MXPA06008063A

MXPA06008063A - Benzimidazole derivatives

Info

Publication number: MXPA06008063A
Application number: MXPA/A/2006/008063A
Authority: MX
Inventors: Gerspacher Marc; Weiler Sven
Original assignee: Novartis Ag
Priority date: 2004-01-14
Filing date: 2006-07-14
Publication date: 2006-12-13

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof;wherein R1-R7 are as disclosed in the specification and pharmaceutical uses thereof.

Description

BENCI IDAZOL DERIVATIVES The present invention relates to bicyclic compounds, in particular to benzimidazole derivatives, and to the pharmaceutical uses thereof. According to the above, the invention provides compounds of the formula (I), or a pharmaceutically acceptable salt or prodrug ester thereof: wherein: R1 is selected from the group consisting of (alkyl of 1 to 6 carbon atoms, lower alkoxy, lower alkoxy-lower alkyl, cycloalkyloxy-lower alkyl, lower thioalkyl, lower alkylthio-lower alkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, and lower alkynyl) optionally substituted; R 2 is selected from the group consisting of (optionally substituted lower alkyl, cycloalkyl, cycloalicycl-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl); R3 is selected from the group consisting of halogen, cyano, (lower alkyl, lower alkoxy, lower thioalkyl, lower thioalkenyl, aryl, aryl-lower alkyl, heteroaryl, lower alkenyl, lower alkynyl, heteroaryl, aryl-lower alkyl, and heteroaryl-lower alkyl and amino) optionally substituted; R 4 is selected from the group consisting of H, halogen, cyano, hydroxyl, (lower alkyl, lower alkoxy, lower thioalkyl, lower thioalkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, alkenyl, alkynyl, and amino) optionally substituted, and the group having the formula R8-Z- (CH2) n-; wherein Z represents a direct bond or is selected from the group consisting of O, NH, CH2, CO, SO, S02, or S; wherein R8 is selected from the group consisting of (optionally substituted aryl, heteroaryl, carbocyclic aryl, cycloalkyl, heterocycloalkyl); and where n is 0, 1, 2, or 3; R5 is selected from the group consisting of H, halogen, cyano, hydroxyl, (lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, alkenyl, alkynyl, and amino) optionally substituted; R6 is selected from the group consisting of halogen, cyano, (lower alkyl, lower alkoxy, lower thioalkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, and amino) optionally substituted; R7 represents one or more substituents independently selected from the group consisting of optionally substituted H, halogen, hydroxyl, (lower alkyl, lower alkoxy, amino, cyano, and carbonyl). The substituent or optional substituents on R 1 -R 8 are independently selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di- -lower-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkylcarbonyl, lower alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or lower dialkyl-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkyl-carbonyl, lower alkoxyl-carbonyl, nitrile, aryl. For the avoidance of doubt, it will be understood that the terms listed below have the following meaning throughout the present description and the claims: The term "lower", when referring to radicals or organic compounds, means a compound or radical that can be branched or unbranched with up to, and including, 7 carbon atoms. A lower alkyl group may be branched, unbranched, or cyclic, and contains from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Lower alkyl represents, for example: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, or 2,2-dimethyl-propyl. A lower alkoxy group may be branched or unbranched, and contains from 1 to 7 carbon atoms, preferably from 1 to 6 carbon atoms. Lower alkoxy represents, for example: methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or tertiary butoxy. Lower alkoxy includes cycloalkyloxy and lower cycloalkyl-alkyloxy. An alkene, alkenyl, or lower alkenoxy group is branched or unbranched, and contains from 2 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, and contains at least one carbon-carbon double bond. Lower alkene, lower alkenyl, or lower alkenyloxy represents, for example, vinyl, prop-1-enyl, allyl, butenyl, isopropenyl, or isobutenyl, and their oxy equivalents. An alkyne or lower alkynyl group is branched or unbranched, and contains from 2 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, and contains at least one carbon-carbon triple bond. Lower alkyl or lower alkynyl or lower alkenyloxy represents, for example, ethynyl or propynyl.

In the present application, oxygen-containing substituents, for example alkoxy, alkenyloxy, alkynyloxy, carbonyl, etc., include their homologues containing sulfur, for example thioalkyl, alkylthioalkyl, thioalkenyl, alkenyl-thioalkyl, thioalkynyl, thiocarbonyl, sulfone, sulfoxide, etc. Halo or halogen represents chlorine, fluorine, bromine, or iodine. Aryl represents carbocyclic aryl, heterocyclic aryl, or biaryl. Carbocyclic aryl is an aromatic cyclic hydrocarbon containing from 6 to 18 ring atoms. It can be monocyclic, bicyclic, or tricyclic, for example naphthyl, phenyl, or phenyl mono-, di-, or tri-substituted by one, two, or three substituents. Heterocyclic aryl is a monocyclic or bicyclic aromatic hydrocarbon containing from 5 to 18 ring atoms, one or more of which are heteroatoms selected from O, N, or S. Preferably there are one or two heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl. Heterocyclic aryl also includes these substituted radicals. Cycloalkyl represents a cyclic hydrocarbon containing from 3 to 12 ring atoms, preferably from 3 to 6 ring atoms. Cycloalkyl represents, for example: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl may be optionally substituted. Heterocycloalkyl represents a mono-, di-, or tri-cyclic hydrocarbon, which may be saturated or unsaturated, and which contains one or more, preferably from one to three heteroatoms selected from O, N, or S. preference contains between 3 and 18 ring atoms. The term "heterocycloalkyl" is also intended to include bridged heterocycloalkyl groups, such as 3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yIo. Pharmaceutically acceptable salts include the acid addition salts with conventional acids, for example mineral acids, for example hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulphonic acids, for example, acetic acid , trifluoroacetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroximic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic, or cyclohexyl sulfamic; also amino acids, such as arginine and lysine. For the compounds of the invention having acidic groups, for example a free carboxyl group, the pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium salts, magnesium or calcium, as well as ammonium salts, which are formed with ammonia or with suitable organic amines.

Agents of the invention comprising free hydroxyl groups may also exist in the form of pharmaceutically acceptable and physiologically dissociable esters, and as such are included within the scope of the invention. These pharmaceutically acceptable esters are preferably derived from prodrug esters, these being convertible by solvolysis or dissociation under physiological conditions to the corresponding agents of the invention, which comprise free hydroxyl groups. Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a monoester of carbonic acid, or a carbamic acid, suitably esters derived from a lower alkanoic acid or an arylcarboxylic acid, optionally substituted. A second aspect of the invention provides a compound of the formula (I '), or a pharmaceutically acceptable salt, or a prodrug ester thereof: (! ') where: R' is selected from the group consisting of (C 1-6 -alkyl, lower alkoxy-lower alkyl, lower alkynyl, lower thioalkyl-lower alkyl, cycloalkyl-lower alkyl) optionally substituted; R'2 is lower alkyl; R'3 is selected from the group consisting of optionally substituted halogen, cyano, lower alkyl, lower alkoxy, lower thioalkyl, lower thioalkenyl, lower alkynyl, aryl, and aryl-lower alkyl; R'4 is selected from the group consisting of H, halogen, cyano, (lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl) optionally substituted, and the group having the formula R'8 -Z- (CH2) n-; wherein Z represents a direct bond or is selected from the group consisting of O, NH, CH2, CO, SO, SO2, or S; wherein R'8 is selected from the group consisting optionally substituted (aryl, pyrazolyl, thiazolyl, cyclobutyl, tetrazolyl, pyridyl, indazolyl, pyrazinyl, furanyl, isoxazolyl, pyrrolidinyl, benzimidazolyl, imidazolyl, oxazolyl) optionally substituted; and where n is 0, 1, 2, or 3; R'5 is H, halogen, or lower alkyl; R'ß is selected from the group consisting of halogen, (lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl) optionally substituted; R'7 represents one or more substituents independently selected from! group that consists of H, halogen, hydroxyl, (lower alkyl, lower alkoxy, amino, cyano, and carbonyl) optionally substituted; the substituent or optional substituents on R '-, - R'8 being selected independently from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, amino-carbonyl, sulfinyl, sulfonyl, sulfanyl , mono- or di-lower alkyl-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkyl-carbonyl, lower alkoxyl-carbonyl, nitrile, aril; all of which, except halogen, are independently optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di-lower alkyl-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkyl-carbonyl, lower alkoxyl-carbonyl, nitrile, aryl . With reference to formulas I and I ', preferably R3 or R'3 is halogen, ethyl, or substituted methyl. For example, R3 or R'3 may be Br, I, or CF3. More preferably, R3 or R3 is Br. Alternatively, preferably R3 or R3 is trifluoromethyl. Alternatively preferably, R3 or R'3 is ethynyl. R7 or R'7 is preferably located at the 2 and / or 2 'position of the phenyl ring.

Preferred compounds of formula 1 are: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1-benzoimidazole, 4-iodo-2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methylsulfanyl- ethyl) -1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methylsulfanyl-ethyl) -1H-benzoimidazole, 4-bromo-1-cyclopropylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, 4-bromo-1-propyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, 4-bromo-1-butyl-2- (4-isopropyl-phenyl) -7-methoxy-1 H-bepzoimidazole, 4-Bromo-1-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1 H-benzoimidazole,. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] -ethyl} -dimethyl-amine, 4-chloro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-. benzoimidazole, 2- (4-isopropyl-phenyl) -7- ethoxy-1- (2-methoxy-ethyl) -4-phenyl-1H-benzoimidazole, 3- [2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-4-yl] -f-enol, 2- (4-isopropyl-phenyl) -7-methoxy-4- [3- (2-methoxy-exoxy) ) -phenyl] -1- (2-methoxy) ethyl) -1H-benzoimidazole, 4- (3,5-dimethoxy-phenyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4- methyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethylsulfanyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo- 2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2 -methylsulfanyl-ethyl) -1 H-benzoimidazole, 4-bromo-1-cyclopropylmethyl-2- (4-cyclopropyl-phenyl) -7-methoxy-1H-benzoimidazole, 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4,5-dibromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1 H-benzoimidazole, 4,5-dibromo-2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4,5-dibromo-2- (4- isopropyl-2-methoxy-phenyI) -7-methoxy-1- (2-methoxy-etiI) -1 H-benzoimidazole, 4-iodo-5-bromo-2- (4-isopropyl-phenyl) -7-methoxy- 1- (2-methoxy-ethyl) -1 H-benzo imidazole, -bromo-4-iodo-2- (4-isopropyl-2-methoxy-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-trifluoromethyl-1H-benzoimidazo I, 4-bromo-1-cyclopropylmethyl-2- (4-isoprop and If-enyl) - 7- methoxy-5-trifluoromethyl-1H-benzoimidazole, 4-bromo-5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-Bromo-4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1! - (2-methoxy-ethyl) -1 H -benzoimidazole, 2- (4-isopropyl-phene) -7 -methoxy-1- (2-methoxy-etiI) -1H-benzoimidazole-5-carbonitrile, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole-5-carbonitrile, 4-bromo-5-fluoro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-benzyl-4 -bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-benzyl-4-iodo-2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-benzyl-4-ethynyl-2- (4-isopro-p-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethynyl-2- (4-i) sopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-5-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H- benzoimidazole, 4-bromo-5-cyclobutylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-5- (3-fluoro- benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-5- (3-chloro-benzyl) -2- ( 4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4-p-propyl-phenyl) -7-methoxy-1- (2 -methoxy-ethyl) -5-thiazole-2-i I methy-1-1H-benzoimidazole, 4-bromo-5- (3,5-difluoro-benzyl) -2- (4-isopropy-phenyl) -7- methoxy-1- (2-m-ethoxy-yl) -1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridine -3-ylmethyl-1 H-benzoimidazole, 4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-benzyl) ~ H- benzoimidazo!, 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfin-1-benzyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo- 2- (4-isopropyl-phenyl) -5- (2-methanesulfonyl-benzyl) -7-methoxy-1- (2-m ethoxy-et i I) -1 H -benzoimidazole, 4-bromo-2- (4 -isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropy-phenyl) -7 -methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-5- (3,4-dimethoxy-benzyl) -2- (4-isopropyl -pheni) -7-methoxy-1- (2-me toxi-eti I) -1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-pyridin-2-ylmethyl) -1H-benzoimidazole, 5-benzyl- 4-Ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy- 5- (3-methoxy-benzyl) -1- (2-methoxy-ethyl) -1 H -benzoimidazole, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy -ethyl) -1H-benzoimidazol-5-yl] - (3-methoxy-phenyI) -methanone, [4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) ) -1H-benzoimidazol-5-yl] - (2-methoxy-phenyl) -methanone, 4-b-romo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (1-f enyl-ethyl) -! H-benzoimidazole, 4-iodo-2- (4-isopropy-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile, 2- (4-isopropyl-phenyl) - 7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-4-carbonitrile, 4-isobutyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1H-benzoimidazole, 4-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4,7-dib-rom 2- (4-isopropyl) -phenyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole, 4,7-dibromo-2- (4-isopropyl-phenyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenyl-1H-benzoimidazole, 4-bromo-5- (3,4-dlmethoxy) phenyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2- m ethoxy-et il) -1 H-benzoimidazole, 3- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole-5- il] -phenol, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-phenyl) - 1 H-benzoimidazole, ethyl ester 3- [4-bromo-2- (4-isopropyl-phen1l) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazol-5-yl] -benzoic acid, 4-ethyl ester 4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzoic acid, 4-bromo-2- (4-isopropyl) phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-3-yl-1 H-benzoimidazole, 3- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy] -1- (2-methoxy-etiI) -1H-benzoimidazol-5-yl] -benzonitrile, 1-. { 5- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -2-methoxy-phenyl} -etanone, 2- [4-bromo-2- (4-isopropyl-phenyl) -7- ethoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzo nitrile, 2- (4 -isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-phenyl) -1 H -benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -5-pyridin-4-yl-1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy) -ethyl) -5- (4-methyl-pyrazol-1-ylmethyl) -1 H -benzoimidazole, 4-bromo-5-imidazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-me toxi-eti I) - 1 H-benzoimidazole, 4-Bromo-5- (4-bromo-5-methyl-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-yl) -1 H-benzoimidazole, 4-b ro o-5- (4-b rom or- 3-met-1-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-methoxy-ethyl) -1 H -benzoimidazole, 4-b-romo-5- (3,5-dimethyl-pi-razo l-1-ylmethyl) -2- (4-isopropyl-f-enyl) -7 -methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 1- [4-bromo-1- (2-hydroxy-ethyl) -2- (4-isopropyl-phenyl) -7- methoxy-1H-benzoimidazol-5-ylmethyl] -1H-imidazole-2-carboxylic acid, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- ( 2-methoxymethylimidazol-1-ylmethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2- methylsulfanyl-imidazol-1-ylmethyl) -1 H -benzoimidazole, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-2 -ol, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylisulfanyl-benzoimidazol-1-ylmethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl-benzoimidazol-1-yl) methyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-b-romo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzo) imidazo 1-1-i I meti I) - 1 - (2-methoxy-yl) -1 H-benzoimidazole, Methyl ester of 3- [4-bromo-1- (2-hydroxy-ethyl) -2- ( 4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazol-5-ylmethyl] -3H-imidazole-4-carboxylic acid, 2- [4-bromo-5-imidazo [4,5-b] pyridin-3-ylmethyl] -2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] ethanol, 2- [4-bromo-5-indazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7- methoxy benzoimidazol-1-yl] ethanol, 2- [4-bromo-2- (4-isopropyl-phene) -7-methoxy-5- (5-methyl-tetrazol-2-ylmethyl) -benzoimidazol-1-yl] ethanol, 4-b-romo-5- (4-bromo-5-methyl-pyrazol-1-ylmethyl) -2- (4-cyclopro-pi-l-enyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole, 4-b-romo-2- (4-isopropyl-l-enyl) -7-m-ethoxy-5- (4-methyl-pyrazol-1-ylmethyl) -1- (2-methylsulfanyl-ethyl) -1 H-benzoimidazole, 4-bromo-5-isopropoxymethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole, 1- [4-bromo] -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] -pyrrolidin-2-one, 4-bromo-2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenylsulfanyl-1H-benzoimidazole, 5-benzenesulfinyl-4-bromo-2- (4-isopropyl-phenyl) -7-methoxy- 1- (2-methoxy-ethyl) -1 H-benzoimidazole, 5-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-tr if I uoromet il -1H-benzoimidazole, 2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-2-ylmethyl-4-tri-fluoro-methyl-1H-benzoimidazole, 2- (4-isopropyl) phenyl) -7-methoxy-1- (2- methoxy-ethyl) -5-pyrazol-1-ylmethyl-4-trifluoromethyl-1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 5-Phenoxymethyl-1 H-benzoimidazole, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -ethanol, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethoxy] -phenoxy} Ethanol,. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethoxy] -phenyl} - ethanol, N-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy-phenyl} -acetamide, 2- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -benzamide, 2- [4- Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -benzenesulfonamide, 2- [4-bromo-2- (4-isopropyl phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -f in lamel, 1-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -etanone, 2- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenol, 2- [4- bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethoxy] -pyridin-3-ol, 4-bromo-2- (4 - isopro pi lf enyl) -7- methoxy- 1 - (2-methoxy-eti I) -5- (pi ridin-2-yloxymethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl- phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methoxy-p-noxy-methyl) -1H-benzoimidazole,. { 3- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H- benzoimidazol-5-ylmethoxy] -2-methyl-phenyl} -methanol, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-3-yloxymethyl) -1H-benzoimidazole, 4-bromo- 2- (4-isopropyl-phenyl) -5- (2-methanesulfonyl-phenoxymethyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 2-. { 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenoxy} - ethanol, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -acetamide, 2-. { 2- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-mephoxy-eyl) -4-trifluoromethyl-1 H -benzo-mido zol-5-ylmethoxy] -phenoxy} - ethanol, 2-. { 2- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethoxy] -phenyl} -ethanol, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -phenyl-amine, [4-bromo- 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoI-5-ylmethyl] - (2-methanesulfonyl-phenyl] -amine, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - [2- (2-methanesulfonyl-ethyl) -phenyl] -amine, 2- (2- {[[4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -amino} -phenyl ) -acetamide, 2- (2- { [4-bromo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1 H-be nzo imidazo-l acid 5-i I methyl] -am i no.}. -benzenesulfonic, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole- 5-ylmethyl] - (2-fluoro-phenyl) -amine, [4-bromo-2 ~ (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyridin-2-yl-amine, 2-methyl ester -. { [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -amino} -benzoic acid, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazol-5-ylmethyl] -pyridin-3-yl-amine, [ 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -methyl-phenyl-amine, [4-bromo-2] - (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - (3-methanesulfonyl-phenyl) -amine, 2- (2- { [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazo! -5-ylmethyl] -amino.} - phenyl) -acetam , [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1 H -benzoimidazol-5-ylmethyl] - (2-methanesulfonyl-phenyl) -amine, [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] - [2- (2-methanesulfonyl-ethyl) - phenyl] -amine, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H methyl ester -imidazole-2-carboxylic acid, Dimethylamide 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - 1H-imide zol-2-carboxylic, 1-. { 1- [4-bromo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-imi azol-2-yl } -etanone, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-indole-2, 3-dione, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-oxazole-2- i I methyl-1 H-benzoimidazole, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H -imidazole-2-carbonitrile, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] methylamide] -1 H-imidazole-2-carboxylic acid, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-bromo-4-trifluoromethyl-1H-benzoimidazole, [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -phenyl-amine, [2- (4-isopropyl-phenyl) -7-methoxy-1- ( 2-methoxy-ethyl) -4-tri-fluoromethyl-1 H -benzoimidazol-5-ylmethyl] -pyridin-2-yl-amine, 2-. { [2- (4-isopropyl-fe nll) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -amino} -benzene-sulfonamide, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenoxy-ethyl-4-trifluoromethyl-1H-benzoimidazole, 2- (4-isopropyl) ~ phenyI) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yloxymethyl) -4-trifluoromethyl-1H-benzoimidazole, 2- [2- (4-isopropyl-phenyl ) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethoxy] -benzenesulfonamide, 4-bromo-2- (4-isopropyl-phenyl) -7- methoxy-1- (2-methoxy-etiI) -5- (pyridin-2-yloxy) -1H-benzoimidazole. According to a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) in association with a pharmaceutically acceptable excipient, diluent or carrier.

According to a fourth aspect of the invention, a compound of the formula (I) is provided to promote the release of parathyroid hormone. It is now well established that the controlled treatment of patients with parathyroid hormone (PTH) and its analogues and fragments can have a pronounced anabolic effect on bone formation. Accordingly, compounds promoting the release of parathyroid hormone, such as the compounds of the present invention, can be used to prevent and treat bone conditions that are associated with increased calcium exhaustion or resorption, or where stimulation is desirable. of bone formation and calcium fixation in bone. Accordingly, in a fifth aspect, the invention includes a method for preventing or treating bone conditions that are associated with increased calcium depletion or excretion, or where stimulation of bone formation and bone formation and calcium fixation is desirable. the bone, wherein an effective amount of a compound of the formula (I) as defined above, or a pharmaceutically acceptable and dissociable ester, or an acid addition salt thereof, is administered to a patient in need of such treatment. In a sixth aspect, the invention provides a process for the preparation of a compound of formula (I) in free or salt form, which comprises: (a) Introducing a group R4 into a corresponding compound of formula II, where R4 is as defined above: wherein X is any suitable group capable of being substituted by R4, and wherein R1, R2, 43, R5, R6, and R7 are as defined above; or (b) for the preparation of compounds wherein R 4 is an aryl-CH 2 group, appropriately introducing this aryl group by reaction with a compound of the formula III: (lll) where Y denotes any of: (i) a leaving group -CH2-, and R1, R2, R3, R5, R6, and R7 are as defined above; or (ii) the group -CH = O; or (c) introduce a group R3 in a compound corresponding to formula IV, where R3 is as defined above: wherein Q is any suitable group capable of being substituted by R3, and wherein R1, R2, R4, R5, R6, and R7 are as defined above; or (d) N-appropriately replacing a corresponding compound of formula V with a group R1 as defined above: (V) wherein R2-R7 are as defined in the above; (e) for the preparation of compounds wherein R 4 is aryl-CO-, oxidize a compound of the formula (VI): (SAW) with a suitable oxidizing agent, where R1, R2, R3, R5, R6, and R7 are as defined above; (f) treating a compound of the formula (VII): (VII) under conditions suitable to effect a ring closure, where R1-R7 is as defined above; transforming the resulting compound into an additional compound of the formula I if appropriate; and recovering the resulting compounds of formula I in free or salt form. The process of the invention is carried out in a conventional manner. In the process variant (a), X is conveniently an iodide group, and the transformation is suitably carried out by a Suzuki coupling, for example by the reaction of compound II with aryl or heteroaryl-B (OH) 2, in the presence of a palladium catalyst. In the process variant (b), Y is conveniently a methyl ester group of methanesulfonic acid, and the compound III can be reacted with the desired aryl or heteroaryl group R4 in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide. In an alternative way, the process variant (b), when Y denotes the group -CH = 0, the compound of the formula (III) can be reacted with a Grignard reagent denoted by aryl-MgBr, in a suitable solvent , for example tetrahydrofuran, to produce, after the subsequent treatment with phosphinic acid and iodine, the corresponding compound of the formula (I). In the process variant (c), R3, for example, can represent a bromine group, which can be introduced by the reaction of N-bromosuccinimide or Br2 / acetic acid in a suitable solvent, with a compound of the formula IV, wherein Q denotes H. The process variant (d) is an N-alkylation, wherein R1 is conveniently an alkyl group, and can be introduced by the reaction of a corresponding bromoalkyl, with a compound of the formula V, into the presence of a base, such as sodium hydride, in a suitable solvent, for example dimethylformamide. A suitable oxidizing agent in the process (e) is, for example, oxalyl chloride in dimethyl sulfoxide in a Swern oxidation reaction. In the process variant (f), the ring closure is conveniently carried out by heating to 100 ° C with acetic acid. If desired, the compound obtained can be further transformed into another compound of formula I. For example, an OH substituent on the aryl ring can be converted to a 2-methoxy-ethoxy group conveniently by reaction with 2- (bromoethyl) -methyl ether, in the presence of a base. The compounds of the formula I in free form can be converted into salt forms in a conventional manner and vice versa. The compounds of the invention can be recovered from the reaction mixture, and can be purified in a conventional manner. Isomers, such as enantiomers, can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from the corresponding asymmetrically substituted starting materials, for example optically active. In a seventh aspect, the invention includes the use of a compound of the formula (I) in the manufacture of a medicament for preventing or treating bone conditions that are associated with a greater calcium exhaustion or resorption, or where the stimulus is desirable. of bone formation and calcium fixation in bone. The agents of the invention can be prepared by the processes described below: Example 1: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole To a stirred solution of 500 milligrams (1.45 millimoles) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole in 11 milliliters of dimethylformamide, NaH (38 milligrams, 1.6 mmol) is added, and stirring is continued for 1 hour at room temperature, and then the reaction mixture is heated to 60 ° C. 0.152 milliliters (0.175 millimoles) of (2-bromoethyl) -methyl ether are added, and stirring is continued at this temperature for another 6 hours. The reaction mixture is cooled to room temperature, poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1) to provide 398 milligrams of the title compound as a colorless oil. Rt = 2.23 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, 1.0 milliliter flow rate / minute). MS: 403 (M + 1) + (79 Br), 405 (M + 1) + (8 Br).

The starting materials can be prepared as follows: a) 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole: A solution of 1.44 grams (3.97 millimoles) of N- (2- amino-3-bromo-6-methoxy-phenyl) -4-isopropyl-benzamide in 25 milliliters of glacial acetic acid is stirred at 100 ° C for 3 hours. The reaction mixture is cooled to room temperature, and 200 milliliters of ethyl acetate are added. The solution is washed with 4N NaOH (2 times) and with water and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1), to give 1.12 grams of the title compound as a slightly reddish solid. b) N- (2-amino-3-bromo-6-methoxy-phenyl) -4-isopropyl-benzamide: A solution of 870 milligrams (4.01 millimoles) of 3-bromo-6-methoxy-benzene-1,2-diamine, 1.16 grams (6.0 millimoles) of EDC, 744 milligrams (6.0 millimoles) of DMAP, and 707 milligrams (4.01 millimoles) ) of 4-isopropylbenzoic acid in 20 milliliters of dichloromethane, is stirred at room temperature for 72 hours. The reaction mixture is concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1), to give 1.44 grams of the title compound as a slightly reddish solid. c) 3-bromo-6-methoxy-benzene-1,2-diamine: A solution of 1.12 grams (4.04 millimoles) of 1-bromo-4-methoxy-2,3-dinitro-benzene in 25 milliliters of tetrahydrofuran is hydrogenated in the presence of 100 milligrams of Raney Nickel (B113W Degussa) at a pressure normal for 3 hours. The catalyst is filtered, and the filtrate is concentrated in vacuo, to provide 871 milligrams of the title compound as a gray crystalline solid. d) 1-bromo-4-methoxy-2,3-dinitro-benzene: 1. 0 grams (4.3 millimoles) of 4-bromo-3-nitroanisole are nitrated by the dropwise addition of 1.0 milliliters of a mixture of 0.4 milliliters of nitric acid (100 percent) and 0.6 milliliters of concentrated sulfuric acid. Stirring is continued for 1 hour. After that, the reaction mixture is poured into water and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water and brine (2 times), dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 1), to provide 630 milligrams of the title compound as yellow crystals.

Example 2: 4-iodo -2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared starting from 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole and (2-bromoethyl) -methyl ether, using the same reaction conditions as described in Example 1. The compound of title is obtained as a colorless oil. Rt = 2.31 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 451 (M + 1) 0 The starting material, 4-iodo-2- (4-isopropyl-phenyI) -7-methoxy-1H-benzoimidazole, is prepared from 4-iodo-3 nitro-anisole, using exactly the same methodology as described in Example 1 a) -d). Example 3: 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methyl-sulphonyl-ethyl) -1H-benzoimidazole.

Using 1-bromo-2-methylsulfanyl-ethane in place of (2-bromoethyl) -methyl ether, prepare the title compound using the same reaction conditions as described for the preparation of Example 1. Rt = 2.47 minutes ( Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 467 (M + 1) 0 Example 4: 4-bromo-2- (4-isopropyl-fe-nyl) -7-methoxy-1 - (2-methyls or If an i-ethyl) -1 H-benzoimidazole.

Br - ° Using 1-bromo-2-methylsulfanyl-ethane in place of (2-bromoethyl) -methyl ether, the title compound is prepared using the same reaction conditions as described for the preparation of Example 1. Rt = 2.36 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute).

MS: 419 (M + 1) + (79Br), 421 (M + 1) + (a? Br) Example 5: 4-bromo-1-cyclopropylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole.

Using bromomethyl-cyclopropane in place of (2-bromoethyl) -methyl ether, prepare the title compound using the same reaction conditions as described for the preparation of Example 1. Rt = 2.34 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 399 (M + 1) + (79Br), 401 (M + 1) + (81Br). Example 6: 4-bromo-1-propyl -2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole.

Using 1-bromo-propane instead of (2-bromoethyl) -methyl ether, the title compound is prepared using the same reaction conditions that are described for the preparation of Example 1. Rt = 2.31 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + TFA 0.05 percent, flow rate 1.0 milliliters / minute). MS: 387 (M + 1) + (79Br), 389 (M + 1) + (81Br). Example 7: 4-bromo-1-butyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole.

Using 1-bromo-butane in place of (2-bromoethyl) -methyl ether, prepare the title compound using the same reaction conditions as described for the preparation of Example 1. Rt = 2.41 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 401 (M + 1) + (79Br), 403 (M + 1) + (81Br). Example 8: 4-bromo-1-ethyl-2- (4-isopropyl-phenyI) -7-methoxy-1H-benzoimidazole.

Using 1-bromo-ethane in place of (2-bromoethyl) -methyl ether, prepare the title compound using the same reaction conditions as described for the preparation of Example 1. Rt = 2.23 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 373 (M + 1) + (79Br), 375 (M + 1) + (81Br).

Example 9: { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] -ethyl} -dimethyl-amine.

Using (2-bromo-ethyl) -dimethyl-amine in place of (2-bromoethyl) -methyl ether, prepare the title compound using the same reaction conditions as described for the preparation of Example 1. Rt = 1.86 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute).

MS: 416 (M + 1) + (79Br), 418 (M + 1) + (blBr).

Example 10: 4-Chloro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole. or The title compound is prepared starting from 4-chloro-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole and (2-bromoethyl) -methyl ether, using the same reaction conditions as are described in Example 1. The title compound is obtained as a colorless oil. Rt = 2.18 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 25.0 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 359 (M + 1) 0 The starting material, 4-chloro-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, is prepared from 4-chloro-3-nitro- anisole, using exactly the same methodology as described in Example 1 a) -d).

Example 11: 4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

A mixture of 17 milligrams (0.04 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-meioxy-eyl) -4-virilir-slan-1-ethynyl-1H-benzoimidazole and 0.5 milliliters of 1N NaOH in 2 milliliters of tetrahydrofuran / methanoi (1: 1), is stirred for 1 hour at 60 ° C. The reaction mixture is cooled to room temperature, and poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified on 0.5 millimeter silica gel plates (hexane: EtOAc = 3: 1), to provide 7 milligrams of the title compound as a yellow oil. Rt = 2.11 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 349 (M + 1) 0 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trimethylsilanyl-ethynyl-1H-benzoimidazole, can be prepared using the following procedure: or A mixture of 50 milligrams (0.111 millimoles) of 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 0.1 milliliters (0.77 millimoles) of triethyl -amine, 0.1 milliliter (0.7 mmol) of ethynyltrimethylsilane, and 5 milligrams of palladium-ll acetate in 1 milliliter of acetonitrile, is stirred at 50 ° C for 3 hours. Then the reaction mixture is cooled to room temperature and poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to give 17 milligrams of the title compound as a colorless oil.

Example 12: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-phenyl-1H-benzoimidazole.

A mixture of 100 milligrams (0.25 millimoles) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazole, 45 milligrams (0.424 millimoles) of sodium carbonate, 34 milligrams (0.275 millimoles) of phenyl boronic acid, and 10 milligrams of tetrakis- (triphenylphosphine) -palladium in 10 milliliters of toluene / water (3:!), is stirred at 100 ° C for 9 hours. Then the reaction mixture is cooled to room temperature and poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 4: 1), to provide 53 milligrams of the title compound as a white crystalline solid. Rt = 2.21 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 401 (M + 1) 0 Example 13: 3- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-yl) -1-H-benzoimidazol-4-yl] -phenol.

The title compound is obtained using 3-hydroxyphenyl boronic acid instead of phenyl boronic acid, using the same procedure as described for the preparation of the Example 12, as a white crystalline solid. Rt = 2.07 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 417 (M + 1) 0 Example 14: 2- (4-isopropyl-phenM) -7-methoxy-4- [3- (2-methoxy-ethoxy) -phenyl] -1- (2-methoxy-ethyl) -1H-benzoimidazo I. milligrams (0.2 millimoles) of NaH are added to a solution of 70 milligrams (0.173 millimoles) of 3- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H- benzoimidazol-4-yl] -phenoI in 2 milliliters of dimethylformamide. This mixture is stirred at room temperature for 1 hour. After that, 28 milligrams (0.207 millimoles) of 2- (bromomethyl) -methyl ether are added, and stirring is continued for another 3 hours. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO, filtered, and concentrated in vacuo. The residue is purified by evaporation chromatography on a gel of silica (hexane: EtOAc = 3: 1), to provide 70 milligrams of the title compound as a colorless oil. Rt = 2.18 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 475 (M + 1) 0 Example 15: 4- (3,5-dimethoxy-phenyl) -2- (4-isopropyl-phenyl) -7-methox? -1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is obtained using 3,5-dimethoxy-phenyl-boronic acid instead of phenyl-boronic acid, using the same procedure as described for the preparation of Example 12, as a colorless oil. Rt = 2.20 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 461 (M + 1) 0 Example 16: 4-Methyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl-1) -1H-benzoimidazole.

The title compound is prepared starting from 4-Methyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole and (2-bromoethyl) -methyl ether, using the same reaction conditions as described in Example 1. The compound of title is obtained as a colorless oil. Rt = 2.01 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 339 (M + 1) 0 The starting material, 4-methyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, is prepared from 4-methyl-3-nitro ~ anisole, using the same method as described in Example 1 a) -d).

Example 17: 4-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy and i) -1 H-benzoimidazole.

To a solution of 150 milligrams (0.223 mmol) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole in 8 milliliters of tetrahydrofuran, slowly add 0.289 milliliters of terbuti-lithium (1.7M in pentane) at -78 ° C. This mixture is stirred for 1 hour at -78 ° C, and then 54 microliters (0.669 mmol) of ethyl iodide are added. The reaction mixture is cooled to room temperature, poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1) to provide 25 milligrams of the title compound as a colorless oil. Rt = 2.05 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 353 (M + 1).

Example 18: 4-Ethylsulfanyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

NaH (2.4 milligrams, 0.1 mmol) is added to a solution of 7-ethylsulfaniI-2- (4-isopropyl-1-enyl) -3- (2-methoxy-ethyl) -3H-benzoimidazol-4-ol (35 milligrams, 0.094). millimoles) in 1 milliliter of dimethylformamide. The mixture is stirred at room temperature for 1 hour, and methyl iodide (6 microliters, 0.1 mmol) is added. Stirring is continued for 1 hour, and then the reaction mixture is poured into water and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 4: 1) to provide 11 milligrams of the title compound as a colorless oil. Rt = 2.13 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 385 (M + 1) 0 The starting material is prepared as follows: 7-ethylsulfanyl-2- (4-isopropyl-f-enyl) -3- (2-methoxy-et-I) -3H-benzoimidazole -4-ol: A mixture of 300 milligrams (0.744 millimoles) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole (Example 1), and 313 milligrams ( 3.72 mmol) of EtSNa in 2 milliliters of dimethylformamide, is stirred at reflux temperature for 4 hours. After that, the reaction mixture is poured into 10 milliliters of concentrated HCl, stirred for 10 minutes, diluted with 25 milliliters of water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 35 milligrams of the title compound as a colorless oil.

Example 19: 4-Bromo -2 - (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound and the precursors can be prepared using the same synthesis sequence as described in Example 1. In place of 4-isopropyl-benzoic acid, 4-cyclopropyl-benzoic acid is used in step b). Rt = 2.06 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 401 (M + 1) + (79Br), 403 (M + 1) + (81Br).

In a similar manner, by using the appropriate alkyl bromides, the following compounds can be prepared: Example 20: 4-bromo-2- (4-cyclopropyl) -phenyl) -7-methoxy-1- (2-methyl- Rt = 2169 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 417 (M + 1) + (79Br), 419 (M + 1) + (81Br).

Example 21: 4-bromo-1-cyclopropylmethyl-2- (4-cyclopropyl-phenyl) -7-methoxy-1 H-benzoimidazole.

Rt = 2174 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 397 (M + 1) + (79Br), 399 (M + 1) + (81Br).

Example 22: 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

Br. N YX? Y? < OR The title compound and the precursors can be prepared using the same synthesis sequence as described in Example 1, starting from 5-bromo-3-methoxy-benzene-1,2-diamine. Rt = 2.13 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 403 (M + 1) + (79Br), 405 (M + 1) + (81Br). a) 5-bromo-3-methoxy-benzene-1,2-diamine: A solution of 2.0 grams (8.1 millimoles) of 4-bromo-2- methoxy-6-nitro-phenyl-amine [Zhou QT et al., Huaxue Xuebao 1980, 38 (5), 507-10] in 50 milliliters of methanol / water (2: 1), is hydrogenated in the presence of 200 milligrams of Pt / C (Engelhard 4709) at normal pressure for 3 hours. The catalyst is then filtered, and the filtrate is concentrated in vacuo to provide 1.5 grams of the title compound as an oil. An alternative form for the preparation of the compound described in Example 22 is illustrated below: a) 2-methoxy-6-nitro-phenyl-amine: To a stirred solution of 20 grams (129.9 millimoles) of 2-hydroxy-6-nitro-aniline in 150 milliliters of dimethylformamide, it was added. add NaH (3.42 grams, 143 millimoles, 95 percent) at 0 ° C, and stirring is continued for 1.5 hours. Mel (9.3 milliliters, 150 millimoles) is added, and the reaction mixture is stirred at room temperature for 1 hour. After that, the reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. To the residue is added 50 milliliters of hexane: diethyl ether = 4: 1, and the resulting suspension is stirred for 5 minutes. 20 grams of the title compound are obtained after filtration of the mixture, as a brown crystalline solid. b) 2-chloro-1-methoxy-3-nitro-benzene: To a mixture consisting of 15.5 grams (92.26 millimoles) of 2-methoxy-6-nitro-phenyl-amine, 31 milliliters of water, and 31 milliliters of concentrated HCl, a solution of 6.36 grams is added slowly and drip (92.26). millimoles) of NaNO2 in 38 milliliters of water from -10 ° C to 0 ° C. After stirring for 0.5 hours, the mixture is added slowly to a solution of 11.88 grams (120 millimoles) of CuCl in 93 milliliters of concentrated HCl. After the addition is complete, stirring is continued for 1.5 hours at room temperature, and for 0.5 hours at the reflux temperature. The reaction mixture is allowed to cool to room temperature, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to give 12.6 grams of the title compound as a crystalline solid. c) (2-methoxy-ethyl) - (2-methoxy-6-nitro-phenyl) -amine: A mixture of 7.5 grams (40 millimoles) of 2-chloro-1 methoxy-3-nitro-benzene, 14 milliliters of di-isopropyl-ethyl-amine, and 35 milliliters of 2-methoxy-1-amine, is heated (oil bath temperature of 180 ° C) in a closed steel reactor for 25 hours. minutes Then the reaction mixture is cooled to room temperature, and concentrated in vacuo (coevaporation with toluene 3 times), to obtain approximately 20 grams (containing 85 percent of the title compound) of a red oil, which is used without further purification in the next step. d) (4-bromo-2-methoxy-6-nitro-phenyl) - (2-methoxy-etiI) -amine: To a solution of approximately 20 grams (contains 15.65 grams, 58.9 millimoles) of (2-methoxy-ethyl) - (2-methoxy-6-nitro-phenyl) -amine in 150 milliliters of glacial acetic acid, 3.0 is slowly added. milliliters (58.9 millimoles) of bromine at room temperature. The reaction mixture is stirred at room temperature for 3 hours. 600 milliliters of EtOAc are added, and this solution is washed with 4N NaOH (2 times), water, and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is recrystallized from diethyl ether / hexane, to provide 13 grams of the pure title compound as orange crystals, and 6.6 grams of an orange oil containing 50 percent of the starting material. e) 5-Bromo-3-methoxy-N * 2 * - (2-methoxy-ethyl) -benzene-1,2-diamine: A solution of 6.1 grams (20 millimoles) of (4-bromo-2-methoxy-6-nitro-phenyl) - (2-methoxy-ethyl) -amine in 140 milliliters of tetrahydrofuran, hydrogenated in the presence of 1.4 grams of Raney Nickel (B113W Degussa) at normal pressure for 25 hours. The catalyst is filtered, and the filtrate is concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1), to give 4.95 grams of the title compound as a reddish oil. f) N- [5-b omo-3-methoxy-2- (2-methoxy-ethyl-arnino) -phenyl] -4-isopropyl-benzamide: A solution of 4.95 grams (18 millimoles) of 5-bromo-3-methoxy-N * 2 * - (2-methoxy-ethyl) -benzene-1,2-diamine, 5.15 grams (27 millimoles) of EDC, 3.3 grams (27 mmol) of 4-dimethylamino-pyridine in 2.94 grams (18 mmol) of 4-isopropyl-benzoic acid in 150 milliliters of dichloromethane is stirred at room temperature for 14 hours. After that, 400 milliliters of EtOAc, and the organic phase is washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 7.48 grams of the title compound as a reddish oil. g) 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole: A solution of 748 milligrams (1.77 millimoles) of N- [5-bromo-3-methoxy-2- (2-methoxy-ethyl-amino) -phenyl] -4-isopropyl-benzamide in 10 milliliters of AcOH is stirred at 100 ° C for 2 hours. The reaction mixture is cooled to room temperature, and added 200 milliliters of ethyl acetate. The solution is washed with 4N NaOH (2 times), and with water and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 625 milligrams of the title compound as a colorless solid.

Example 23: 4,5-dibromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-et i) -1 H -benzoimidazole.

To a solution of 403 milligrams (1.0 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole in 8 milliliters of glacial acetic acid, 240 milligrams (1.5 millimoles) of bromine are slowly added at 10 ° C. The reaction mixture is allowed to warm to room temperature, and is stirred for 3 hours. 250 milliliters of EtOAc are added, and this solution is washed with 1N NaOH (2 times), water, and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is recrystallized from EtOAc / hexane, to provide 30 milligrams of the title compound as colorless crystals. Rf = 0.23 (hexane / EtOAc = 3: 1). MS: 481 (M + 1) + (2x 79 Br), 483 (M + 1) + (79 Br, 81 Br), 485 (M + 1) + (2x 81 Br).

Example 24: 4,5-dibromo-2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The compound is prepared as described in Example 23, by the use of 4-cyclopropyl-benzoic acid in place of 4-isopropyl-benzoic acid. Rt = 2455 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 479 (M + 1) + (2x 79 Br), 481 (M + 1) + (79 Br, 81 Br), 483 (M + 1) + (2x 81 Br). Using the methods described for the preparation of Examples 1 and 23, the following compound can be prepared (using 2-methoxy-4-isopropyl-benzoic acid in the appropriate step): Example 25: 4,5-dibromo-2- (4-isopropyl-2-methoxy-phenyl) -7-methoxy-1 - (2-m and oxy-ethyl) -1 H-benzoimidazole.

Rt = 2.34 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 511 (M + 1) + (2x 79 Br), 513 (M + 1) + (79 Br, 81 Br), 515 (M + 1) + (2x 81 Br).

Example 26: 4-iodo-5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole. or A solution of 100 milligrams (0.248 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole and 61 milligrams (0.273 millimoles) of N -iodo-succinimide in 3 milliliters of acetonitrile, is refluxed for 12 hours. The reaction mixture is cooled to room temperature, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 4: 1) and recrystallization from hexane / diethyl ether, to provide 82 milligrams of the title compound as colorless crystals. Rt = 2.60 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 529 (M + 1) + (79Br), 531 (M + 1) + (81Br). Using the methods described for the preparation of Examples 1 and 26, the following compound can be prepared (using 2-methoxy-4-isopropyl-benzoic acid in step appropriate): Example 27: 5-bromo-4-iodo-2- (4-isopropyl-2-methoxy-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

Rt = 2.38 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 559 (M + 1) + (79Br), 561 (M + 1) + (81Br).

Example 28: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-trifluoromethyl-1H-benzoimidazole.

The title compound and the precursors can be prepared using the same synthesis sequence as described in Examples 1 and 23, from 5-trifluoromethyl-3-methoxy-benzene-1,2-diamine.

R, = 2.73 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 471 (M + 1) + (79Br), 473 (M + 1) + (81Br).

Example 29: 4-bromo-1-cyclopropylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-5-trifluoromethyl-1H-benzoimidazole.

The title compound can be prepared using the same synthesis sequence as described in Example 28, by using bromo-methyl-cyclopropane in place of 1-bromo-2-methoxy-ethane. Rt = 2.79 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 467 (M + 1) + (79Br), 469 (M + 1) + (81Br). a) 5-Trifluoro-3-methoxy-benzene-1,2-diamine can be prepared starting from 1-methoxy-3-nitro-5-trifluoromethyl-benzene, using the same reaction sequence as described for Preparation of 3-bromo-6-methoxy-benzene-1,2-diamine, as it is described in Example 1 (steps c and d).

Example 30: 4-Bromo-5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared starting from 4-bromo-5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, using the same reaction conditions as described for the preparation of the Example 1. Rt = 2.52 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 529 (M + 1) + (79Br), 531 (M + 1) + (81Br). The starting material can be prepared as follows: a) 4-bromo-5-iodo-2- (4-isopropyl-pheny!) - 7-methoxy-1H-benzoimidazole: To a solution of 200 milligrams (0.51 mmol) of 5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1 H-benzoimidazole in 3 milliliters of glacial acetic acid, 82 milligrams (0.51 millimoles) of bromine are added slowly. The reaction mixture is stirred for 45 minutes. 30 milliliters of EtOAc are added, and this solution is washed with 2N NaOH, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), and recrystallized from EtOAc / diethyl ether, to provide 126 milligrams of the title compound as white crystals. b) 5-Iodo-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole is prepared starting from 4-iodo-2-methoxy-6-nitro-phenylamine, using the same sequence of reaction described in Examples 1 and 23. c) 4-iodo-2-methoxy-6-nitro-phen i lamina: A mixture of 6.2 grams (36.9 millimoles) of 2-methoxy-6-nitro-phenylamine, 9.4 grams (37 millimoles) of iodine, and 5.8 grams (18.5 millimoles) of silver sulfate in 90 milliliters of glacial acetic acid, is stirred at 60 ° C for 12 hours. The reaction mixture is cooled to room temperature, poured into water, and extracted (3). times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo.The residue is purified by chromatography on silica gel (hexane: EtOAc = 2: 1). ), to provide 8.57 grams of the title compound as bright red crystals.

Example 31: 5-bromo-4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m and oxy-ethyl) -1 H -benzoimidazole.

The title compound is prepared starting from -bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, using the same methodology as described for the preparation of Example 11. Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 427 (M + 1) + (79Br), 429 (M + 1) + (81Br).

Example 32: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile.

A mixture of 430 milligrams (1.07 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole (Example 22), 125 milligrams (1.07 millimoles) of zinc cyanide, and 20 milligrams of tetrakis- (triphenylphosphine) -palladium in 5 milliliters of dimethylformamide, is heated in a microwave oven for 75 minutes (180 ° C). After that, the reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (3 times) and brine, dried over MgSO 4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 250 milligrams of the title compound as a colorless solid. Rt = 2.27 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 350 (M + 1) 0 Example 33: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile.

A mixture of 110 milligrams (0.315 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazole-5-carbonitrile and 56 milligrams (0.315 millimoles) of N -bromosuccinimide in 5 milliliters of acetonitrile, stir at reflux for 3 hours. Then the solvents are evaporated and the residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), and recrystallized from EtOAc / diethyl ether / hexane, to provide 60 milligrams of the title compound as colorless crystals. Rt = 2.59 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 428 (M + 1) + (79Br), 430 (M + 1) + (81Br).

Example 34: 4-bromo-5-fluoro-2- (4-isopropyl-phenyl) -7-methoxy-1 (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared from 4-bromo-5-fluoro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, using the method described in Example 1. Rt = 2.30 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 421 (M + 1) + (79Br), 423 (M + 1) + (81Br). Preparation of the starting material of 5-fluoro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole: To a solution of 400 milligrams (0.98 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole in 3 milliliters of dry tetrahydrofuran, n-BuLi (0.740 milliliters, 1.18 milli-moles) is slowly added at -78 ° C. After stirring for 45 minutes at -78 ° C, N-fluoro-bis (phenylsulfonyl) amine (568.7 milligrams, 1.77 millimoles) is added. Stirring at -78 ° C is continued for another hour, and then the reaction mixture is warmed to room temperature. After that, the reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (3 times) and brine, dried over MgSO4, filtered, and Concentrate to vacuum. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1 -> 1: 1), to provide 40 milligrams of the title compound as a colorless oil. Example 35: 5-benzyl-4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole. 6 microliters (0.122 millimoles) of bromine are added to a solution of 48 milligrams (0.116 millimoles) of 5-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole in 6 milliliters of glacial acetic acid. The reaction mixture is stirred at room temperature for 10 minutes. 25 milliliters of EtOAc are added, and this solution is washed with 4N NaOH (2 times), water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is recrystallized from dichloromethane / diethyl ether / hexane to give 40 milligrams of the title compound as colorless crystals. Rt = 2.38 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 493 (M + 1) + (79Br), 495 (M + 1) + (81Br).

The starting materials can be prepared as follows: a) 5- be nci 1-2- (4-iso pro pi lf enyl) -7-methoxy-1- (2-m ethoxy-et i I) -1H-benzoimidazole : A solution of 150 milligrams (0.317 mmol) of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -phenyl-methyl-ester of the acetic acid in 8 milliliters of tetrahydrofuran: MeOH = 1: 2, hydrogenated in the presence of 50 milligrams of Pd / C (Engelhard 4505). The catalyst is then filtered, and the filtrate is concentrated in vacuo to provide 120 milligrams of the title compound as a colorless oil. b) [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -phenyl-methyl-ester of acetic acid: A solution of 136 milligrams (0.30 millimoles) of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoI-5-yl] -phenyl-methanol, 46 microliters (0.66 millimoles) of acetyl chloride, and 125 microliters (0.90 millimoles) of triethylamine in 3 milliliters of dichloromethane, is stirred at room temperature for 1 hour. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 1), to provide 140 milligrams of the title compound as a colorless oil. c) [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -phenyl-methanol: A solution of 150 milligrams (0.426 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde in 2 milliliters of tetrahydrofuran is treat with an excess of phenyl magnesium bromide (prepared from 112 microliters of bromobenzene and 26 milligrams of magnesium in 5 milliliters of diethyl ether). The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 2), to provide 136 milligrams of the title compound as a white solid. d) 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaIdehyde: - ° r O A mixture of 480 milligrams (1.37 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile (Example 32), 15 milligrams of Raney nickel (in water), 967 milligrams (11.0 mmol) of sodium hypophosphite (in 10 milliliters of water), 10 milliliters of acetic acid, and 20 milliliters of pyridine, is stirred for 6 hours at 60 ° C. The catalyst is filtered, and the filtrate is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 1), to provide 330 milligrams of the title compound as a white crystalline solid.

Example 36: 5-benzyl-4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1 (2-m et oxy-I i) -1 H-benzoimidazole. 417 milligrams (1.78 millimoles) of N-iodo-succinimide are added to a solution of 670 milligrams (1.62 millimoles) of 5-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy). ethyl) -1H-benzoimidazole in 25 milliliters of acetonitrile. The reaction mixture is stirred at reflux temperature for 3 hours. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 4: 1), to provide 582 milligrams of the title compound as a white crystalline solid. Rt = 2.39 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 541 (M + 1) 0 Example 37: 5-benzyl-4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared starting from 5-benzyl-4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, using the same methodology described for the preparation of Example 11. Rt = 2.27 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 TFA percent, flow rate of 1.0 milliliters / minute). MS: 439 (M + 1) 0 Example 38: 4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared starting from 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy) ethyl) -1H-benzoimidazole, using the same methodology as described for the preparation of Example 11. Rt = 2.26 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 469 (M + 1) 0 Example 39: 4-bromo-5-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. (Instead of phenylmagnesium bromide, ethyl magnesium bromide is used). Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 431 (M + 1) + (79Br), 433 (M + 1) + (81Br).

Example 40: 4-bromo-5-cyclobutylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. (Instead of phenylmagnesium bromide, cyclobutyl methyl magnesium bromide is used). Rt = 2.53 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 471 (M + 1) + (79Br), 473 (M + 1) + (81Br).

Example 41 4-bromo-5- (3-f luoro-benzyl) -2- (4-isopropyl-f-enyl) -7-methoxy-1- (2-methoxy-et-1) -1H-benzoimidazole, The title compound is prepared using the same methodology as described for the preparation of Example 35. (In place of phenylmagnesium bromide, 3-fluoro- bromide is used. phenyl magnesium). Rt = 2.43 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 511 (M + 1) + (79Br), 513 (M + 1) + (81Br).

Example 42: 4-bromo-5- (3-chloro-benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. (Instead of phenylmagnesium bromide, 3-chloro-phenylmagnesium bromide is used). Rt = 2.42 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 527 (M + 1) + (35Cl, 79Br), 529 (M + 1) + (35Cl, 81 Br / 37Cl, 79 Br), 531 (M + 1) + (37Cl, 81 Br).

Example 43: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-thiazole-2-ylmethyl-1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. In place of phenylmagnesium bromide, 2-lithium-iazole (prepared from 2-bromo-thiazole and n-BuLi) is used. ). Rt = 2.14 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 500 (M + 1) + (79Br), 502 (M + 1) + (81Br).

Example 44: 4-bromo-5- (3,5-difluoro-benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole .

The title compound is prepared using the same methodology as described for the preparation of Example 35. In place of fenll-magnesium bromide, 3,5-bromide is used. dif I uoro-f in i I-magnesium. Rt = 2.40 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 529 (M + 1) + (79Br), 531 (M + 1) + (81Br).

Example 45: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-3-methylmethyl-1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. In place of phenylmagnesium bromide, 3-lithium-pyridine (prepared from 3-bromo-pyridine and n-BuLi) is used. ). Rt = 1.89 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 494 (M + 1) + (79Br), 496 (M + 1) + (81Br).

Example 46: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methyl-ethyl) -5- (2-methyl-sulfanyl-benzyl) -1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. Rt = 2388 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 539 (M + 1) + (79Br), 541 (M + 1) + (81Br). The starting material can be prepared as follows: a) 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-benzyl) -1H-benzoimidazole .

To a mixture of 797 milligrams (1.67 millimoles) of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - (2-methylsulfanil) phenyl) -methanol, and 436 milligrams of iodine in 13 milliliters of acetic acid (100 percent), 0.88 milliliters of phosphinic acid (approximately 5 equivalents) are added at room temperature. The mixture is heated to 60 ° C and stirred for 1 hour. After that, the reaction mixture is allowed to cool to room temperature environment, and 100 milliliters of ethyl acetate are added. The combined organic layers are washed with a 4N NaOH solution (4 times), water (2 times), and brine, dried over MgSO4, filtered, and the filtrate concentrated in vacuo to provide 914 milligrams of the title compound as a colorless oil. b) [2- (4-Isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - (2-methyl-sulfanyl-phenyl) -methanol.

The title compound is prepared using the same methodology as described for the preparation of Example 35 (step c). In place of phenyl magnesium bromide, 1-bromo-magnesium-2-methyl-suivane-benzene (prepared from 1-bromo-2-methyl-sulfanyl-benzene and magnesium) is used.

Example 47: 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methan-sulfinyl-benzyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole. 53 microliters (0.122 millimoles) of bromine are added to a solution of 496 milligrams (1.03 millimoles) of 2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl-benzyl) -7-methoxy-1- (2-meioxy-eyl) -1H-benzoimidazole, in 22 milliliters of glacial acetic acid. The reaction mixture is stirred at room temperature for 10 minutes. Then 25 milliliters of EtOAc are added, and this solution is washed with 4N NaOH (2 times), water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 4) to give 340 milligrams of the title compound as colorless crystals. Rt = 2.12 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 555 (M + 1) + (79Br), 557 (M + 1) + (81Br). The starting material can be prepared as follows: a) 2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl-benzyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

A mixture of 714 milligrams (1.32 millimoles) of 2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -5- (2-methyl-sulfanyl-benzyl) -1H-benzoimidazole and 142 microliters (1.39 mmol) of a hydrogen peroxide solution ( 30 percent) in 13 milliliters of acetic acid, is stirred at room temperature for 1.5 hours. After that, 25 milliliters of EtOAc are added, and this solution is washed with 4N NaOH (2 times), water, and a sodium acid sulfite solution, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (EtOAc) to provide 496 milligrams of the title compound as colorless crystals.

Example 48: 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfonyl-benzyl) -7-methoxy-1- (2-m and oxy-ethyl) -1H-benzoimidazole.

A mixture of 140 milligrams (0.252 mmol) of 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl-benzyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole and 30 microliters (0.265 millimoles) of a solution of hydrogen peroxide (30 percent) in 3 milliliters of acetic acid, is stirred at reflux temperature for 3 hours. After that, the reaction mixture is allowed to cool to room temperature, and 25 milliliters of EtOAc are added, and this The solution is washed with 4N NaOH (2 times), water, and a sodium sulfite acid solution, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 1), to give 112 milligrams of the title compound as pale red crystals. Rt = 2.23 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 571 (M + 1) + (79Br), 573 (M + 1) + (81Br).

Example 49: 4-bromo-2- (4-isopropyl-phenM) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-2-ylmethyl-1 H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. Rt = 1.90 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 494 (M + 1) + (79Br), 496 (M + 1) + (81Br).

The starting material can be prepared as follows: a) 2- (4-Isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-2-ylmethyl-1H-benzoimidazole.

To a solution of approximately 250 milligrams of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoamidazol-5-yl] -pyridin-2-yl -methyl-sulfonic acid methyl ester in 7 milliliters of tetrahydrofuran, 50 milligrams of LiAIH4 are added. The mixture is heated to reflux temperature and stirred for 3 hours. After that, the reaction mixture is allowed to cool to room temperature, and a solution of 1N NaOH is added, and this mixture is stirred for 30 minutes and filtered. The filtrate is extracted with ethyl acetate (3 times). The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and the filtrate concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (CH2Cl2: MeOH = 95: 5), to provide 40 milligrams of the title compound as an oil. b) [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -pyridin-2-yl-methyl-ester of methanesulfonic acid.

A mixture of 330 milligrams (0.76 mmol) of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-yl] -pyridin-2-yl -methanol, 0.6 milliliters of ethyl-di-isopropyl-amine, and 0.25 milliliters of methanesulfonyl chloride, is stirred at 0 ° C for 1 hour. The reaction mixture is then poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title product as an oil, which is used directly in the next step. c) [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -pyridin-2-yl-methanol.

The title compound is prepared using the same methodology as described for the preparation of Example 35 (step c). In place of phenyl magnesium bromide, 2-lithium pyridine (prepared from 2-bromo-pyridine and n-BuL) is used.

Example 50: 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole.

OR The title compound is prepared starting from [4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-eyl) -1 H -benzoimidazol-5-yl] - ( 2-methoxy-phenyl) -methanol, using the same methodology as described for the preparation of Example 46 (step a). Rt = 2.37 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 571 (M + 1) 0 The starting material can be prepared as follows: The title compound is prepared from 4-iodo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde and 2-methoxy-phenyl bromide magnesium, as described in Example 35. 4-iodo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde.

The title compound is prepared from 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde (for the preparation, see Example 35) , as described in Example 59.

Example 51: 4-Bromo-2- (4-isopropyl-phenyI) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared starting from [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-meioxy-eyl) -1 H -benzoimidazoI-5-yl] - ( 2-methoxy-phenyl) -methanol, using the same methodology as described for the preparation of Example 46 (step a). Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 523 (M + 1) + (79 Br), 525 (M + 1) + (8 Br). The starting material can be prepared as follows: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - ( 2-methoxy-phenyl) -methanol.

The title compound is prepared from 4-bromo-2- (4-isopro pil -fe nil) -7-methoxy-1- (2-methoxy-etl) -1 H-benzoimidazo 1-5 -carbaldehyde (see Example 41, step c), and 2-methoxyphenyl-magnesium bromide, as described in Example 35.

Example 52: 4-Bromo-5- (3,4-dimethoxy-benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

The title compound is prepared using the same methodology as described for the preparation of Example 35. In place of phenylmagnesium bromide, 3,4-dimethoxy-phen-1-magnesium bromide is used. Rt = 2.26 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 553 (M + 1) + (79Br), 555 (M + 1) + (81Br).

Example 53: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-yl) -5- (3-methoxy-pyridin-2-ylmethyl) -1 H- benzoimidazole The title compound is prepared using the same methodology as described for the preparation of Example 35. In place of phenylmagnesium bromide, 2-lithio-3-methoxy-pyridine is used. Rt = 1.94 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 524 (M + 1) + (79Br), 526 (M + 1) + (81Br).

Example 54: 5-Benzyl-4-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

A solution of 58 milligrams (0.13 millimoles) of 5- Benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-vinyl-1H-benzoimidazole in 5 milliliters of methanol, is hydrogenated in the presence of 10 milligrams of Nickel of Raney (B113W Degussa) at normal pressure for 25 hours. The catalyst is filtered, and the filtrate is concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 6: 1), to provide 26 milligrams of the title compound as a white crystalline solid. Rt = 2.29 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 443 (M + 1). The starting material can be prepared as follows: 5-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-vinyl-1H-benzoimidazole.

A mixture of 300 milligrams (0.566 millimoles) of 5-benzyl-4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 40 milligrams of bis (triphenylphosphine) -palladium (II) dichloride and 0.2 milliliters of tributyl- (vinyl) -stannate in 3 milliliters of tetrahydrofuran, is stirred at reflux temperature for 24 hours. hours. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 6: 1), to provide 278 milligrams of the title compound as a yellow crystalline solid. Example 55: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (3-methoxy-benzyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole.

A mixture of 125 milligrams (0.233 millimoles) of [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - (3 -methoxy-phenyl) -metanone (Example 26o), 45 milligrams of KOH granules, 3.2 milliliters of hydrazine monohydrate, 0.5 milliliters of water, and 13 milliliters of ethylene glycol ,. stir at 190 ° C for 2 hours. After that, the reaction mixture is poured into a 4N HCl solution, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1) to give 20 milligrams of the title compound as a white crystalline solid. R, = 2.33 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 523 (M + 1) + (79Br), 525 (M + 1) + (81Br).

Example 56: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-yl] - (3-methoxy-phenyl) - methanone To a solution of 0.16 milliliters of oxalyl chloride in 4 milliliters of dichloromethane, 0.27 milliliters of dimethyl sulfoxide (in 0.8 milliliters of dichloromethane) is slowly added at -60 ° C. This mixture is stirred under argon at -60 ° C for 0.5 hours. Then, 250 milligrams (0.463 millimoles) of [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoI-5-yl] is added. - (3-methoxy-phenyl) -methanol (in 2 milliliters of dichloromethane), and stirring is continued at -60 ° C for 1 hour. 1 milliliter of triethylamine is added, and the reaction mixture is allowed to warm to room temperature, poured into water, and extracted (3 times) with dichloromethane. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1), to give 179 milligrams of the title compound as a colorless oil. Rt = 2.47 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 537 (M + 1) + (79Br), 539 (M + 1) + (81Br). The starting material can be prepared as follows: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - ( 3-methoxy-phenyl) -methanol.

The title compound is prepared from 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-eyl) -1 H -benzoimidazo I-5-carbaldehyde and bromide of 3-methoxy-phenyl-magnesium, as described in Examples 35 and 51.

Example 57: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-yl] - (2-methoxy-phenyl) - methanone The title compound can be prepared as described in Example 56, using 2-methoxy-phenylmagnesium bromide in place of 3-methoxy-phenylmagnesium bromide. Rt = 2.37 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 537 (M + 1) + (79Br), 539 (M + 1) + (81Br).

Example 58: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (1-phenyl-ethyl) -1H-benzoimidazole: The title compound is prepared from 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (1-phenyl-ethyl) -1H-benzoimidazole, using the methodology described in Example 35. Rt = 2.39 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, speed flow rate of 1.0 milliliters / minute). MS: 507 (M + 1) + (79Br), 509 (M + 1) + (81Br). The starting materials can be prepared as follows: a) 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (1-f in i-l and i) -1 H-benzoimidazole: The title compound is prepared from 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etl) -1H-benzoimidazol-5-yl] -1-phenyl Ethanol, using the methodology described in Example 46 (step a). b) 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoim ida zol-5-yl] -1-phenyl-ethanol: A solution of 163 milligrams (0.445 millimoles) of 1- [2- (4-isopropy-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -ethanone in 2 milliliters of tetrahydrofuran is treated with an excess of phenylmagnesium bromide (prepared from 112 microliters of bromobenzene and 26 milligrams of magnesium in 5 milliliters of diethyl ether). The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1), to provide 109 milligrams of the title compound as an oil. c) 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -ethanone: To a solution of 0.17 milliliters of oxalyl chloride in 4 milliliters of dichloromethane, 0.285 milliliters of dimethyl sulfoxide (in 0.8 milliliters of dichloromethane) is slowly added at -60 ° C. This mixture is stirred under argon at -60 ° C for 0.5 hours.

Then, 180 milligrams (0.488 millimoles) of 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazoI-5-yl] -ethanol (in 2 milliliters of dichloromethane), and stirring is continued at -60 ° C for 1 hour. 1 milliliter of triethylamine is added, and the reaction mixture is allowed to warm to room temperature, poured into water, and extracted (3 times) with dichloromethane. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue purify by evaporation chromatography on silica gel (hexane: EtOAc = 3: 1) to give 163 milligrams of the title compound as a colorless oil. d) 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-yl] -ethanol: "oX? y? o A solution of 150 milligrams (0.426 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazole-5-carbaldehyde in 2 milliliters of tetrahydrofuran is treat with an excess of methyl magnesium iodide (prepared from 207 milligrams of methyl iodide and 35 milligrams of magnesium in 5 milliliters of diethyl ether). The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 180 milligrams of the title compound as an oil.

Example 59: 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile.

A mixture of 50 milligrams (0.143 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile, 36 milligrams (0.143 millimoles) of iodine , and 22 milligrams (0.072 millimoles) of silver sulfate in 1 milliliter of acetic acid, is stirred at reflux for 3 hours. The filtrate is then poured onto 2N NaOH, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 10 milligrams of the title compound as a white crystalline solid. Rt = 2.64 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 476 (M + 1) 0 Example 60: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-4-carbonitrile.

The title compound is prepared from 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole (Example 1), using the same methodology as described for the preparation of Example 32. Rt = 2.42 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 350 (M + 1) 0 Starting from 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-4-carbonitrile (Example 60), the following compounds can be prepared using the same reaction sequence as described for the preparation of Example 35: Example 61: 4-Isobutyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

Rt = 2.16 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 381 (M + 1) 0 Example 62: 4-Benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

Rt = 2.23 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 415 (M + 1) 0 Example 63: 4,7-dibromo-2- (4-isopropyl-phenyl) -1 - (2-methoxy-ethyl) -1H-benzoimidazole.

Rt = 2.73 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 451 (M + 1) + (2x 79 Br), 453 (M + 1) + (79 Br, 81 Br), 455 (M + 1) + (2x 8 Br). The title compound and the precursors are prepared from 3,6-dibromo-benzene-1,2-diamine [Naef, R .; Balli, H. Helvetica Chimica Acta 1978, 61 (8), 2958-73], using the same methodology described for the preparation of Example 1.

Example 64: 4,7-dibromo-2- (4-isopropyl-phenyl) -1- (2-methoxy-ethyl) ' 1 H-benzoimidazole. or Rt = 2.82 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 465 (M + 1) + (2x 79 Br), 467 (M + 1) + (79 Br, 81 Br), 469 (M + 1) + (2x 81 Br). The title compound is prepared using the same methodology as described for the preparation of Example 63.

Example 65: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenyl-1H-benzoimidazole.

A mixture of 150 milligrams (0.283 millimoles) of 4-bromo-5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole (Example 30) , 38 milligrams (0.312 millimoles of phenylboronic acid, 60 milligrams (0.567 millimoles) of sodium carbonate, and 16 milligrams (0.014 millimoles) of tetrakis (triphenylphosphine) palladium in 6 milliliters of toluene / water (3: 1), is stirred 100 ° C for 12 hours, then the reaction mixture is poured into water, and extracted (3 times) with ethyl acetate.The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, The residue is purified by evaporation chromatography on silica gel (hexane: EtOAc = 3: 1) to give 40 milligrams of the title compound as a white solid, Rt = 2.42 minutes (Waters Symmetry). C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA to, flow rate of 1.0 milliliters / minute). MS: 479 (M + 1) + (79Br), 481 (M + 1) + (81Br).

Using the same methodology as described in Example 65, the following compounds are prepared from the corresponding boronic acids: Example 66: 4-bromo-5- (3,4-dimethoxy-phenyl) -2- (4-isopropyl-n-nyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole Rt = 2.31 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 539 (M + 1) + (79Br), 541 (M + 1) + (8 Br).

Example 67: 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -phenol.

Rt = 2.21 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 495 (M + 1) + (79Br), 497 (M + 1) + (81Br).

Example 68: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-phenyl) -1 H -benzoimidazole.

Rt = 2.42 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 509 (M + 1) + (79Br), 511 (M + 1) + (81Br).

Example 69: 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzoic acid ethyl ester. c o ^ Rt = 2.50 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 551 (M + 1) + (79Br), 553 (M + 1) + (81Br).

Example 70: 4- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzoic acid ethyl ester.

Rt = 2.51 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 551 (M + 1) + (79Br), 553 (M + 1) + (81Br).

Example 71: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-3-yl-1 H-benzoimidazole.

Rt = 2.00 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 480 (M + 1) + (79Br), 482 (M + 1) + (81Br).

Example 72: 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzonitrile.

Rt = 2.38 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 504 (M + 1) + (79Br), 506 (M + 1) + (81Br).

Example 73: 1 -. { 5- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole-5-yl] -2-methoxy-f in i } -etanone.

Rt = 2,305 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 551 (M + 1) + (79Br), 553 (M + 1) + (81Br).

Example 74: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzonitrile.

OR Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 504 (M + 1) + (79Br), 506 (M + 1) + (81Br).

Example 75: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -5- (3-methoxy-phenyl) -1 H -benzoimidazole.

(The title compound is prepared from 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, instead of 4-bromo- 5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole). Rt = 2.06 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 417 (M + 1) 0 Example 76: 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-4-yl-1 H-benzoimidazole.

The compound is prepared using the methodology described in Example 40. The product of this reaction, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-4- il-1H-benzoimidazole, was iodinated as described in Example 59, to provide the product. Rt = 2,008 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 528 (M + 1) 0 Example 77: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (4-methyl-pyrazol-1-ylmethyl) -1 H -benzoimidazole.

NaH (7 milligrams, 0.3 mmol) is added to a solution of 23 microliters (0.30 millimoles) of 4-methylpyrazole in 2 milliliters of dimethylformamide. The resulting mixture is stirred at room temperature for 1 hour, and then 119 milligrams (0.23 millimoles) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) are added. -1H-benzoimidazol-5-ylmethyl ester of methanesulfonic acid. Stirring is continued for 20 hours. ThereafterThe reaction mixture is poured into water and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (dichloromethane: isopropanol = 95: 5), to provide 80 milligrams of the title compound as a white foam.

Rt = 2.28 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 479 (M + 1) + (79Br), 499 (M + 1) + (81Br). The starting materials can be prepared as follows: a) 4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl- methanesulfonic acid ester.

A mix .23 mmol) of [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazol-5-yl] -methanol, 26 microliters (0.33 mmol) ) of methanesulfonyl chloride, and 60 microliters (0.35 millimoles) of diisopropylethylamine in 4 milliliters of dichloromethane, is stirred at 0 ° C for 2 hours. The reaction mixture is poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 120 milligrams of the title compound as an oil, which is used directly in the next reaction . b) [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -methanol.

NaBH4 (65 milligrams, 1.72 millimoles) is added to a solution of 370 milligrams (0.858 millimoles) of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H -benzoimidazole-5-carbaldehyde in 5 milliliters of absolute ethanol at 0 ° C. The reaction mixture is stirred at 0 ° C for 20 minutes. The reaction mixture is then poured into water, and extracted (3 times) with dichloromethane / isopropanol (3: 1). The combined organic layers are washed with water (2 times) and brine, dried over MgSO, filtered, and concentrated in vacuo to provide 380 milligrams of the title compound as a pure crystalline solid. c) 4-bromo-2 ~ (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde.

OR The title compound is prepared from 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimide zol-5-carbonitrile (Example 33 ), using the same reaction conditions as described in Example 35, step d).

The reaction of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl-ester of methanesulfonic acid with any of imidazole, -bromo-3-methyl-1 H-pyrazole, 3,5-dimethyl-1 H-pyrazole, 1 H-imidazo [4,5-b] -pyridine, indazole, or 5-methyl-2H-tetrazole, using the same reaction conditions as described for the preparation of Example 77, led to the following compounds: Example 78: 4-bromo-5-imidazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m and oxy-ethyl) -1 H-benzoimidazole.

Rt = 1.93 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 483 (M + 1) + (79Br), 485 (M + 1) + (81Br).

Example 79: 4-bromo-5- (4-bromo-5-methyl-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole Rt = 2.37 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 575 (M + 1) + (2x 79 Br), 577 (M + 1) + (79 Br, 81 Br), 579 (M + 1) + (2x 81 Br).

Example 80: 4-bromo-5- (4-bromo-3-methyl-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole Rt = 2.36 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 575 (M + 1) + (2x 79 Br), 577 (M + 1) + (79 Br, 81 Br), 579 (M + 1) + (2x81 Br).

Example 81: 4-bromo-5- (3,5-dimethyI-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-eti I) -1 H -benzoimidazole.

Rt = 5.39 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 511 (M + 1) + (79Br), 513 (M + 1) + (81Br).

Example 82: 1- [4-Bromo-1- (2-hydroxy-ethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1H-benzo-imidazol-5-ylmethyl] -1H ethylester -imidazole-2-carboxylic acid.

Rt = 2.08 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 555 (M + 1) + (79Br), 557 (M + 1) + (81Br).

Example 83: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-yl) -5- (2-methoxymethyl-imidazol-1-ylmethyl) -1H- benzoimidazole Rt = 1.96 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 527 (M + 1) + (79Br), 529 (M + 1) + (81Br).

Example 84: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-imidazol-1-ylmethyl) -1 H -benzoimidazole.

Rt = 1.98 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 529 (M + 1) + (79Br), 531 (M + 1) + (81Br).

Example 85: 1 - [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-benzoimidazole-2-ol or Rt = 2.20 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 549 (M + 1) + (79Br), 551 (M + 1) + (81Br).

Example 86: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-benzoimidazol-1-ylmethyl) -1H-benzoimidazole.

Rt = 2.18 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 579 (M + 1) + (79Br), 581 (M + 1) + (81Br).

Example 87: 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methan-sulfinyl-benzoimidazol-1-ylmethyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole .

Rt = 2.20 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 595 (M + 1) + (79Br), 597 (M + 1) + (81Br).

Example 88: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzoimidazol-1-ylmethyl) -1- (2-methoxy-ethyl) -1H-benzoimidazole.

Rt = 2.26 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 563 (M + 1) + (79Br), 565 (M + 1) + (81Br).

Example 89: 3- [4-Bromo-1- (2-hydroxy-ethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoamidazol-5-ylmethyl] -3H- methyl ester imidazole-4-carboxylic acid.

Rt = 2.02 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 541 (M + 1) + (79Br), 543 (M + 1) + (81Br).

Example 90: 2- [4-bromo-5-imidazo [4,5-b] pyridin-3-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] -ethanol.

Rt = 2.05 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ).

MS: 534 (M + 1) + (aBr), 536 (M + 1) + (a? Br).

EXAMPLE 91 2- [4-Bromo-5-indazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] -ethanol.

Rt = 2.34 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 533 (M + 1) + (79Br), 535 (M + 1) + (81Br).

Example 92: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (5-methyl-tetrazol-2-methylmethyl) -benzoimidazol-1-ii] -ethanol.

Rt = 2.21 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ).

S: 499 (M + 1) + (/ aBr), 501 (M + 1) + (b1Br).

Example 93: 4-bromo-5- (4-bromo-5-methyl-pyrazol-1-methylmethyl) -2- (4-cyclopropyl-phenyl) -7-m H-benzoimidazole.

The compound is prepared as described in Example 79, using 4-cyclopropyl-benzoic acid in place of 4-isopropyl-benzoic acid. Rt = 2.28 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 573 (M + 1) + (2x 79 Br), 575 (M + 1) + (79 Br, 81 Br), 577 (M + 1) + (2x 81 Br).

Example 94: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (4-methyl-pyrazol-1-ylmethyl) -1- (2-methylsulfanyl-ethyl) -1H-benzoimidazole.

The compound is prepared as described in Example 77, using 1-bromo-2-methylsulfanyl-ethane in place of 1-bromo-2-methoxy-ethane. Rt = 2.33 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 513 (M + 1) + (79 Br), 515 (M + 1) + (81 Br).

Example 95: 4-bromo-5-isopropoxymethyl-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoI.

The title compound is prepared using the same methodology as described in Example 77, using 2-propanol (instead of 4-methyl-pyrazole). Rt = 2.33 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 475 (M + 1) + (79Br), 477 (M + 1) + (81Br).

Example 96: 1 - [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] -pyrrolidin-2-one. ón? xx o The title compound is prepared from 1- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] - pyrrolidin-2-one, using the same methodology as described in Example 35. Rt = 2.12 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 500 (M + 1) + (79Br), 502 (M + 1) + (81Br). The starting material can be prepared as follows: a) 1- [2- (4-isopropyI-phenyl) -7-methoxy-1- (2-meioxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyrrolidine -2-ona.

A solution of 50 milligrams (0.143 mmol) of C- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - methyl amine, 28 milligrams (0.143 millimoles of ethyl 4-bromobutyrate, and 28 microliters (0.2 millimoles) of triethylamine in 4 milliliters of 3-methyl-1-butanol, is stirred at reflux temperature for 8 hours. The reaction mixture is then poured into water, and extracted (3 times) with EtOAc The combined organic layers are washed with water (2 times) and brine, dried over MgSO, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (EtOAc: MeOH = 98: 2), to give 20 milligrams of the title compound as a colorless oil, b) C- [2- (4- isopro-pil-nil) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzo imide zol-5-yl] -me thi-amine.

To a solution of 100 milligrams (0.286 mmol) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile in 4 milliliters of tetrahydrofuran , LiAIH4 (54 milligrams, 1.43 millimoles) is added. The reaction mixture is stirred at reflux temperature for 2 hours. After that, methanol (0.5 milliliters), and 5 milliliters of a 15 percent NaOH solution are added. This mixture is filtered, and the filtrate is extracted (3 times) with EtOAc. The combined organic layers are washed with water (2 times) and brine, dried over MgSO 4, filtered, and concentrated vacuum, to provide 60 milligrams of the title compound as an oil.

Example 97: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenylsulfanii-1 H-benzoimidazole.

The title compound is prepared from 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenyl-sulfanyl-1H-benzoimidazole, using the method described for Preparation of Example 35. Rt = 2.49 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H2O in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 511 (M + 1) + (79Br), 513 (M + 1) + (81Br). The starting material, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenylsulfanyl-1H-benzoimidazole, can be prepared as follows: A mixture of 200 milligrams (0.491 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole (Example-22), 354 milligrams of Cs2C03, 9 milligrams of Cul, 56 microliters of Ph-SH, and 2 milliliters of N-methylpyrrolidone, is stirred at 200 ° C for 2 hours. The reaction mixture is then poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 3: 1), to provide 55 milligrams of the title compound as an oil.

Example 98: 5-Benzenesulfinyl-4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-1-ethyl) -1 H-benzoimidazole.

The title compound is prepared from 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenylsulfanyl-1H-benzoimidazole, using the method described for the preparation of Example 47 (oxidation reaction carried out at 40 ° C for 4 hours). Rt = 2.45 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 527 (M + 1) + (79 Br), 529 (M + 1) + (8 Br).

Example 98a: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-f-enoxy-1 H-benzoimidazole.

The title compound is prepared using the method described for the preparation of Example 97. Rt = 2.39 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute). MS: 495 (M + 1) + (79Br), 497 (M + 1) + (81Br).

Example 99: 5-Benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trif-Ioromethyl-1-1H-benzoy-idazole.

The title compound is prepared from 2- (4-isopro-p-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoro-methyl-1H-benzoimidazole-5-carbaldehyde and phenyl magnesium bromide, as described in Examples 35 and 51. Rt = 2.40 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + TFA at 0.05 percent, flow rate of 1.0 milliliters / minute). MS: 483 (M + 1) 0 The starting material, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole- 5-carbaldehyde, can be prepared as follows: O A mixture of 550 milligrams (1.45 millimoles) of 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde (Example 26k) ), 28 milligrams of Cul (0.145 millimoies), 555 microliters (4.36 millimoles) of methyl-2, 2-difluoro-2- (fluorosulfonyl) acetate, and 2 milliliters of dimethylformamide, is stirred at 120 ° C for 2 hours. The reaction mixture is then poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (100 percent hexane -> 100 percent EtOAc), to provide 525 milligrams of the title compound as a colorless crystalline solid. Using the same method, the following compounds are also prepared: Example 100: 2- (4-isopropyl-phenyI) -7-methoxy-5- (2-methoxy-benzyl) '1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole.

Rt = 2.40 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 513 (M + 1) +.

Example 101: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-2-methylmethyl-4-trifluoromethyl-1H-benzoimidazole.

Rt = 1.99 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 484 (M + 1) 0 Example 101a: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-thiazole-2-ylmethyl-4-trifluoromethyl-1H-benzoimidazole.

Rt = 2.22 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 490 (M + 1) 0 Example 102: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyrazol-1-ylmethyl-4-tri-fluoro-methyl-1H-benzoimidazole. cx / The title compound is prepared from 2- (4-isopro-p-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl-ester of methanesulfonic acid and pyrazole, as described in Examples 35 and 77. Rt = 2.25 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H20 in 2 minutes + TFA at 0.05 percent, flow rate of 1.0 milliliters / minute). MS: 473 (M + 1) 0 The starting material, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoro-methyl-1H-benzoimidazole -5-ylmethyl-methanesulfonic acid ester, can be prepared from 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-tri-fluoro-methyl-1 H- benzoimidazo 1-5-carbaldehyde (see Example 99), using the method described for the preparation of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-et i) - 1 H-benzoimidazol-5-ylmethyl ester of methanesulfonic acid (Example 77).

Example 103: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenoxy-methyl-1H-benzoimidazole. > OR To a cooled solution (ice bath) of phenol (7.2 milligrams, 0.077 millimoles) in 1 milliliter of dimethylformamide, add NaH (3.1 milligrams, 0.077 millimoles, 60 percent in mineral oil), and the reaction is heated to temperature ambient. 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl-ester of methanesulfonic acid (30 milligrams, 0.059 mmol) is added, and the reaction mixture is heated at 60 ° C for 1 hour. After that, the reaction mixture is extracted with a saturated solution of NaHCO 3 and diethyl ether. The combined organic layers are washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 1: 1), to provide 28 milligrams of the title compound as pale yellow crystals. Rt = 2.42 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 509 (M + 1) + (79Br), 511 (M + 1) + (81Br). The starting materials can be prepared as described in Example 77 (steps aac): a) 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazol-5-ylmethyl-ester of methanesulfonic acid: A solution of 200 milligrams (0.462 mmol) of [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -methanol, it is dissolved in 5 milliliters of CH2Cl2. The solution is cooled to 0 ° C, and methanesulfonyl chloride (47 microliters, 0.600 mmol) and Huenig base (103 microliters, 0.600 mmol) are added. After 1 hour, the reaction is extracted with CH2Cl2 / 10 percent citric acid. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo, to give 240 milligrams of a material that is used without further purification. b) [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazol-5-yl] -methanol: 2. 08 grams (4.82 millimoles) of 4-bromo-2- (4-isopropyl-fenll) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde, are dissolved in 60 milliliters of ethanol , and NaBH4 (365 milligrams, 9.64 millimoles) is added. After stirring for 30 minutes, ice / water is added, and the reaction mixture is extracted with ethyl acetate (3 times). The organic layer is washed with water (3 times) and brine (2 times), dried (Na2SO4), and concentrated in vacuo. The residue is crystallized from diethyl ether / hexanes, to give 1.85 grams of colorless crystals. c) 4-bromo-2- (4-isopropyl-phenyI) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoI-5-carbaldehyde: 3. 0 grams (8.51 millimoles) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde are dissolved in 90 milliliters of acetic acid. Bromine (437 microliters, 8.51 mmol) is added dropwise, and the reaction is stirred for 5 hours at room temperature. Ice / water is added, and the reaction mixture is extracted with ethyl acetate (3 times). The organic layer is washed with water (3 times) and brine (2 times), dried (Na2SO4), and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexanes / EtOAc), to give 2.08 grams of colorless crystals. d) 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbaldehyde: To a solution of 7.02 grams (20.1 mmol) of 1- (2-hyd-ethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1 H-benzo imide zol-5-carbonitrile in 280 milliliters of pyridine , 140 milliliters of acetic acid are added. After the addition of a solution of 14.1 grams (161 millimoles) of sodium hypophosphite in 140 milliliters of water, and heating to 50 ° C, Raney Nickel is added in 50 milligram portions (3 times for 12 hours), until the reaction is over. The reaction mixture is cooled to room temperature, ice / water is added, and the reaction mixture is extracted with ethyl acetate (3 times). The organic layer is washed with water, under vacuum, and azeotroped with toluene. The residue is suspended in 100 milliliters of CH 2 Cl 2, filtered, and washed with CH 2 Cl 2 and ethyl acetate. The mother liquor is evaporated and purified by chromatography by evaporation on silica gel (hexanes / EtOAc) to give 3.78 grams of colorless crystals. e) 1- (2-hyd-ethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1 H-benzoimidazole-5-carbonitrile: A solution of 1.42 grams (3.52 millimoles) of 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole and 455 milligrams (3.87 millimoles) of cyanide of zinc in 15 milliliters of dimethylformamide, is stirred under argon for 10 minutes at room temperature. Tetrakis (triphenylphosphine) palladium (214 milligrams, 0.176 millimoles) is added, and the reaction is heated at 180 ° C for 90 minutes. After cooling to room temperature, ice / water is added, and the reaction mixture is extracted with ethyl acetate (3 times). The organic layer is washed with water, dried (Na2SO4), and concentrated in vacuo, and the material is used without further purification.

Using the same synthetic method, the following examples are prepared: Example 104: 2- { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -ethanol.

Rt = 2.26 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 553 (M + 1) + (79Br), 555 (M + 1) + (81Br).

Example 105: 2- { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenoxy} -ethanol.

Rt = 2.21 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 569 (M + 1) + (79Br), 571 (M + 1) + (81Br).

Example 106: { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -methanol.

Rt = 2.22 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 539 (M + 1) + (79Br), 541 (M + 1) + (81Br).

Example 107: N-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethoxy] -phenyl} -acetamide.

OR Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 566 (M + 1) + (79Br), 568 (M + 1) + (81Br).

Example 108: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -benzamide.

Rt = 2.17 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 one hundred to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 552 (M + 1) + (79Br), 554 (M + 1) + (81Br).

Example 109: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -benzenesulfonamide.

Rt = 2.20 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 588 (M + 1) + (79Br), 590 '(M + 1) + (81Br).

Example 110: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethoxy] -phenylamine.

Rt = 1.98 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 524 (M + 1) (79 Br), 526 (M + 1) + (81 Br).

Example 111: 1 -. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -etanone.

Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 551 (M + 1) + (79Br), 553 (M + 1) + (81Br).

Example 112: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenol.

Rt = 2.28 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 525 (M + 1) + (79Br), 527 (M + 1) + (81Br).

Example 113: 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -pyridin-3-ol.

Rt = 2.01 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 526 (M + 1) + (79Br), 528 (M + 1) + (81Br).

Example 114: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-yl) -5- (pyridin-2-yloxymethyl) -1 H -benzoimidazole.

Rt = 2.07 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 510 (M + 1) + (79Br), 512 (M + 1) + (81Br).

Example 115: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-et i) -5- (2-methoxy-phenoxymethyl) -1 H -benzoimidazole.

Rt = 2.36 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 539 (M + 1) + (79Br), 541 (M + 1) + (81Br).

Example 116:. { 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl-methoxy] -2-methyl-phenyl} -methanol. or Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 553 (M + 1) + (79Br), 555 (M + 1) + (81Br).

Example 117: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-yl) -5- (pyridin-3-yloxymethyl) -1 H -benzoimidazole. x Rt = 1.95 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 510 (M + 1) + (79Br), 512 (M + 1) + (81Br).

Example 118: 4-Bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfonyl-phenoxymethyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole.

OR Rt = 2.28 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 587 (M + 1) + (79Br), 589 (M + 1) + (81Br).

Example 119: 2- { 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenoxy} -ethanol.

Rt = 2.18 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 569 (M + 1) + (79Br), 571 (M + 1) + (81Br).

Example 120: 2- { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -acetamide.

Rt = 2.14 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 566 (M + 1) + (79Br), 568 (M + 1) + (81Br). Using the same method, but using 5-bromomethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole (see Example 136) in Instead of 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl-methanesulfonic acid ester, the following are prepared compounds: Example 121: 2- { 2- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethoxy] -phenoxy} -ethanol or Rt = 2.14 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 559 (M + 1) 0 Example 122: 2- { 2- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1 H -benzoimidazol-5-ylmethoxy] -phenyl} -ethanol. or Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 543 (M + 1) 0 Example 123: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -phenyl-amine.

To a solution of 20 milligrams (0.039 millimoles) of 4-bromo-2- (4-lsopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl ester of the methanesulfonic acid in dimethylformamide, aniline (excess) is added, and the reaction is stirred for 1 hour at 60 ° C. The reaction mixture is extracted with Saturated NaHC03 / water. The organic layer is evaporated, and the residue is purified by reverse phase RP18 chromatography, to give 3.3 milligrams of the title compound. Rt = 2.26 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 508 (M + 1) + (79Br), 510 (M + 1) + (81Br). Using the same synthetic method, the following examples are prepared: Example 124: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-yl) -1H-benzoimidazol-5-ylmethyl] - (2-methansulfonyl-fe nil) -amine.

Rt = 2.29 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 586 (M + 1) + (79Br), 588 (M + 1) + (81Br).

Example 125: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1 - (2- methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - [2 - (2-methanesulfonyl-ethyl) -phenyl-amine.

Rt = 2.23 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 614 (M + 1) + (79Br), 616 (M + 1) + (81Br).

Example 126: 2- (2- { [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - amino.}. phenyl) -acetamide.

Rt = 2.10 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 565 (M + 1) + (79Br), 567 (M + 1) + (81Br).

Example 127: 2- Acid. { [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy- 1 - . 1- (2-M-ethoxy-yl) -1H-benzoimidazol-5-ylmethyl] -amino} -benzenesulfonic.

Rt = 2.09 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 586 (M-1) "(79Br), 481 (M-1)" (81Br).

Example 128: [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] - (2-f luoro-phenyl) -amine.

Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 526 (M + 1) + (79Br), 528 (M + 1) + (81Br).

Example 129: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-4-ylmethyl] -pyridin-2-yl-amine.

Rt = 1.91 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 509 (M + 1) + (79Br), 511 (M + 1) + (81Br).

Example 130: Methyl ester of 2- acid. { [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-m-ethoxy-yl) -1H-benzoimidazol-5-ylmethyl] -amino} -benzoic.

Rt = 2.44 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 566 (M + 1) + (79Br), 568 (M + 1) + (81Br).

Example 131: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyridin-3-yl-amine.

Rt = 1.89 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 509 (M + 1) + (79Br), 511 (M + 1) + (81Br).

Example 132: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -methyl-phen-i-amine.

Rt = 2.34 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 522 (M + 1) + (79Br), 524 (M + 1) + (81Br).

Example 133: [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - (3-methanesulfonyl-phenyl) - amine.

Rt = 2.18 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 586 (M + 1) + (79Br), 588 (M + 1) + (81Br). Using the same method, but using 5-bromo-methyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole instead of 4- Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl-ester of methanesulfonic acid, the following compounds are prepared: Example 134: 2- (2- { [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -amino .}.-phenyl) -acetamide.

Rt = 2.19 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 555 (M + 1) 0 Example 135: [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-tr? Uoro-methyl-1 H-benzoimidazol-5-ylmethyl] - (2-methanesulf nil -fe nor I) -amine.

Rt = 2.36 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 576 (M + 1) 0 Example 136: [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] - [2- (2-methanesulfonyl-ethyl) ) -phenyl] -amine.

Rt = 2.32 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 604 (M + 1) 0 Preparation of the starting material: a) 5-brornomethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifiuoromet i 1 -1 H-benzoimidazole: / o To a solution of 655 milligrams (1.52 millimoles) of [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-yl ] -methanol in 10 milliliters of tetrahydrofuran, added 604 milligrams (2.28 millimoles) of triphenylphosphine and 764 milligrams (2.28 millimoles) of carbon tetrabromide at 0 ° C. The mixture is stirred at 0 ° C for 10 minutes, and at room temperature for 30 minutes. The reaction mixture is then poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography by evaporation on silica gel (hexane: EtOAc = 2: 1 -> 1: 1), to provide 660 milligrams of the title compound as a colorless crystalline solid. b) [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoro-methyl-1H-benzoimidazol-5-yl] -methanol: To a solution of 710 milligrams (1.69 mmol) of 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazole-5-carbaldehyde (Example 54c) in 5 milliliters of ethanol, 128 milligrams (3.38 millimoles) of NaBH4 are added at 0 ° C. The mixture is stirred for 30 minutes at room temperature. The reaction mixture is then poured into water, and extracted (3 times) with ethyl acetate. The combined organic layers are washed with water (2 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is crystallized from hexane: EtOAc to give 655 milligrams of the title compound as a colorless crystalline solid.

Using the synthetic methods described above, the following compounds can also be prepared: Example 137: 1 - [4-Bromo-2- (4-isopropyl- phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-imidazole-2-carboxylic acid.

Rt = 2.05 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 541 (M + 1) + (79Br), 543 (M + 1) + (81Br).

Example 138: 1- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-imidazole-dimethylamide 2 -carboxylic.

Rt = 1.98 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ).

S: 554 (M + 1) + ('aBr), 556 (M + 1) + (a? Br) Example 139: 1-. { 1- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] -1 H -imidazol-2-yl} -etanone.

Rt = 2.12 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate 1.0 milliliters / minute ). MS: 525 (M + 1) + (79Br), 527 (M + 1) + (81Br).

Example 140: 1 - [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-indole-2,3 -Diona.

Rt = 2.29 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ).

S: 562 (M + 1) + (/ aBr), 564 (M + 1) + (a? Br).

Example 141: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-oxazol-2-ylmethyl-1 H-benzoimidazole.

Rt = 1.85 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 484 (M + 1) + (79Br), 486 (M + 1) + (81Br).

Example 142: 1 - [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzo-midazol-5-ylmethyl] -1 H- imidazole -2-carbonitrile.

Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 508 (M + 1) + (79Br), 510 (M + 1) + (81Br).

Example 143: 1- (4-Bromo-2- (4-isopropyl-n-nyl) -7-methoxy-1- (2-m-ethoxy-yl) -1H-benzoimidazol-5-ylmethyl] -1-methylamide H-imidazole -2-carboxylic acid.

Rt = 1.79 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 540 (M + 1) + (79Br), 542 (M + 1) + (81Br).

Example 144: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-b-rom -4 -trifluoromethyl-1H-benzoimidazole.

Rt = 2.50 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 one hundred to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 471 (M + 1) + (79Br), 473 (M + 1) + (81Br).

Example 145: [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1 H -benzoimidazol-5-ylmethyl] -phenylamine.

Rt = 2.35 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 498 (M + 1) 0 Example 146: [2- (4-i so propyl-phenyl) -7-m-ethoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -pyridin-2-yl- amine.

Rt = 1.97 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 one hundred to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 499 (M + 1) 0 Example 147: 2- { [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -amino} -benzenesulfonamide.

O Rt = 2.17 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection of 210 to 250 nanometers, CH3CN of 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute). MS: 577 (M + 1) 0 Example 148: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenoxymethyl-4-trifluoromethyl-1H-benzoimidazole.

Rt = 2.48 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 499 (M + 1) 0 Example 149: 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yloxymethyl) -4-trifluoromethyl-1H-benzoimidazole.

Rt = 2.14 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 500 (M + 1) 0 Example 150: 2- [2- (4-isopro-yl-phenol) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethoxy] -benzenesulfonamide.

Rt = 2.29 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 578 (M + 1) 0 Example 151: 4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yloxy) -1H-benzoimidazole.

Rt = 2.24 minutes (Waters Symmetry C8, 2.1 x 50 millimeters, detection from 210 to 250 nanometers, CH3CN from 10 percent to 95 percent in H20 in 2 minutes + 0.05 percent TFA, flow rate of 1.0 milliliters / minute ). MS: 496 (M + 1) + (79Br), 498 (M + 1) + (81Br). The Agents of the Invention, as defined in the foregoing, for example of the formula (I), in particular as exemplified, in free form or pharmaceutically acceptable acid addition salt, exhibit pharmacological activity, and are useful as products. pharmaceuticals, for example for therapy, in the treatment of diseases and conditions as stipulated later herein.

Inositol Phosphate Formation Assay: In order to determine the antagonist activity in the human parathyroid calcium (PcaR) detection receptor, the compounds are tested in functional assays that measure the inhibition of calcium-induced inositol phosphate formation in CCL39 fibroblasts stably transfected with human PcaR. Cells are seeded in 24-well plates, and grown to confluence. The cultures are then labeled with [3 H] inositol (74 Mbq / milliliter) in a serum-free medium for 24 hours. After labeling, the cells are washed once with a modified Hepes regulated salt solution (mHBS: 130 mM NaCl, 5.4 mM KCl, 0.5 mM CaCl2, 0.9 mM MgSO4, 10 mM glucose, 20 mM HEPES, pH 7.4) , and incubated with mHBS at 37 ° C in the presence of LiCl, to block the activity of inositol monophosphatase. The test compounds are added 3 minutes before stimulating the PcaR with 5.5 mM calcium, and the incubations are continued for an additional 20 minutes. Subsequently, the cells are extracted with ice-cold 10 mM formic acid, and the inositol phosphates formed are determined using anion exchange chromatography and counting with liquid scintillation.

Assay for free intracellular calcium: An alternative method to determine antagonism in PcaR is to measure the inhibition of intracellular calcium transients stimulated by extracellular calcium.

CCL39 fibroblasts stably transfected with human PcaR are seeded at 40,000 cells / well in 96-well Viewplate plates and incubated for 24 hours. The medium is then removed and replaced with fresh medium containing Fluo-3 AM 2μM (Molecular Probes, Leiden, The Netherlands). In routine experiments, cells are incubated at 37 ° C with 5 percent C02 for 1 hour. Then, the plates are washed twice with mHBS, and the wells are refilled with 100 microliters of mHBS containing the test compounds. The incubation is continued at room temperature for 15 minutes. To record the changes of free intracellular calcium, the plates are transferred to a fluorescence imaging plate reader (Molecular Devices, Sunnyvale, CA, E.U.A.). A baseline is recorded consisting of 5 measurements of 0.4 seconds each (laser excitation at 488 nanometers). Then the cells are stimulated with calcium (2.5 mM final), and the fluorescence changes are recorded over a period of 3 minutes. When measured in the above assays, the Agents of the Invention typically have IC50s in the range of about 1,000 nM down to about 10 nM or less. It is now well established that the controlled treatment of patients with parathyroid hormone (PTH) and its analogues and fragments can have a pronounced anabolic effect on bone formation. Therefore, it can use compounds that promote the release of parathyroid hormone, such as the Agents of the Invention, to prevent or treat bone conditions that are associated with increased calcium depletion or excretion, or where stimulation of bone formation is desirable and the fixation of calcium in the bone. In accordance with the foregoing, the Agents of the Invention are indicated to prevent or treat all bone conditions that are associated with increased calcium exhaustion or resorption, or where the stimulation of bone formation and calcium fixation is desirable. , for example osteoporosis of various genesis (eg, juvenile, menopausal, post-menopausal, post-traumatic, caused by aging or by corticosteroid therapy, or by inactivity), fractures, osteopathy, including acute and chronic conditions associated with the skeletal demineralization, osteo-malacia, periodontal bone loss or bone loss due to arthritis or osteoarthritis, or for the treatment of hypoparathyroidism. Additional diseases and disorders that could be prevented or treated include, for example, seizures, embolisms, head trauma, spinal cord injury, nerve cell damage induced by hypoxia ta! as in cardiac arrest or in neonatal insufficiency, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscular tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, congestive heart failure; hypertension; disorders of bowel mobility such as diarrhea, and spastic colon and dermatological disorders, for example in the healing of tissue, for example burns, ulcerations and wounds. The Agents of the Invention are indicated in particular to prevent or treat osteoporosis of various genesis. For all the above uses, an indicated daily dosage is preferably in the range of about 0. 03 to about 1,000 milligrams, more preferably 0.03 to 30, and still most preferably 0.1 to 10 milligrams of a compound of the invention. The Agents of the Invention can be administered twice a day, or up to twice a week. The Agents of the Invention can be administered in free form or in pharmaceutically acceptable salt form. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free compounds. The present invention also provides a pharmaceutical composition comprising an Invention Agent in the form of a free base or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or carrier. These compositions can be formulated in a conventional manner. The Agents of the Invention may be administered by any conventional route, for example parenterally, for example in the form of injectable solutions or suspensions, enterally, for example orally, for example in the form of tablets or capsules, or in a transdermal, nasal, or suppository form. In accordance with the above, the present invention further provides: a) an Invention Agent or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical product; b) a method for preventing or treating the aforementioned disorders and diseases, in a subject in need of such treatment, which method comprises administering to this subject an effective amount of an Invention Agent or a pharmaceutically acceptable salt thereof; c) an Agent of the Invention or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition, for example for use in the method mentioned in b) above. According to a further embodiment of the invention, the Agents of the Invention can be used as adjuncts or adjuvants for another therapy, for example a therapy using a bone resorption inhibitor, for example as in osteoporosis therapy, in particular a therapy employing calcium, a calcitonin or an analogue or derivative thereof, for example salmon, eel, or human calcitonin, a steroidal hormone, for example an estrogen, a partial agonist of estrogen or a combination of estrogen-gestagen, a SERM (Selective Estrogen Receptor Modulator), for example raloxifene, lasofoxifene, TSE-424, FC1271, Tibolone (Livial®), vitamin D or an analogue thereof, or parathyroid hormone (PTH), a fragment of parathyroid hormone or a derivative of parathyroid hormone, for example PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1- 31) NH2, or PTS 893. When the Agents of the Invention are administered in conjunction with, for example, as an adjuvant for therapy of inhibition of bone resorption, of course, dosages for the co-administered inhibitor will vary depending on the type of inhibitory drug used, for example if it is a steroid or a calcitonin, of the condition to be treated, if it is a curative or preventive therapy, of the regime, etc.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof: (i) wherein: R 1 is selected from the group consisting of (C 1-6 -alkyl, lower alkoxy, lower alkoxy-lower alkyl, cycloalkyloxy-lower alkyl, thio-lower alkyl, lower-thio-lower alkyl, cycloalkyl, cycloalkylalkyl-lower , lower alkenyl, and lower alkynyl) optionally substituted; R 2 is selected from the group consisting of (optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl); R3 is selected from the group consisting of halogen, cyano, (lower alkyl, lower alkoxy, lower cycloalkyl, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkenyl, lower alkynyl, heteroaryl, aryl-lower alkyl, and optionally substituted heteroaryl-lower alkyl and amino); R 4 is selected from the group consisting of H, halogen, cyano, hydroxyl, (lower alkyl, lower alkoxy, lower thioalkyl, lower thioalkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, alkenyl, alkynyl , and amino) optionally substituted, and the group having the formula R8-Z- (CH2) n-; wherein Z represents a direct bond or is selected from the group consisting of O, NH, CH2, CO, SO, S02, or S; wherein R8 is selected from the group consisting of (optionally substituted aryl, heteroaryl, carbocyclic aryl, cycloalkyl, heterocycloalkyl); and where n is 0, 1, 2, or 3; R5 is selected from the group consisting of H, halogen, cyano, hydroxyl, (lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, alkenyl, alkynyl, and amino) optionally substituted; R6 is selected from the group consisting of halogen, cyano, (lower alkyl, lower alkoxy, lower thioalkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl, and amino) optionally substituted; R7 represents one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, (lower alkyl, lower alkoxy, amino, cyano, and carbonyl) optionally substituted. the substituent or optional substituents on R1-R8 being independently selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or dialkyl lower-amino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di-lower alkyl -aminocarbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkylcarbonyl, lower alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di-lower alkyl-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkyl-carbonyl, lower alkoxyl-carbonyl, nitrile, aryl .

2. A compound of the formula (I ') or a pharmaceutically acceptable salt or prodrug ester thereof: d ') where: R 0 is selected from the group consisting of (optionally substituted C 1-6 -alkyl, lower alkoxy-lower alkyl, lower alkynyl, lower thioalkyl-lower alkyl, cycloalkyl-lower alkyl); R'2 is lower alkyl; R'3 is selected from the group consisting of halogen, cyano, (lower alkyl, lower alkoxy, lower thioalkyl, lower thioalkenyl, lower alkynyl, aryl, and aryl-lower alkyl) optionally substituted; R'4 is selected from the group consisting of H, halogen, cyano, (lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl) optionally substituted, and the group having the formula R'8- Z- (CH2) n-; wherein Z represents a direct bond or is selected from the group consisting of O, NH, CH2, CO, SO, S02, or S; wherein R'8 is selected from the group consisting of (optionally substituted aryl, pyrazolyl, thiazolyl, cyclobutyl, tetrazolyl, pyridyl, indazolyl, pyrazinyl, furanyl, isoxazolyl, pyrrolidinyl, benzimidazolyl, imidazolyl, oxazolyl); and where n is 0, 1, 2, or 3; R'5 is H, halogen, or lower alkyl; R'6 is selected from the group consisting of halogen, (lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl) optionally substituted; R'7 represents one or more substituents independently selected from the group consisting of optionally substituted H, halogen, hydroxyl, (lower alkyl, lower alkoxy, amino, cyano, and carbonyl); the substituent or optional substituents on R0-R'8 being selected independently from the group consisting of halogen, hydroxyl, lower alkyl, mono- or di-lower alkyl-amino, amino-carbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di-lower alkyl-amino-carbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkyl-carbonyl, lower alkoxyl-carbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxyl, lower alkyl, mono- or d-lower alkyl-amino, aminocarbonyl, sulfinyl, sulfonyl, mono- or lower di-lower alkylaminocarbonyl, amino, carboxyl, lower alkoxy, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, lower alkylcarbonyl, lower alkoxycarbonyl, nitrile, aryl.

3. A compound according to claim 1 or claim 2, wherein R3 or R'3 is halogen, ethyl, or substituted methyl.

4. A compound according to claim 1, selected from: 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1 H- benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7- methoxy-1- (2-methylsulfanyl-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methylsulfanyl-ethyl) -1H-benzoimidazole, 4- bromo-1-cyclopropylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, 4-b-rom-1-propyl-2- (4-isopropyl-phenyl) -7-methoxy-1 H-benzoimidazole, 4-bromo-1-butyl-2- (4-isopro pyl-phenyl) -7-methoxy-1H-benzoimidazole, 4-bromo-1-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazole, . { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] -ethyl} -dimethyl-amine, 4-chloro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethynyl-2- (4-isopropyl-phenyl) ) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-phenyl-1H -benzoimidazole, 3- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-4-yl] -phenol, 2- (4-isopropyl-phenyl) -7-methoxy-4- [3- (2-methoxy-ethoxy) -phenyl] -1- (2-methoxy-ethyl) -1H-benzoimidazole, 4- (3,5-dimethoxy-phenyl) -2- ( 4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1 H-benzoimidazole, 4-methyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethyl-2- (4-isopropyl-phenyl) -7-meloxy-1- (2-meioxy-ethyl) -1 H -benzoimidazole, 4-ethyl sulphonyl-2- (4-isopro-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1H-benzoimidazole, 4-bromo-2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-cyclopropyl-phenyl) - 7-methoxy-1- (2-methylsulfanyl-ethyl) -1H-benzoimidazole, 4-bromo-1-cyclopropylmethyl-2- (4-cyclopropyl-phenyl) -7-methoxy-1H-benzoimidazole, 5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4,5-dibromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2 -methoxy-ethyl) -1H-benzoimidazole, 4,5-dibromo-2- (4-cyclopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4,5-dibromo- 2- (4-isopropyl-2-methoxy-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-iodo-5-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-bromo-4-iodo-2- (4-isopropyl-2-methoxy-phenyl) -7-methoxy-1- (2 -methoxy-e ti I) - 1 H-be nzoimidazole, 4-bromo-2- (4-isopro-p-phenyl) -7-methoxy-1- (2-ethoxy-ethyl) -5-trifluoromethyl-1H-benzoimidazole, 4-b-romo-1-cyclopro-p-methyl-2 - (4- isopro pil-fe nil) -7-methoxy-5-tri-fluoro-methyl-1 H-benzoimidazole, 4-bromo-5-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-bromo-4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile, 4-b romo-2- (4-isopro pil-fe nil) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-carbonitrile, 4-bromo-5-fluoro-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-benzyl-4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 5-benzyl-4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, -benzyl-4-ethynyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-ethynyl-2- (4-isopropyl-phenyl) -7 -methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy eti I) -1 H-benzoimidazole, 4-bromo-5-ethyl-2- (4-isopropyl-phenyl) -7-methoxy- 1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-5-cyclobutylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy) ethyl) -1 H-benzoimidazole, 4-bromo-5- (3-fluoro-benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole , 4-b-romo-5- (3-chloro-benzyl) -2- (4-isopro-p-p-phenyl) -7-methoxy-1- (2-methioxy-ethyl) -1 H -benzoimidazole, 4-bromo -2- (4-isopro pil-fe nil) -7-methoxy-1- (2-methoxy-ethyl) -5-thia zo I-2-ylmethyl-1 H-benzoimidazole, 4-bromo-5- ( 3, 5-di-fluoro-benzyl) -2- (4-isopro-p-p-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-3-ylmethyl 1-1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy -1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-benzyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl-benzyl) - 7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfonyl! -benzyl!) - 7-methoxy-1 - (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl-phenyI) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) ) -1H-benzolmidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2-methoxy-benzyl) -1- (2- methoxy-ethyl) -1 H-benzoimidazole, 4-bromo-5- (3,4-dimethoxy-benzyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1 H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-pyridin-2-ylmethyl) -1 H- benzoimidazole, 5-Benzyl-4-ethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (3-methoxy-benzyl) -1- (2-methoxy-ethyl) -1 H -benzoimidazole, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-methoxy-ethyl) -1 H -benzoimidazol-5-yl] - (3-methoxy-phenyl) -methanone, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] - (2-methoxy-phenol) -methanone, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2- methoxy-ethyl) -5- (1-phenyl-ethyl) -1 H -benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole-5-carbonitrile, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-4-carbonitrile, 4-isobutyl-2- (4-lsopropyl) phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 4-benzyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) - 1H-benzoimidazole, 4,7-dibromo-2- (4-isopropyl-phenyl) -1- (2-methoxy-etl) -1 H -benzoimidazole, 4,7-dibrsm-2- (4-isopropyl) phenyl) -1- (2-methoxy-etiI) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenyl-1H-benzoimidazole, 4-bromo-5- (3,4-dimethoxy-phenyl) ) -2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 3- [4-bromo-2- (4-isopropyl-phenyl) -7- methoxy-1- (2-methoxy-ethyl) -1 H- benzoimidazol-5-yl] -phenol, 4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-f in ii) - 1 H-benzoimidazole, 3- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-me toxy-ethyl) -1H-benzo imidazo l-5-yl] ethyl ester] -benzoic acid, 4- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzoic acid ethyl ester, 4 -bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-3-yl-1H-benzoimidazole, 3- [4-bromo-2] - (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzo imide zol-5-i I] -benzo nitrile, 1 ~. { 5- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1 ~ (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -2-methoxy-phenyl} -etanone, 2- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-yl] -benzo-nitrile, 2- (4 -isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (3-methoxy-phenyl) -1 H -benzoimidazole, 4-iodo-2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -5-pyridin-4-yl-1 H-benzoimidazoi, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy) -ethyl) -5- (4-methyl-pyrazol-1-ylmethyl) -1 H -benzoimidazole, 4-bromo-5-imidazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-1 - (2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-5- (4-bromo-5-methyl-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy- 1- (2-methoxy-ethyl) -1H-benzoimidazoI, 4-bromo-5- (4-bromo-3-methyl-pyrazol-1-ylmethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-b romo-5- (3,5-dimethyl-pi-razo 1-1-ylmethyl) -2- (4-isopro-p-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H-benzoimidazole, 1 - [4-bromo-1- (2-hydroxy-ethyl) -2- (4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazol-5-ylmethyl] -1H-imidazole acid ethyl ester -2-carboxylic, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methoxymethyl-imidazol-1-ylmethyl) -1 H -benzoimidazole, 4-bromo -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-imidazoI-1-ylmethyl) -1 H -benzoimidazole, 1- [4-bromo] -2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-2-ol, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy -1- (2-methoxy-ethyl) -5- (2-methylsulfanyl-benzoimidazol-1-ylmethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -5- (2-methanesulfinyl) -benzoimidazol-1-ylmethyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (2- methoxy-benzoimidazol-1-ylmethyl) -1- (2-methoxy-yl) -1H-benzoimidazole, Methyl ester of 3- [4-bromo-1- (2-hydroxy-ethyl) -2- ( 4-isopropyl-phenyl) -7-methoxy-1H-benzoimidazol-5-ylmethyl] -3H-imidazole-4-carboxylic acid, 2- [4-bromo-5-imidazo [4,5-b] pyridin-3-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazol-1-yl] ethanol, 2- [4- Bromo-5-indazol-1-ylmethyl-2- (4-isopropyl-phenyl) -7-methoxy-benzoimidazole-1-yl] ethanol, 2- [4-bromo-2- (4-isopropyl-phenyl) - 7-methoxy-5- (5-methyl-tetrazole-2-) ylmethyl) -benzoimidazol-1-yl] ethanol, 4-bromo-5- (4-bromo-5-methyl-pyrazol-1-ylmethyl) -2- (4-cyclopropyl-phenyl) -7-methoxy-1- ( 2-methoxy-ethyl) -1 H -benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-5- (4-methyl-pyrazol-1-ylmethyl) -1- (2-methylsulfanil -ethyl) -1 H-benzoimidazole, 4-bromo-5-isopropoxymethyl-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 1- [4 -bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyrrolidin-2-one, 4-bromo-2- (4 -isopro pil-fe nil) -7-methoxy-1- (2-methoxy-ethyl) -5-pheni Isulfan i I-1 H-benzoimidazole, 5-benzenesulfinyl-4-bromo-2- (4-isopropyl-phenyl) ) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazole, 5-benzyl-2- (4-isopropyl-phene) -7-methoxy-1- (2-methoxy-ethyl) -4 -trifluoro methyl-1 H-benzoimidazole, 2- (4-isopropyl-phenyI) -7-methoxy-5- (2-methoxy-benzyl) -1- (2-methoxy-ethyl) -4-trifluoromethyl-1H -benzoimidazole, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-pyridin-2-ylmethyl-4-trifluoromethyl-1H-benzoimidazole, 2- (4 -isop rop i lf enil) -7-methoxy-1- (2-methoxy-eti I) -5-pyrazol-1-ylmethyl-4-trifluoromethyl-1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -5-phenoxymethyl-1H-benzoimidazole, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -ethanol, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazoi-5-ymethoxy] -phenoxy} - ethanol,. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -etanol, N-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -acetamide, 2- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1 ~ (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -benzamide, 2- [4- bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazoi-d-ylmethoxy-benzenesulfonamide, 2- [4-bromo-2- (4-isopropyl phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -f-enylamine, 1-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -fe nil} - ethanone, 2- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenol, 2- [4- bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -pyridin-3-ol, 4-bromo-2- (4- isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yl-loxymethyl) -1H-benzoimidazole, 4-bromo-2- (4-isopropyl-phenyl) -7 -methoxy-1- (2-methoxy-ethyl) -5- (2-methoxy-phenoxymethyl) -1 H-benzoimidazole,. { 3- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -2-methyl-phenyl} -methanol, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-3-) i loxymethyl) -1 H-benzoimidazole, 4-b rom o-2- (4-isopropyl-phenyl) -5- (2-methanesulfonic acid I -fe n oxy metal) -7-methoxy-1- (2- methoxy-ethyl) -1 H-benzoimidazole, 2-. { 3- [4-Bromo-2- (4-isopropyl-phenyl) -7- ethoxy-1- (2-methoxy-ethyl) -1 H -benzo imide zol-5-ylm-ethoxy] -phenoxy} - ethanol, 2-. { 2- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethoxy] -phenyl} -acetamide, 2-. { 2- [2- (4-isopro pil -fe nil) -7-methoxy-1- (2-methoxy-ethyl) -4-tri-fluoro-methyl-1H-benzoimidazol-5-ylmethoxy] -phenoxy} -ethanol, 2-. { 2- [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-tri-fluoro-methyl-1H-benzoimidazol-5-ylmethoxy] -phenyl} -ethanol, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -phenylamine, [4-bromo- 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - (2-methanesulfonyl-phenyl] -amine, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] - [2- (2-methanesulfonylethyl) phenyI] amine, 2- (2-. { . [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -amino.} - phenyl) -acetamide, Acid 2- (2- { [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -amino. -benzenesulfonic, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etiI) -1H-benzoimidazol-5-ylmethyl] - (2-fluoro-phenyl) -amine, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyridin-2-yl-amine, 2- Methyl ester. { [4-bromo ~ 2- (4 ~ isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -amino} -benzoic acid, [4-b-romo-2- (4-isopro-pil-nil) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -pyridin-3-yl -amine, [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -methyl-phenyl-amine, [4- Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H -benzoimidazol-5-ylmethyl] - (3-methanesulfonyl-phenyl) -amine, 2- (2 - { [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1 H -benzoimidazol-5-ylmethyl] -amino.} - phenyl) -acetamide, [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] - (2-methanesulfonyl-phenyl) -amine , [2- (4-isopro pil-faith nil) -7-methoxy-1- (2-methoxy-ethyl) -4-t-trifluoromethyl-1 H-benzoimidazol-5-ylmethyl] - [2- (2-methanesulfonyl -ethyl) -phenyl] -amine, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazole-5-methyl ester ylmethyl] -1H-imidazole-2-carboxylic acid, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-etii) -1H-benzoimidazole-1-dimethylamide] 5-ylmethyl] - 1H-imidazole-2-carboxylic, 1-. { 1- [4-Bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-imidazol-2-yl} - ethanone, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H-benzoimidazol-5-ylmethyl] -1H-indole-2,3 -dione, 4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-oxazole-2-yl methyl-1H-benzoimidazole, 1- [ 4-bromo-2- (4-isopropyI-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1 H- benzoimidazol-5-ymethyl] -1H-imidazole-2-carbonitrile, 1- [4-bromo-2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -1H acid methylamide -benzoimidazol-5-ylmethyl] -1H-imidazole-2-carboxylic acid, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-bromo-4-trifluoro-methyl-1 H-benzoimidazole, [2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-trifluoromethyl-1H-benzoimidazol-5-ylmethyl] -phenyl-amine, [2- ( 4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -4-tri-fluoromethyl-1 H -benzoimidazol-5-ylmethyl] -pyridin-2-yl-amine, 2-. { [2- (4-isopropyl-phen i) -7-methoxy-1- (2-methoxy-ethyl) -4-ylfluoromethyl-1 H -benzoimidazol-5-ylmethyl] -amino} -benzene-sulfonamide, 2- (4-isopropyl-phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5-phenoxymethyl-4-trifluoromethyl-1H-benzoimidazole, 2- (4-isopropyl- phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yl-oxymethyl) -4-trifluoromethyl-1H-benzoimidazole, / 2- [2- (4-iso pro-pil -fe niI) -7-methoxy-1- (2-methoxy-eti I) -4-trlf luoromethyl-1 H-benzoimidazol-5-ylmethoxy] -benzenesulfonamide, 4-bromo-2- (4-isopropyl- phenyl) -7-methoxy-1- (2-methoxy-ethyl) -5- (pyridin-2-yloxy) -1 H-benzoimidazole.

5. A pharmaceutical composition, which comprises a compound of the formula (I) as defined in claim 1, in association with a pharmaceutically acceptable excipient, diluent or carrier.

6. A pharmaceutical composition according to claim 5, which contains from 0.03 to 300 milligrams of the composed of the title of the formula (I).

7. A compound of the formula (I) as defined in claim 1, for promoting the release of the parathyroid hormone.

8. A method for preventing or treating bone conditions that are associated with an increase in calcium exhaustion or resorption, or where the stimulation of bone formation and calcium fixation in bone is desirable, wherein a an effective amount of a compound of the formula (I) as defined in claim 1, or a pharmaceutically acceptable and dissociable ester or an acid addition salt thereof, to a patient in need of such treatment.

9. A process for the preparation of a compound of the formula (I) as defined in claim 1, which comprises: (a) Introducing a group R4 into a corresponding compound of the formula II, wherein R4 is as defined in Claim 1: (II) where X is any suitable group capable of being substituted by R4, and wherein R1, R2, 43, R5, R6, and R7 are as defined in claim 1; or (b) for the preparation of compounds wherein R 4 is an aryl-CH 2 group, appropriately introducing this aryl group by reaction with a compound of the formula III:it is. (lll) where Y denotes any of: (i) a leaving group -CH2-, or (ii) the group -CH = 0; and R1, R2, R3, R5, R6, and R7 are as defined in claim 1; or (c) introducing a group R3 into a corresponding compound of formula IV, wherein R3 is as defined in claim 1: (IV) where Q is any suitable group capable of being substituted by R3, and wherein R1, R2, R4, R5, R6, and R7 are as defined in claim 1; or (d) N-appropriately replacing a corresponding compound of formula V with a group R1 as defined in claim 1: (V) wherein R2-R7 are as defined in claim 1; or (e) for the preparation of compounds wherein R 4 is aryl-CO-, oxidizing a compound of the formula (VI): (SAW) with a suitable oxidizing agent, wherein R1, R2, R3, R5, R6, and R7 are as defined in claim 1; or (f) treating a compound of the formula (VII): (Vile) under conditions suitable to effect a ring closure, where R1-R7 is as defined in claim 1; and recovering the resulting compound of formula (I) in free or salt form.

10. The use of a compound of the formula (I) in the manufacture of a medicament for preventing or treating bone conditions that are associated with an increase in calcium exhaustion or resorption, or where the stimulation of the formation of calcium is desirable. bone and calcium fixation.

11. All compounds, processes, methods, and novel uses, substantially as described hereinabove, with particular reference to the Examples.