example 67 using 1-Nt-butoxycarbonylpiperazine instead of 4-t-butoxycarbonylaminopiperidine and 2-chloro-1- [1- (1-phenyl-4-cyclohepten-1-yl) 4-piperidinyl-benzoimidazole as starting material, which was prepared in preparation 9. The total yield was 40.3%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 11.07 (1 H, s a), 9.61 (3H, s a), 8. 65 (1 H, d, J = 7.9 Hz), 7.83-7.75 (2H, m), 7.62-7.50 (4H, m), 7.38-7.24 (2H, m), 5.77-5.72 (2H, m), 4.534 .43 (1 H, m), 3.75-2.85 (16H, m), 2.65-2.45 (4H, m), 2.15-1.80 (4H, s). MS (El) m / z: 455 (M +), 399, 331, 284, 252, 203, 184, 134. IR (KBr); 3400, 2920, 1650, 1456 cm "1. Analysis calculated for C29H3 N5-3HCI4H2O: C, 54.67; H, 7.59; N, 10.99. Finding: C, 54.44; H, 8.09; N, 11.10.

EXAMPLE 80 3- ( { 1-ri- (1-Phenyl-cycloheptyl) -4-piperidin-1H-benzoimio! Azole-2-yl> sulfonyl) -1-propanamide A solution of 1- [1- (1-phenylcycloheptyl) 4-piperidinyl] phenylene-1,2-diamine (prepared in Preparation 1, 114 mg, 0.314 mmol) and carbon disulfide (0.0944 mL) in EtOH (3 ml) was heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, CH 2 Cl 2 / MeOH: 15/1) to give 96.9 mg (76.2%) of a brown solid. A mixture of this solid (96.9 mg, 0.239 mmol), 3-t-butoxycarbonylaminopropyl bromide (84.8 mg), a solution of NaOH (29.2 mg) in water (1 ml) and EtOH (3 ml) was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO), filtered and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, hexane / acetone: 7/3) to give 102 mg (75.9%) of a colorless foam. 1 H NMR (270 MHz, CDCl 3) d 7.66-7.62 (1 H, m), 7.53-7.50 (3H, m), 7.38-7.31 (2H, m), 7.23-7.15 (2H, m), 6.14-6.04 (1H, m), 4.144.04 (1H, m) , 3.46-3.40 (2H, m), 3.28-3.21 (2H, m), 3.03-2.99 (2H, m), 2.42-2.24 (4H, m), 2.21-2.10 (4H, m), 2.01-1.91 ( 2H, m), 1.78-1.71 (5H, m), 1.59-1.42 (5H, m), 1.47 (9H, s). To a stirred solution of this Boc derivative (58.9 mg, 0.105 mmol) in AcOH (0.5 mL) was added a solution of KMn04 (38.1 mg, 0.241 mmol) in water (4 mL) at 0 ° C. After stirring for 2 hours at room temperature, the reaction mixture was diluted with NaHSO 4 solution at 0 ° C and basified with a 25% solution of NH 4 OH. The reaction mixture was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (0.5 mm x 2 plate, hexane / acetone: 4/1) to give 16.2 mg (26%) of a colorless syrup. 1 H NMR (270 MHz, CDCl 3) d 7.84-7.72 (2H, m), 7.54-7.50 (2H, m), 7.45-7.31 (3H, m), 7.27-7.20 (2H, m), 5.24-5.16 (1 H, m), 5.034.93 (1 H, m), 3.83-3.76 (2H, m), 3.37-3.29 (2H, m), 3.02-2.98 (2H, m), 2.44-2.27 (4H, m) , 2.26-2.17 (2H, m), 2.15-2.04 (2H, m) 1.96-1.93 (2H, m) 1.79-1.69 (3H, m), 1. 61-1.53 (3H, m), 1.46 (9H, s). A solution of this Boc derivative (16.2 mg) and HCl solution in MeOH (1 ml) in CH2Cl2 (1 ml) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was dried at 45 ° C to give 10 mg of the title compound as an HCl salt. MS (ESI positive) m / z: 495 (M + H) +. IR (KBr): 3400, 2934, 1690, 1485, 1387 cm "1.

Analysis Calculated for C28H38N4O-2HCl4H2O: C, 52.57; H, 7. 56; N, 8.76. Found: C, 52.20; H, 7.51; N, 8.59.

EXAMPLE 81 1 -f 1 -f 1 -Fenylcyclooctyl) -4-piperidinyl-1 H-benzoimidazole-2 -amine This was prepared according to the procedure described in preparation 4 and in example 31 using cyclooctanone in place of cyclononanone and phenylmagnesium bromide in place of 4-fluorophenylmagnesium bromide. The total yield from cyclooctanone was 8. 6% ? NMR (270 MHz, CDCl 3) d 7.46-7.20 (7H, m), 7.13-7.01 (2H, m), 3.88-3.75 (1H, m), 3.21-3.15 (2H, m), 2.37-1.95 (8H , m), 1.80-1.35 (14H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless amorphous solid. MS (El) m / z: 434 (M +), 349, 321, 216, 134, 109, 82. IR (KBr): 3350, 1670 cm. "Analysis Calculated for C27H35FN4-2HCM .7H2O: C, 60.26; H, 7. 57; N, 10.41. Found: C, 60.29; H, 7.62; N, 10.19.

EXAMPLE 82 2-Amino-N-. { 1-f1 - (1-phenylcyclooct8l) -4-piperidin-1 H-benzoimidazole-2-H} - acetamide This was prepared according to the procedure described in Example 70 using 1- [1- (1-phenylcyclooctyl) 4-piperidinyl] -1H-benzoimidazol-2-amine. The total yield was 49.6%. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.15 (10H, m), 4.704.50 (1 H, m), 3.53 (2H, s), 3.47 (2H, s), 3.22-3.10 (2H, m) , 2.45-2.00 (8H, m), 1.85-1.30 (12H, m). This free amine was converted to the HCl salt using a solution of HCl in MeOH to give a colorless solid, mp 217-221 ° C. MS (ESI positive) m / z: 403 (M + H) + IR (KBr): 3387, 2922, 1742, 1553, 1475 cm. "Analysis Calculated for C28H37N5O-2HCI-0.7CH2Cl2: C, 58.23; H, 6.88; N, 11.83, Found: C, 58.22; H, 6.57; N, 11.95.

EXAMPLE 83 (2S, 3S) -2-Amino-3-methyl-N-1-M - (1-methylcycloheptyl) -4-piperidinin-1H-benzoimidazol-2-yi > pentanamide This was prepared according to the procedure described in Examples 10 and 70 using? / - 1- [1- (1-methylcycloheptyl) 4-piperidinyl] -1,2-benzenediamine as a starting material which was prepared in the preparation 8 and Boc-L-isoleucine. Trifluoroacetic acid and CH2Cl2 were used for the deprotection reaction at the HCl and MeOH site. The total yield was 33.1%. Finally, the trifluoroacetic acid salt was converted to the HCl salt using HCl in MeOH. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.74 (1 H, sa), 8.38 (3H, sa), 8.25-8.10 (1H, m), 7.63-7.53 (1 H, m), 7.32-7.23 (2H, m), 5.46-5.33 (1H, m), 3.75-3.60 (3H, m), 3.55-3.10 (4H, m), 2.30-1.20 (18H, m), 1.50 (3H, s), 1.00 (3H, d, J = 6.9 Hz), 0.92 (3H, t, J = 7.3 Hz). MS (El) m / z: 439 (M +), 424, 395, 382, 353, 328, 285, 247, 193, 136. IR (KBr): 3387, 2934, 1734, 1626, 1578 cm "1. Calculated for C 26 H 41 N 5 O-2 HCl-5.5 H 2 O: C, 51.06; H, 8. 90; N, 11.45. Found: C, 51.06; H, 8.41; N, 11.25.

EXAMPLE 84 3-Amino-? Mi -f 1 - (1-phenylcycloheptyl) 4-piperidin-1 H-benzoimidazol-2-yl} propanamide This was prepared according to the procedure described in Example 83 using 3-f-butoxycarbonylaminopropionic acid and Example 10 as a starting material. The total yield was 86%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.96 (1 H, sa), 8.70-8.60 (1 H, m), 8.19 (3 H, sa), 7.93-7.80 (2H, m), 7.73-7.65 (1 H , m), 7.58-.30 (6H, m), 5.50-5.30 (1 H, m), 3.20-1.20 (24H, m). MS (ESI positive) m / z: 460 (M + H +). IR (KBr): 3400, 2932, 1736, 1624, 1583 cm. "Analysis Calculated for C28H37N5O-2HCl4.5H2O: C, 54.81; H, 7.88; N, 11.41, Found: C, 54.97; H, 7.64; N , 11.02.

EXAMPLE 85 2-Amino-2-methyl- / V-. { 1 -H - (1-phenylcycloheptyl) -4-piperidinin-1H-benzoimidazol-2-yl} propanamide This was prepared according to the procedure described in Example 83 using 2-f-butoxycarbonylaminoisobutyric acid and Example 10 as a starting material. The total yield was 38.1%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.51 (1 H, sa), 8.32 (3 H, s), 8.10-8.00 (1 H, m), 7.95-7.85 (2 H, m), 7.60-7.40 (5H , m), 7.27-7.20 (2H, m), 5.25-5.10 (1H, m), 3.30-3.15 (2H, m), 2.90-2.75 (2H, m), 2.65-2.50 (2H, m), 1.95-1.80 (4H, m), 1.70-1.25 (10H, m), 1.48 (6H, s). MS (ESI positive) m / z: 474 (M + H) + IR (KBr): 3400, 2934, 1730, 1624, 1555 cm "1. Analysis Calculated for C29H39N5O-2HCI4.2H2O-1.2CH2Cl2: C, 55. 30; H, 7.91; N, 11.07. Found: C, 55.59; H, 7.49; N, 11.16.

EXAMPLE 86 (2S. 3S) -2-Amino-3-methyl- / V-. { 1-M - (1-phenylcycloheptyl) -4-piperidinin-1H-benzoimidazol-2-yl > pentanamide This was prepared according to the procedure described in Example 83 using Boc-L-isoleucine and Example 190 as a starting material and diethyl phosphorocyanidate,? /, / V-diisopropylethylamine and DMF instead of WSC and CH2Cl2 for the coupling reaction. The total yield was 28.8%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.63 (1H, sa), 8.29 (3H, sa), 8.20-8.05 (1H, m), 7.95-7.85 (2H, m), 7.65-7.40 (5H, m ), 7.35-7.20 (2H, m), 5.25-5.10 (1H, m), 3.30-3.15 (3H, m), 2.90-2.75 (2H, m), 2.15-2.50 (2H, m), 2.15- 1.75 (6H, s), 1.70-1.20 (8H, m), 1.05-0.85 (6H, m). MS (ESI positive) m / z: 502 (M + H) +. IR (KBr): 3395, 2934, 1736, 1578 cm'1. Analysis Calculated for C3? H43N5O-2HCI4.6H2OO.4CH2Cl2: C, 54.54; H, 8.02; N 10.13. Found: C, 54.14; H, 7.65; N, 10.62.

EXAMPLE 87 (2S) -2-Amino-3-methyl- / V- (1-ri- (1-phen-lc 8 -cloheptyl) -4-piperidin-1-t-benzoimidazole-2-di-butanamide This was prepared according to the procedure described in Example 86 using Example 10 as a starting material. The total yield was 33.7%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.55 (1 H, sa), 8.23 (3 H, sa), 8.10-8.00 (1 H, m), 7.93-7.85 (2H, m), 7.60-7.45 (5H , m), 7.35-7.20 (2H, m), . 20-5.00 (1 H, m), 3.30-3.15 (4H, m), 2.90-2.75 (2H, m), 2.65-2.50 (2H, m), 2. 35-2.25 (1 H, m), 1.95-1.80 (5H, m), 1.65-1.20 (8H, m), 1.03 (3H, d, J = 6.6 Hz), 1.01 (3H, D, J = 6.9 Hz). MS (ESI positive) m / z: 488 (M + H) +. IR (KBr): 3396, 2934, 1734, 1580 cm "1. Calculated for C3oH41N5O-2HCI4H2O-0.35CH2CI2: C, 55.03; H, 7.87; N, 10.57. Found: C, 55.38; H, 7.73; N, 10.96.

EXAMPLE 88 (2S) -2-Amino-? 1 -H - (1-phenylcycloheptyl-4-piperidinyl * l-1 H-benzoimidazol-2-yl propanamide This was prepared according to the procedure described in Example 86 using (S) -Boc-alanine and Example 10 as a starting material. The total yield was 20.8%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.74 (1H, sa), 8.36 (3H, sa), 8.23 (1H, sa), 7.95-7.85 (2H, m), 7.65-7.40 (5H, m), 7.35-7.20 (2H, m), 5.35-5.15 (1H, m), 3.50-3.10 (5H, m), 2.90-2.75 (2H, m), 2.65-2.50 (2H, m), 1.95-1.80 (5H , m), 1.65-1.20 (7H, m), 1.46 (3H, d, J = 7.1 Hz). IR (KBr): 3408, 2932, 1736, 1626, 1582 cm. "1 Analysis Calculated for C28H3 N5? -2HCI-3.7H2? -0.1 CH2Cl2: C, 55.54; H, 7.73; N, 11.52. Found: C, 55.20; H, 7.34; N, 11.70.

EXAMPLE 89 2S) -2-Amino-4- (methylsulfanyl) -? / - (1 -H - (1-phenylcyanoheptyl -piperidinylH-tf-benzoimidazol-2-yl> butanamide This was prepared according to the procedure described in Example 70 using (S) -Boc-methionine and Example 10 as a starting material. The total yield was 66.1%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.72 (1 H, sa), 8.44 (3H, sa), 8.18 (1 H, sa), 7.95-7.75 (2H, m), 7.60-7.40 (5H, m) , 7.30-7.15 (2H, m), 5.30-5.10 (1 H, m), 3.90-3.75 (1 H, m), 3.55-3.10 (6H, m), 2.90-2.40 (4H, m), 2.20- 2.00 (2H, m), 2.05 (3H, s), 1.95-1.75 (5H, m), 1.65-1.20 (7H, m). IR (KBr): 3404, 2930, 1734, 1624, 1582 cm. "1 Calculated for C3oH4? N5OS-2HCI-3.3H2O-0.2CH2CI2: C, 54.21; H, 7.53; N, 10.47 Found: C, 54.35; H, 7.21; N, 10.49.

EXAMPLE 90 (2S) -? 1 -p- (1-phenylcyclohept-4-piperidinip-1-t-benzoimidazol-2-yl.} -2- pyrrolidinecarboxamide This was prepared according to the procedure described in Example 86 using (s) -Boc-proline and Example 10 as a starting material. The total yield was 48.9%. The HCl salt was an amorphous solid. NMR (270 MHz, DMSO-d6) d 10.70 (1 H, sa), 10.01 (1 H, sa), 8.67 (1 H, sa), 8.35-8.20 (1 H, m), 8.00-7.85 (2H, m), 7.65-7.45 (4H, m), 7.35-7.20 (2H, m), 5.40-5.20 (1H, m), 4.354.15 (2H, m), 3.50-3.10 (9H, m), 2.90 - 2.75 (2H, m), 2.65-2.50 (2H, m), 2.40-2.25 (1H, m), 2.15-1.75 (6H, m), 1.65-1.20 (6H, m). MS (ESI positive) m / z: 486 (M + H) +. IR (KBr): 3404, 2932, 1736, 1624, 1583 cm. "Analysis Calculated for C3oH3gN5O-2HCI4H2? -0.1 CH2Cl2: C, 56.56; H, 7.76; N, 10.96 Found: C, 56.27; H, 7.36; N, 11.16.

EXAMPLE 91 4-Amino-? Mi -H -f 1 -phenylcycloheptyl) -4-piperidinip-1 V-benzoimidazol-2-iD-2-butanamide This was prepared according to the procedure described in Example 83 using 4-β-butoxycarbonylaminobutyric acid and Example 10 as a starting material. The total yield was 68%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 11.06 (1 H, sa), 8.68 (1 H, sa), 8.16 (3 H, s), 7.95-7.80 (2H, m), 7.80-7.65 (1 H, m ), 7.60-7.35 (5H, m), 5.65-5.35 (1H, m), 3.25-3.00 (6H, m), 3.00-2.70 (7H, m), 2.65-2.45 (2H, m), 2.20- 1.75 (6H, m), 1.70-1.20 (6H, m). IR (KBr): 3412, 2935, 1734, 1624, 1583 cm. "Analysis Calculated for C29H39N5O-2HCI H2? -0.1CH2Cl2: C, 55.73; H, 7.91; N, 11.17. Found: C, 55.55; H, 7.55; N, 11.06.

EXAMPLE 92 (2S) -2-Amino-3-methyl (methylsulfanyl) -? / -. { 1-f 1 - (1-phenylcycloheptyl) 4-piperidinyl-1/7-benzoimidazol-2-yl} -1 -butanamide This was prepared according to the procedure described in Example 83 using WSC and 1-hydroxybenzotriazole hydrate as coupling reagents, and / V-f-Boc-S-methyl-L-penicillamine and Example 10 as a starting material. The total yield was 78%. The HCl salt was an amorphous solid. H NMR (270 MHz, DMSO-d6) d 10.62 (1 H, sa), 8.40-8.00 (5H, m), 7.90-7.70 (2H, m), 7.50-7.30 (5H, m), 7.20-7.05 ( 2H, m), 5.30-5.00 (1 H, m), 4.00-3.00 (5H, m), 2.80-2.60 (2H, m), 2.55-2.40 (3H, m), 1.96 (3H, s), 1.85 -1.65 (4H, m), 1.55-1.10 (8H, m), 1.37 (3H, s), 1.26 (3H, s). MS (ESI positive) m / z: 534 (M + H) +. IR (KBr): 3387, 2932, 1732, 1560 cm. "Analysis Calculated for C3? H45N5? S-2HCI-2H2OO.4CH2Cl2: C, 55.57; H, 7.69; N, 10.32 Found: C, 55.49; 7.60; N, 10.34.

EXAMPLE 93 (2R) -2-Amino-? Hi -f1 - (1-phenylcycloheptyl) -4-piperidinin-1 H -benzoimidazol-2-yl > -1 -propanamide This was prepared according to the procedure described in Example 83 using (R) -Boc-alanine and Example 10 as a starting material. The total yield was 77.6%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.75 (1 H, sa), 8.37 (3 H, sa), 8.26 (1 H, sa), 7.95-7.85 (2H, m), 7.65-7.40 (4H, m ), 7.35-7.20 (2H, m), 5.40- 5.20 (1 H, m), 4.00-3.10 (7H, m), 2.90-2.70 (2H, m), 2.65-2.45 (2H, m), 2.00- 1.75 (4H, m), 1.65-1.20 (6H, m), 1.46 (3H, d, J = 6.8 Hz). MS (ESI positive) m / z: 460 (M + H) +. IR (KBr): 3396, 2934, 1736, 1582 cm. "Analysis Calculated for C28H37N5? -2HCI-3H2O-0.5CH2Cl2: C, 54.42; H, 7.37; N, 11.13, Found: C, 54.73; H, 7.28; N, 11.45.

EXAMPLE 94 (2S) -2-Amino-3-phenyl-? / -. { 1-p- (1-phenylcycloheptyl) -4-piperidin-1H-benzoimidazol-2-yl) propanamide This was prepared according to the procedure described in Example 83 using (S) -Boc-phenylalanine and Example 10 as a starting material. The total yield was 81%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.74 (1 H, sa), 8.40 (3H, sa), 8.18 (1 H, sa), 7.95-7.80 (2H, m), 7.60-7.40 (4H, m) , 7.35-7.10 (7H, m), 5.10-4.85 (1H, m), 4.10-3.95 (1H, m), 3.30-3.00 (8H, m), 2.90-2.75 (2H, m), 2.65-2.40 (2H, m), 1.95-1.70 (4H, m), 1.65-1.15 (6H, m). MS (ESI positive) m / z: 536 (M + H) +. IR (KBr): 3396, 2932, 1734, 1622, 1578, 1558 cm "1.

Analysis Calculated for C 34 H 1 N 5 O-2 H 2 -2 H 2 O-0.5 CH 2 Cl 2: C, 64.30; H, 7.04; N, 10.19. Found: C, 60.44; H, 6.80; N, 10.48.

EXAMPLE 95 1 -Amino-? Hi -f1- (1-phenylcycloheptyl) -4-piperidinin-1 H-benzoimidazol-2-yl > cyclopentanecarboxamide This was prepared according to the procedure described in Example 92 using 1-β-butoxycarbonylaminocyclopentanecarboxylic acid and Example 10 as a starting material. The total yield was 80%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.96 (1 H, sa), 8.40 (3H, sa), 8.16 (1 H, sa), 7.95-7.85 (2H, m), 7.60-7.35 (4H, m) , 7.30-7.10 (7H, m), 5.40-5.20 (1H, m), 3.50-3.15 (6H, m), 2.90-2.70 (2H, m), 2.65-2.40 (2H, m), 2.30-2.10 (2H, m), 2.00-1.70 (10H, m), 1.65-1.20 (6H, m). MS (ESI positive) m / z: 500 (M + H) +. IR (KBr): 3398, 2934, 1724, 1556 cm'1. Analysis Calculated for C3? H41N5O-2HCI-3.2H2O: C, 59.08; H, 7.90; N, 11.11. Found: C, 59.08; H, 7.85; N, 10.89.

EXAMPLE 96 f2R) -2-Amino-3-methyl- / V- (1 -H - (1-phenylcycloheptyl) -4-piperidinip-1 H -benzoimidazol-2-yl) butanamide This was prepared according to the procedure described in Example 92 using (R) -Boc-valine acid and Example 10 as a starting material. The total yield was 91%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.73 (1H, sa), 8.35 (3H, sa), 8.20 (1H, sa), 7.95-7.70 (2H, m), 7.60-7.30 (4H, m) , 7.30-7.10 (2H, m), 5.35-5.15 (1H, m), 3.70-3.00 (7H, m), 2.90-2.70 (2H, m), 2.65-2.40 (2H, m), 2.40-2.20 (2H, m), 1.95-1.70 (4H, m), 1.65-1.15 (6H, m), 1.02 (3H, d, J = 5.6 Hz), 1.00 (3H, d, J = 5.1 Hz). MS (ESI positive) m / z: 488 (M + H) +. IR (KBr): 3400, 2930, 1738, 1583 cm "1. Analysis calculated for C3oH? N5O-2HCI4.7H2O: C, 55.84; H, 8.18; N, 10.85. Found: C, 55.77; H, 7.79; N , 10.82.

EXAMPLE 97 (2S) -2-Amino-4- (methylsulfonyl) -? Mi -H -f 1 -phenylcycloheptyl) -4-piperidine »n-1 H -benzoimidazol-2-yl > butanamide This was prepared according to the procedure described in Example 92 using (S) -Boc-methionine sulfone and Example 10 as a starting material. The total yield was 85%. The HCl salt was an amorphous solid. ? NMR (270 MHz, DMSO-d6) d 10.70 (1 H, sa), 8.52 (3H, sa), 8.22 (1 H, sa), 8.00-7.80 (2H, m), 7.65-7.40 (4H, m) , 7.35-7.15 (2H, m), 5.35-5.15 (1H, m), 4.10-3.10 (10H, m), 2.99 (3H, s), 2.90-2.70 (2H, m), 2.65-2.40 (2H , m), 2.40-2.20 (2H, m), 2.00-1.75 (4H, m), 1.65-1.20 (6H, m). MS (ESI positive) m / z: 552 (M + H) +. IR (KBr): 3396, 2934, 1732, 1580 cm "1. Analysis calculated for D8H4iN5? 3S-2HCI4H2O-0.5CH3OH: C, 51. 40; H, 7.49; N, 9.83. Found: C, 51.57; H, 7.36; N, 9.56.

EXAMPLE 98 2-Amino-3- (methylsulfinyl) - / V-. { 1 - | i - (1-phenylcycloheptyl) -4-piperidinyl-1 H-benzoimidazol-2-yl} butanamide This was prepared according to the procedure described in Example 92 using Boc-methionine sulfoxide and Example 10 as a starting material. The total yield was 79%. The HCl salt was an amorphous solid. 1 H NMR (270 MHz, DMSO-d 6) d 10.64 (1H, sa), 8.48 (3H, sa), 8.18 (1H, sa), 7.95-7.70 (2H, m), 7.60-7.35 (4H, m) , 7.30-7.15 (2H, m), 5.30-5.10 (1 H, m), 4.00-3.10 (10H, m), 3.00-2.70 (4H, m), 2.56 and 2.54 (total 3H, each s), 2.35 -2.20 (2H, m), 2.00-1.75 (4H, m), 1.65-1.15 (6H, m). MS (ESI positive) m / z: 576 (M + H) +. IR (KBr): 3395, 2932, 1738, 1582 cm "1. Analysis calculated for C3oH4? N5O2S-2HCI-5H2O: C, 51.57; H, 7. 65; N, 10.02. Found: C, 51.60; H, 7.37; N, 10.01. The chemical structures of the compounds of formula (I) prepared in examples 1 to 98 are summarized in the following table. Z1, Z2, Z3 and Z4 of the compounds prepared in the working examples are all hydrogen except for the compounds of example 45 in which Z4 is fluorine, of example 46 in which Z2 is fluorine and of example 47 in which Z1 is It is fluorine.

TABLE PICTURE (CONTINUED) PICTURE (CONTINUED)

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the following formula: or a salt thereof, wherein R is selected from the group consisting of cycloalkyl (C3-Cn), bicycloalkyl (C6-C6), tricycloalkyl (C6-C16) and tetracycloalkyl (C8-Ci6), where said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? -C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C -? - C7), mono-, di- or tri-halo -alkyl (C C7), alkenyl (C2-C5), alkynyl (C2-C5), phenyl-(C-1-C5) alkyl, aryl and heterocyclic aromatic or non-aromatic groups comprising four to ten ring atoms, wherein from one to four ring atoms are independently selected from heteroatoms, and said phenyl radical being optionally substituted in the phenyl-(C 1 -C 5) alkyl, the aryl or the aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of group consisting of halo, hydroxy, alkyl (C? -C4), haloalkyl (C? -C4), alkoxy (Cr C), haloalkoxy (C?? C), alkyl (C? -C4) - CO-, phenyl, benzyl, -CHO, cyano, alkyl (C.-C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (d-C4) -NH-, di (alkyl- ( C C4)) - N-, alkyl (C? -C4) -CO-NH-, alkyl (C? -C) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = N-OH; Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (C? -C-? 2) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M-, aryl-M-, heterocyclic-M-aromatic or non-aromatic, aryl-alkyl (C? -C5) -M-, heterocycloalkyl (C? -C5) -M- aromatic or non-aromatic, said aromatic heterocyclic radical or non-aromatic of said groups of four to ten ring atoms, wherein from one to four ring atoms are independently selected from heteroatoms, and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NQ, NQCO and CONQ, where Q is selected from the group consisting of hydrogen and (C? -C6) alkyl, said alkyl radical (C? -C12), cycloalkyl (C3-C7) or alkenyl (C2-C6) being optionally substituted? ) in said groups, with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, alkyl (CrC) -NH-, di-alkyl (CrC4) -N-, hydrazino, azido, ureido, amidino, gua nidino, (C -? - C4) alkoxy, alkyl (C -? - C) -S-, alkyl (CrC) -SO- and alkyl (C? -C) -SO2-, and said aryl or radical being optionally substituted aromatic or non-aromatic heterocyclic of said groups, with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? .C), haloalkyl (C -? - C4), hydroxy (CC), halo- alkoxy (C? -C), alkyl (C? C4) -CO-, phenyl, benzyl, CHO, cyano, (C1-C4) alkyl -CO-, NH2-CO-, -NH2-NH2-, amino, (C 1 -C 4) alkyl-NH-, di- (alkyl d-C 4) -N-, alkyl (C 1 -C 4) -CO-NH-, alkyl (C 4) -NH-CO-, hydrazino, azido ureido , amidino, guanidino, oxo y = N-OH; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, alkyl (C? -C), haloalkyl (C? -C4), alkoxy (C?? C4), alkylsulfonium (CrC), (C 1 -C 4) alkyl, -CO-, carboxy, (C 1 -C 4) alkyl -COO-, amino, NH 2 CO-, alkyl (C 4) -CO-NH-, alkyl (C 4) - SO2-NH-, phenyl and naphthalene.

2. The compound according to claim 1, or a salt thereof, wherein R is selected from the group consisting of cycloalkyl (C3-C11) and cycloalkenyl (C3-C11), said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (Ci-C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C -? - C7), mono-, di, or tri-halo-alkyl (C? -C), alkenyl (C2-C5), alkynyl (C2-C5) and aryl, and heterocyclic aromatic or non-aromatic groups comprising four to six atoms of ring, wherein from one to two ring atoms are independently selected from heteroatoms and aryl, or aromatic or non-aromatic heterocycle, wherein each of said groups mentioned above is optionally substituted with up to three substituents independently selected from the group consisting of halo , (C1-C4) alkyl, haloalkyl (CrC), alkoxy (CrC4), -CHO, cyano, alkyl (CrC4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (CC) - NH-, di (alkyl- (C? -C4)) - N-, alkyl (C4), -CO-NH- and alkyl (d-C4) -NH-CO-; Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (C? -C-? O) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M-, aryl-M-, heterocyclic-M-aromatic or non-aromatic, aryl-alkyl (C? -C5) -M- and heterocycloalkyl (CrC5) -M- aromatic or non-aromatic, said aromatic or non-aromatic heterocyclic radical comprising said groups from four to six ring atoms, wherein from one to two ring atoms are independently selected from heteroatoms and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NH, N ((alkyl) (C -? - C6), CONH and NHCO, said alkyl radical (dC-io), (C3-C7) cycloalkyl and (C2-C6) alkenyl being optionally substituted in said groups, with up to three substituents independently selected from the group composed of halo, hydroxy, amino, alkyl (CrC4) -NH-, di-C1-C4-alkyl- N-, hydrazino, azido, ureido, amidino, guanidino, alkyl, (C? -C4) -S-, alkyl (C -? - C4) -SO- and alkyl (C? -C4) ) -SO-, and said aryl or aromatic or non-aromatic heterocyclic radical of said groups being optionally substituted, with substituents independently selected from the group consisting of halo, hydroxy, alkyl (CrC), halo- (C1-C4) alkyl, alkoxy (C1-C4), alkyl (C4) -CO-, phenyl, benzyl, amino, alkyl (Ct-C4) -NH-, di- (alkyl CrC) -N-, alkyl (CrG -CO-NH-, NH2-CO-, alkyl (CrC) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = N-OH; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo.

3. The compound according to claim 2, or a salt thereof, wherein R is selected from cycloalkyl (C3-Cn), cycloalkenyl (C3-C11), mono-, di- or tri-halo-cycloalkyl (C3-Cn), mono-, di- or tri-halo-cycloalkenyl (C3-C11); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C -? - C), alkenyl (C2-C5), selected aryl between the group consisting of phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, oxazinyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and thiazinyl, said aryl or aromatic heterocycle being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C -? - C4) alkyl, haloalkyl (CrC4) and alkoxy (C) -? - C4); Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (C? -C10) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M-, aryl-M -, heterocyclic-M-aromatic or non-aromatic, aryl-alkyl (C -? - C5) -M-, aromatic or non-aromatic-alkyl heterocycle (Ci-CsJ-M-, said aryl radical being selected from said groups from the group composed of phenyl and naphthyl, said aromatic or non-aromatic heterocyclic radical being selected from said groups from the group consisting of azetidinyl, furyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, piperidino, morpholinyl, morforino, pyrimidinyl, piperazinyl, pyridazinyl, aziridinyl, pyrrolidinyl, piperazinyl and thiamorpholino, M is selected from the group consisting of a covalent bond O, S, SO, SO2, CO, NH, CONH, N (C6 alkyl) and NHCO, said alkyl radical being optionally substituted (C1-C10) ), (C3-C7) cycloalkyl and (C2-Ce) alkenyl of said groups with up to three substituents selected independently of the group consisting of halo, hydroxy, amino, alkyl, (C? -C4) -NH-, di-alkyl (C -? - C4) -N ~, hydrazino, azido, ureido, amidino, guanidino, alkyl ( d-C4) -S-, alkyl (C4) -SO- and alkyl (C? -C4) -S? 2-, and said aryl radical or aromatic or non-aromatic heterocyclic radical of said groups with up to three being optionally substituted. substituents selected from the group consisting of halo, hydroxy, alkyl (C? -C4), haloalkyl (Cr C), alkoxy (C? -C4), alkyl (C? -C4) -CO-, phenyl, benzyl, amino, alkyl (C? -C4) -NH-, di (alkyl (C.-C4)) - H-, alkyl (C4) -CO-NH-, NH2-CO-, alkyl (CrC4) -NH- CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = NOH; and Z1 and Z2 are independently selected from the group consisting of hydrogen and halo, and both Z3 and Z4 are hydrogens.

4. The compound according to claim 3, or a salt thereof, wherein R is cycloalkyl (Ce-Cio); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl, (C? -C7) and alkenyl (C2-Cs), phenyl and naphthyl; Y is selected from the group consisting of hydrogen, amino, alkyl (CrCβJ-M-, piperidyl, piperidino and piperazinyl, M is selected from the group consisting of a covalent bond O, SO 2, CO, NH, CONH and NHCO, optionally said alkyl alkyl radical (CrC6) -M with up to three substituents independently selected from the group consisting of amino and guanidino, and said piperidyl, piperidino or piperazinyl being optionally substituted with up to three substituents independently selected from alkyl (Cr C4); Z1, Z2, Z3 and Z4 are hydrogens

5. The compound according to claim 4, or a salt thereof, wherein R is cycloalkyl (C-C9); A is attached to the carbon atom of R with that R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl; Y is selected from the group consisting of amino, alkyl (C? -C6) -NH ~, amino-alkyl ( d-C6) -O-, amino-alkyl (d- C6) -CONH-, amino-alkyl (d-C6) -SO2- and piperazinyl substituted with alkyl (d-d); and Z1, Z2, Z3 and Z4 are hydrogens.

6. The compound according to claim 1, selected from the group consisting of N-methyl-1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1 H-benzoimidazol-2-amine; 2- (4-methylpiperazino) -1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazole; 1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazole; 2- (4-methylpiperazino) -1- [1- (1-phenylcyclooctyl) 4-piperidinyl] -1 H -benzoimidazole; 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -2- (4-piperidinyl) -1 H -benzoimidazole; N-methyl-1- [1- (1-meth ylcyclononyl) -4-piperidinyl] -1 H -benzoimidazol-2-amine; 1 - [1 - (1-phenylcyclononyl) 4-piperidinyl] -1 H -benzoimidazol-2-amine; N-. { 1- [1- (1-phenylcycloheptyl) 4-p-peridinyl] -1 H -benzoimidazol-2-yl} -acetamide; 2- (4-methylpiperazino) -1- [1- (1-methylcyclooctyl) 4-piperidinyl] -1 H- benzoimidazole; 3-amino-1-. { 1- [1- (1-phenylcyclohexyl) -4-piperidinyl] -1H-benzoimidazol-2-yl} -1-propanone; N-methyl-1 - [1 - (1-methylcyclooctyl) 4-piperidinyl] -1 H -benzoimidazol-2-amine; 4-. { 1 - [1 - (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl} -1-piperidinecarboximidamide; 4-. { 1 - [1 - (1-methylcyclooctyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl} -1-piperazinecarboximidamide; 2-amino-N-. { 1 - [1 - (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazoI-2-yl} acetamide; 2- ( { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl}. Oxy) -1-ethanamide; 3- ( { 1- [1- (1-phenyl-cycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl}. Sulfonyl) -1-propanamide; 1 - [1 - (1-phenylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazol-2-amine; 2-amino-N-. { 1- [1- (1-phenylcyclooctyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamide; and (2S) -2-amino-N-. { 1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl} propanamide or a room thereof.

7. The compound according to claim 6, selected from the group consisting of 2- (4-methylpiperazino) -1- [1- (1-phenolcycloheptyl) 4-piperidinyl] -1H-benzoimidazole; 1 - [1 - (1-phenylcyclononyl) 4-piperidinyl] -1 H -benzoimidazol-2-amine; N-methyl-1- [1- (1-methylcyclooctyl) -4-p-peridinyl] -1 H -benzoimidazol-2-amine; 2-amino-N-. { 1 - [1 - (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamide; 2- ( { 1 - [1 - (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl.} Oxy) acetamide; 3- ( { 1 - [1 - (1-phenylcycloheptyl) -4-piperidinyl] -1 H -benzoimidazol-2-yl.] Sulfonyl) -1-propanamine; and 2-amino-N-. { 1- [1- (1-phenylcycloheptyl) 4-piperidinyl] -1 H -benzoimidazol-2-yl} acetamida, or a salt thereof.

8. - A pharmaceutical composition for the treatment of a disorder or condition mediated by the ORL1 receptor and its endogenous ligands in a mammal, including a human, or to anesthetize a mammal, including a human, comprising an effective amount of the compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutically composition for the treatment of a disorder or condition selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, eating disorders, arterial blood pressure disorders, tolerance to narcotic analgesics, dependence on narcotic analgesics , anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias, epilepsy and seizures, useful as an analgesic, anesthetic, neuroprotective agent or analgesic enhancer, or useful for controlling water balance , to regulate hearing, to control the excretion of sodium ions or to improve brain function, comprising an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of such disorder or condition in a mammal, including a human being hand, and a pharmaceutically acceptable vehicle.

10. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder or condition, or for anesthetizing a mammal, including the human, treatment or anesthetic that they can be made or facilitated by the activation of the ORL1 receptor in said mammal, including a human.

11. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of a disorder or condition in a mammal, including a human being, wherein the disorder or condition is selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, eating disorders, arterial blood pressure disorders, tolerance to narcotic analgesics, dependence on narcotic analgesics, anxiety, stress disorders, psychic trauma , schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias, epilepsy and seizures, or to anesthetize a mammal, including humans, or to relieve pain, produce a neuroprotective effect, potentiate analgesics, control the water balance, regulate hearing, control the excretion of ions sodium or improve brain function in a mammal, including a human being.

12. A process for preparing a compound of formula (I), wherein R is selected from the group consisting of cycloalicylate (C3-C11), bicycloalkyl (C6-Ci6), tricycloalkyl (C6-6) and tetracycloalkyl (C8) -C? 6), where said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5) alkyl and (C3-C7) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the pioperidine ring, and is selected from the group consisting of (C 1 -C 7) alkyl, mono-, di- or tri-halo-alkyl (C1-C7), alkenyl (d-Cs), alkynyl (C2-C5), phenylalkyl (C1-C5), aryl and heterocyclic aromatic or non-aromatic groups comprising four to ten ring atoms, where from one to four ring atoms are independently selected from heteroatoms, and said phenyl radical being optionally substituted in the phenyl-(C1-C5) alkyl, the aryl or the aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 4) alkyl, halo (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halo (C 1 -C 4) alkoxy, alkyl (C 1 -C) -CO-, phenyl, benzyl, - CHO, cyano, alkyl (d-C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (d-C4) -NH-, di (alkyl- (d-C4)) - N-, alkyl (dd) -CO-NH-, alkyl (C? -C4) -NH-CO-, hydrazino, azido, ureido, amidino, guanidino, oxo y = N-OH; Y is selected from the group consisting of hydrogen, halo, amino, mercapto, alkyl (dC? 2) -M-, cycloalkyl (C3-C7) -M-, alkenyl (C2-C6) -M-, aryl-M- , heterocycle-M-, aromatic or non-aromatic, aryl-alkyl (C? -C5) -M-, aromatic or non-aromatic or non-aromatic heterocycle-alkyl (d-C5) -M-, said heterocyclic aromatic radical or not aromatic of said groups of four to ten ring atoms, wherein from one to four ring atoms are independently selected from heteroatoms, and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NQ , NQCO and CONQ, where Q is selected from the group consisting of hydrogen and alkyl (dd), said alkyl (dC., 2), (C3-C7) cycloalkyl or alkenyl (dd) radical being optionally substituted in said groups, with to three substituents independently selected from the group consisting of halo, hydroxy, amino, alkyl (C? -d) -NH-, di-alkyl (C? -C4) -N-, hydrazino, azido, ureido, amidino, guanidino, alkoxy (dd), alkyl (C? -C4) -S-, alkyl (dC) -SO- and alkyl (C1-C4) -S? 2-, and said aryl or aromatic heterocyclic radical being optionally substituted or non-aromatic of said groups, with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C? -C), haloalkyl (dC), alkoxy (d-C4), haloalkoxy (C? -C), alkyl (C? -d) -CO-, phenyl, benzyl, -CHO, cyano, alkyl (d-C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (C? -C4) -NH-, di- (C 1 -C 4 alkyl) -N-, alkyl (dC 4) -CO-NH-, (C 1 -C 4) alkyl -NH-CO-, hydrazino, azido, ureido , amidino, guanidino, oxo y = N-OH; and Z1, Z2, Z3 and Z4 is independently selected from the group consisting of hydrogen, halo, (C1-C4) alkyl, haloalkyl (d-C4), alkoxy (dd), alkylsulfonyl (C1-C4), (C1-C4) alkyl-CO-, carboxy, alkyl (d-C4) -COO-, amino, NH2CO-, alkyl (C4) -CO-NH-, alkyl (C? -C) -SO2-NH- , phenyl and naphthyl, which comprises (a) coupling compounds of the formulas wherein R, A, and Z1 are defined as indicated above, and L is halo, to give the compound of formula (b) reducing the compound of formula (IX) to the compound of formula (X) by reduction or hydrogenation; and (c) subjecting the resulting compound of formula (X) to benzoimidazole formation to give the compound of formula (I) - 13.- The process of claim 12, wherein step (a), the coupling reaction is carried out in the presence of a base in a solvent inert to the reaction, at a temperature in the temperature range environment at the reflux temperature of the reaction mixture, for a period of 0.5 to 48 hours; in step (b), the reduction is carried out in the presence of a reduction reagent in a solvent inert to the reaction, at a temperature in the range from room temperature to the reflux temperature of the reaction mixture, over a period of time from 0.5 to 48 hours, and the hydrogenation is carried out in the presence of a metal catalyst at a temperature in the range of 0 ° C to 100 ° C, under an atmosphere of hydrogen, in a solvent inert to the reaction, for a period of 0.5 to 48 hours; and in step (c), the benzoimidazole formation is carried out with a coupling reagent selected from the group consisting of carboxylic acids, aminocarboxylic acids, acid anhydrides, formamides, alkylcarbonyl halides, arylcarbonyl halides, arylalkylcarbonyl halides, acids heteroarylcarboxylics, carbon disulfides, cyanogen halides, cyanamide and trialkyl orthoformates, in the presence of a peptide coupling reagent in a solvent inert to the reaction, at a temperature in the range of 0 ° C to the reflux temperature of the reaction mixture, for a period of 1 minute to 120 hours. 14. The process of claim 13, wherein in step (a), the base is selected from the group consisting of K2C? 3 and amines; in step (b), the reducing reagent is selected from the group consisting of SnCl2, zinc catalysts and iron catalysts, and the metal catalyst used in the hydrogenation is selected from the group consisting of Raney nickel catalysts, palladium catalysts and platinum catalysts; and in step (c), the peptide coupling reagent used in the formation of the benzoimidazole is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ( WSC), benzotriazole-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and diphenylphosphorylazide (DPPA). 15. A compound of formula wherein R is selected from the group consisting of cycloalkyl (C3-C11), bicycloalkyl (C6-C6), tricycloalkyl (d-dS) and tetracycloalkyl (C8-C6), where said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (d-C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and are selected from the group consisting of (C 1 -C 7) alkyl, mono, di-, or tri-halo-alkyl (d-C7), (C2-C5) alkenyl, (C2-C5) alkynyl, phenylalkyl (d-Cs), aryl and aromatic or non-aromatic heterocyclics comprising from four to ten ring atoms, wherein from one to four atoms of ring are independently selected from heteroatoms, and said phenyl radical being optionally substituted in the phenyl-C 1 -C 5 alkyl, the aryl or aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 4) alkyl, halo (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, haloalkoxy (dd), alkyl (C 1 -d) -CO-, phenyl, benzyl, -CHO, cyano, alkyl (C C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (C4) -NH-, di (alkyl- (C? -C4)) - N-, alkyl (C4) -CO-NH-, alkyl (dd) -NH-CO-, hydrazino, azido, ureido, amid ino, guanidino, oxo y =: N-OH; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, alkyl (dd), haloalkyl (dd), alkoxy (d-C4), alkylsulfonyl (d-C4), alkyl ( C1-C4) -CO-, carboxy, alkyl (C? -C) -COO-, amino, NH2CO-, alkyl (d-C4) -CO-NH-, alkyl (C? -C4) -SO2-NH- , phenyl and naphthyl. 16. The compound of claim 15, wherein R is selected from the group consisting of cycloalkyl (d-d-i) and cycloalkenyl (d-C-11), said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (d-C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of the group consisting of alkyl (dd), mono-, di- or tri-halo -alkyl (C1-C7), alkenyl (C2-d), alkynyl (C2-C5), alkynyl (C2-C5), aryl and aromatic or non-aromatic heterocycles comprising four to six ring atoms, wherein one to two ring atoms are independently selected from heteroatoms, and aryl or aromatic or non-aromatic heterocycle wherein each of said groups mentioned above is optionally substituted with up to three substituents independently selected from halo, (C? -C) alkyl, haloalkyl ( C? -C4), (C? -C4) alkoxy, -CHO, cyano, (C1-C4) alkyl -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (d-C4) -NH- , di (alky1- (dC4)) - N-, alkyl (dC4) -CO-NH-, and alkyl (C4) -NH-CO-; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo. 17. The compound according to claim 16, wherein R is selected from the group consisting of cycloalkyl (C3-C11), cycloalkenyl (d-Cn), mono-, di- or tri-halo-cycloalkyl (C3) -C11), mono-, di- or tri-halo-cycloalkenyl (C3-C11); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (dd), alkenyl (C2-C5), aryl selected from the group consisting of by phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl or aromatic heterocycle being optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl (dd), haloalkyl (dC) and (C 1 -C 4) alkoxy; and Z1 and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogens. 18. The compound according to claim 17, wherein R is cycloalkyl (C6-C? O); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (d-C7) and alkenyl (dd), phenyl and naphthyl, and Z1 , Z2, Z3 and Z4 are hydrogens. 19. The compound according to claim 18, wherein R is (C7-C8) cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl; and Z1, Z2, Z3 and Z4 are hydrogens. 20. The compound of formula wherein R is selected from the group consisting of cycloalkyl (C3-Cn), bicycloalkyl (d-dβ). tricycloalkyl (d-dβ) and tetracycloalkyl (dCi 6), wherein said groups are partially saturated, fully saturated or totally unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (C 1 -C 5) ) and cycloalkyl (d-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C? -C), mono, di-, or tri-halo- alkyl (C? -C7), alkenyl (dd), alkynyl (C2-C5), phenylalkyl (C1-C5), aryl and heterocyclic aromatic or non-aromatic groups comprising from four to ten ring atoms, where from one to four ring atoms are independently selected from heteroatoms, and said phenyl radical being optionally substituted in phenyl-(C1-C5) alkyl, aryl or the aromatic or non-aromatic heterocycle, with up to three substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 4) alkyl, halo (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halo (C 1 -C 4) alkoxy, alkyl (dC 4) -CO-, phenyl, benzyl, -CHO, cyano , alkyl (d-C4) -CO-, NH2-CO-, NH2-CH2-, amino, alkyl (C4) -NH-, di (alkyl- (CrC4)) - N-, alkyl (d-C4) -CO-NH-, alkyl (d-dJ-NH-CO-, hydrazino, azido, ureido, a midino, guanidino, oxo y = N-OH; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, alkyl (dd), haloalkyl (dd), alkoxy (d-C4), alkylsulfonyl (C1-C4), alkyl ( d-C4) -CO-, carboxy, (C1-C4) alkyl -COO-, amino, NH2CO-, alkyl (C? -C4) -CO-NH-, alkyl (d-C4) -S02-NH-, phenyl and naphthyl. 21. The compound of claim 20, wherein R is selected from the group consisting of cycloalkyl (C3-Cn) and cycloalkenyl (C3-C11), said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, alkyl (d-C5) and cycloalkyl (C3-C7); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C 1 -C 7) alkyl, mono-, di- or tri-halo-alkyl (C? -d), (C2-C5) alkenyl, (C2-C5) alkynyl, (C2-C5) alkynyl, aryl and aromatic or non-aromatic heterocycles comprising from four to six ring atoms, wherein from one to two ring atoms are independently selected from heteroatoms, and aryl or aromatic or non-aromatic heterocycle where each of said groups mentioned above is optionally substituted with up to three substituents independently selected from halo, (C1-C4) alkyl, halo-alkyl (d-) C4), (C1-C4) alkoxy, -CHO, cyano, alkyl (d-C4) -CO-, NH2-CO-, NH2-CH-, amino, alkyl (C? -C4) -NH ~, d (alkyl- (C? -C4)) - N-, alkyl (d-C4) -CO-NH-, and alkyl (d-C4) -NH-CO-; and Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo. 22. The compound according to claim 21, wherein R is selected from the group consisting of cycloalkyl (C3-C11), cycloalkenyl (C3-Cn), mono-, di- or tri-halo-cycloalkyl (C3) -Cn), mono-, di- or tri-halo-cycloalkenyl (C3-Cn); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (d-C7), alkenyl (C2-d), aryl selected from a group consisting of phenyl and naphthyl, and aromatic heterocycles selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazole, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thiinyl, pyridyl, oxazinyl, thiazinyl , pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl or aromatic heterocycle being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C 1 -C 4) alkyl, halo (C 1 -C 4) alkyl and (C 1 -C 4) alkoxy C4); and Z1 and Z2 are independently selected from the group consisting of hydrogen and halo; and both Z3 and Z4 are hydrogens. 23. The compound according to claim 22, wherein R is cycloaikyl (C6-C10); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of alkyl (C? -C7) and alkenyl (C2-C5), phenyl and naphthyl; and Z1, Z2, Z3 and Z4 are hydrogens. 24. The compound according to claim 23, wherein R is cycloalkyl (C-C9); A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of the group consisting of methyl and phenyl; and Z1, Z2, Z3 and Z4 are hydrogens.