Aryl imidazoles and related compounds as C5a receptor modulators

FIELD OF THE INVENTION

[0002] This invention includes substituted aryl imidazoles and related compounds that modulate a mammalian complement C5a receptor. Certain compounds provided herein act as high affinity C5a receptor ligands and/or act as antagonists (including inverse agonists) of complement C5a receptors, preferably human C5a receptors. This invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds for treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

BACKGROUND OF THE INVENTION

[0003] C5a, a 74 amino acid peptide, is generated in the complement cascade by the cleavage of the complement protein C5 by the complement C5 convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects. Therefore, it is active in engendering both the vascular and cellular phases of inflammatory responses. Because it is a plasma protein and, therefore, generally almost instantly available at a site of an inciting stimulus, it is a key mediator in terms of initiating the complex series of events that results in augmentation and amplification of an initial inflammatory stimulus. The anaphylatoxic and chemotactic effects of the C5a peptide are believed to be mediated through its interaction with the C5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupled receptor (GPCR). C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury. C5a is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also “primes” or prepares neutrophils for various antibacterial functions (e.g., phagocytosis). Additionally, C5a stimulates the release of inflammatory mediators (e.g., histamines, TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and the release of lysosomal enzymes and other cytotoxic components from granulocytes. Among its other actions, C5a also promotes the production of activated oxygen radicals and the contraction of smooth muscle.

[0004] Considerable experimental evidence implicates increased levels of C5a in a number of autoimmune diseases and inflammatory and related disorders.

[0005] Agents that block the binding of C5a to its receptor other agents, including inverse agonists, which modulate signal transduction associated with C5a-receptor interactions, can inhibit the pathogenic events, including chemotaxis, associated with anaphylatoxin activity contributing to such inflammatory and autoimmune conditions.

SUMMARY OF THE INVENTION

[0006] The present invention provides substituted aryl imidazoles and related compounds of Formula I, below. Such compounds are useful as modulators of C5a receptor and preferably inhibit C5a receptor activation and/or C5a receptor-mediated signal transduction.

[0007] The invention provides compounds of Formula I:

[0008] and the pharmaceutically acceptable salts thereof, wherein

[0009] the ring system represented by

[0010] is a 5 membered heteroaryl ring system, in which x is 0, A is chosen from carbon and heteroatoms nitrogen, oxygen, and sulfur, and E and G are independently carbon or nitrogen, provided that the 5 membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom, or a 6 membered heteroaryl ring system, in which x is 1, and A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6 membered heteroaryl ring system does not contain more than 3 nitrogen atoms.

[0011] R and R1 independently represent:

[0012] i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, or C1-C6haloalkoxy,

[0013] ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkanoyl, C1-C6alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- or di-C1-C6alkylamino, mono- or di-C1-C6alkylaminoC1-C6alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —SO,(C1-C6alkyl), —NHSOnC1-C6alkyl, —SOnN(C1-C6alkyl) (C1-C6alkyl), phenyl-SOn—, each of which is optionally substituted, or

[0014] iii) naphthyl, phenyl, phenylC1-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroarylC1-C4carbhydryl, each of which is optionally substituted.

[0015] When E is Nitrogen, R2, is chosen from C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3-C7cycloalkyl(C1-C4alkyl), benzyl, and C1-C6haloalkyl, each of which is optionally substituted; and when E is Carbon, R2 is chosen from (i) hydrogen, halogen, hydroxy; C1-C6haloalkyl, and C1-C6haloalkoxy, and (ii) C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, C1-C7alkylamino, C3-C7cycloalkyl(C1-C4alkyl), and benzyl; each of which is optionally substituted;

[0016] R3 is hydrogen, C1-C6alkyl, C2-C6 alkenyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(C1-C4alkyl).

[0017] When x is 0, R, and R3 may be joined to form an optionally substitued cycloalkyl ring having from 3 to 7 carbon atoms.

[0018] R4 is C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is optionally substituted; or

[0019] R4 is

[0020] (i) optionally substituted arylC1-C4alkyl having from 1 ring or 2 fused or pendant rings,

[0021] (ii) an arylC1-C4alkyl group, wherein the aryl portion is fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy,

[0022] (iii) optionally substituted heterocycloalkyl(C0-C4alkyl),

[0023] (iv) optionally substituted heteroarylC0-C2alkyl, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, or

[0024] (v) optionally substituted saturated or partially unsaturated heterocyclic(C0-C4alkyl) wherein the heterocyclic portion has from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon.

[0025] R5 and R6 are independently chosen from hydrogen and C1-C6alkyl, and z is 1, 2, or 3.

[0026] Ar1 represents (i) optionally substituted aryl, (ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy, or (iii) optionally substituted heteroaryl, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S.

[0027] Ar2 represents:

[0028] (i) C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl, each of which is optionally substituted

[0029] (ii) an optionally substituted aryl having 1 ring or 2 fused or pendant rings,

[0030] (iii) an optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy, or

[0031] (iv) optionally substituted heteroaryl, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S.

[0032] In Formula I n is independently chosen from 0, 1, or 2; and y is an integer of from 1 to 6.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Chemical Description and Terminology

[0034] Compounds of the present invention are generally described using standard nomenclature.

[0035] The term “aryl imidazole,” as used herein, encompasses all compounds that satisfy one or more of Formulas I, IA, and II-XIV herein, as well as pharmaceutically acceptable salts, prodrugs and hydrates of such compounds.

[0036] Certain compounds described herein contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like (e.g., asymmetric carbon atoms) so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. Unless otherwise specified all optical isomers and mixtures thereof are encompassed for compounds having asymmetric centers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather encompasses all tautomeric forms.

[0037] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C.

[0038] Certain compounds are described herein using a general formula, such as Formula I, which includes variables, such as Ar1, R1, and R2. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said group may optionally be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0039] A “substituent,” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a “ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (i.e., a compound that can be isolated, characterized and tested for biological activity). When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a tetrahydropyridone.

[0040] The phrase “optionally substituted” indicates that a group may either be unsubstituted or substituted at one or more of any of the available positions, typically 1, 2, 3, 4, or 5 positions, by one or more suitable substituents such as those disclosed herein. Various groups within the compounds and formulae set forth herein are “optionally substituted” including, for example, R1, R2, and Ar1. Optional substitution may also be indicated by the phrase “substituted with from 0 to X substituents,” in which X is the maximum number of substituents.

[0041] Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, —COOH, SO2NH2, alkyl (e.g., C1-C8alkyl), alkenyl (e.g., C2-C8alkenyl), alkynyl (e.g., C2-C8alkynyl), alkoxy (e.g., C1-C8alkoxy), alkyl ether (e.g., C2-C8alkyl ether), alkylthio (e.g., C1-C8alkylthio), mono- or di-(C1-C8alkyl)amino, haloalkyl (e.g., C1-C6haloalkyl), hydroxyalkyl (e.g., C1-C6hydroxyalkyl), aminoalkyl (e.g., C1-C6aminoalkyl), haloalkoxy (e.g., C1-C6haloalkoxy), alkanoyl (e.g., C1-C8alkanoyl), alkanone (e.g., C1-C8alkanone), alkanoyloxy (e.g., C1-C8alkanoyloxy), alkoxycarbonyl (e.g., C1-C8alkoxycarbonyl), mono- and di-(C1-C8alkyl)amino, mono- and di-(C1-C8alkyl)aminoC1-C8alkyl, mono- and di-(C1-C8alkyl)carboxamido, mono- and di-(C1-C8alkyl)sulfonamido, alkylsulfinyl (e.g., C1-C8alkylsulfinyl), alkylsulfonyl (e.g., C1-C8alkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g., (C6-C18aryl)C1-C8alkyl, such as benzyl and phenethyl), aryloxy (e.g., C6-C18aryloxy such as phenoxy), arylalkoxy (e.g., (C6-C18aryl)C1-C8alkoxy) and/or 3- to 8-membered heterocyclic groups. Certain groups within the formulas provided herein are optionally substituted with from 1 to 3, 1 to 4 or 1 to 5 independently selected substituents.

[0042] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH2 is attached through the carbon atom.

[0043] As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms. Thus, the term C1-C6alkyl, as used herein, indicates an alkyl group having from 1 to 6 carbon atoms. “C0-C4alkyl” refers to a bond or a C1-C4alkyl group. Alkyl groups include groups having from 1 to 8 carbon atoms (C1-C8alkyl), from 1 to 6 carbon atoms (C1-C6alkyl) and from 1 to 4 carbon atoms (C1-C4alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. “Aminoalkyl” is an alkyl group as defined herein substituted with one or more —NH2 groups. “Hydroxyalkyl” is a hydroxy group as defined herein substituted with one or more —OH groups.

[0044] “Alkenyl” refers to a straight or branched hydrocarbon chain comprising one or more unsaturated carbon-carbon bonds, such as ethenyl and propenyl. Alkenyl groups include C2-C8alkenyl, C2-C6alkenyl and C2-C4alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively), such as ethenyl, allyl or isopropenyl.

[0045] “Alkynyl” refers to straight or branched hydrocarbon chains comprising one or more triple carbon-carbon bonds. Alkynyl groups include C2-C8alkynyl, C2-C6alkynyl and C2-C4alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups include for example groups such as ethynyl and propynyl.

[0046] “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0047] The term “alkanoyl” refers to an acyl group in a linear or branched arrangement (e.g., —(C═O)-alkyl). Alkanoyl groups include C2-C8alkanoyl, C2-C6alkanoyl and C2-C4alkanoyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “C1alkanoyl” refers to {C═O)—H, which (along with C2-C8alkanoyl) is encompassed by the term “C1-C8alkanoyl.”

[0048] The term, “alkyl ether” refers to a linear or branched ether substituent linked via a carbon-carbon bond. Alkyl ether groups include C2-C8alkyl ether, C2-C6alkyl ether and C2-C6alkyl ether groups, which have 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. By way of example, a C2alkyl ether group has the structure —CH2—O—CH3.

[0049] The term “alkoxycarbonyl” refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure C(═O—alkyl). Alkoxycarbonyl groups include C2-C8, C2-C6, and C2-C4alkoxycarbonyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “Cialkoxycarbonyl” refers to —C(═O)OH, and is encompassed by “C1-C8alkoxycarbonyl.”

[0050] “Alkanoyloxy,” as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure —O—C(═O)alkyl). Alkanoyloxy groups include C2-C8, C2-C6, and C2-C4alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.

[0051] As used herein, the term “alkylthio” refers to an alkyl group attached via a thioether linkage. Alkylthio groups include C1-C8alkylthio, C1-C6alkylthio and C1-C4alkylthio, which have from 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively.

[0052] “Alkylsulfinyl,” as used herein, refers to an alkyl group attached via a sulfinyl linkage. Alkylsulfinyl groups include C1-C8alkylsulfinyl, C1-C6alkylsulfinyl, and C1-C4alkylsulfinyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.

[0053] By “alkylsulfonyl,” as used herein, is meant an alkyl group attached via a sulfonyl linkage. Alkylsulfonyl groups include C1-C8alkylsulfonyl, C1-C6alkylsulfonyl, and C1-C4alkylsulfonyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.

[0054] “Alkylamino” refers to a secondary or tertiary amine having the general structure —NH-alkyl or —N(alkyl)(alkyl), wherein each alkyl may be the same or different. Such groups include, for example, mono- and di-(C1-C8alkyl)amino groups, in which each alkyl may be the same or different and may contain from 1 to 8 carbon atoms, as well as mono- and di-(C1-C6alkyl)amino groups and mono- and di-(C1-C4alkyl)amino groups. Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure -alkyl-NH-alkyl or

[0055] -alkyl-N(alkyl)(alkyl)). Such groups include, for example, mono- and di-(C1-C8alkyl)aminoC1-C8alkyl, mono- and di-(C1-C6alkyl)aminoC1-C6alkyl, and mono- and di-(C1-C4alkyl)aminoC1-C4alkyl, in which each alkyl may be the same or different.

[0056] The term “carboxamido” or “amido” refers to an amide group (i.e., —(C═O)NH2). “Alkylcarboxamido” refers to —NHC(═O)alkyl, preferably —NHC(═O)C1-C2alkyl.

[0057] “Carbhydryl” is intended to include both branched and straight-chain hydrocarbon groups, which is saturated or unsaturated, having the specified number of carbon atoms.

[0058] The term “cycloalkyl” refers to hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from. Cycloalkyl groups include C3-C8, and C3-C7 cycloalkyl groups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, as well as bridged and caged saturated ring groups such as norbornane or adamantane and the like.

[0059] In the term “(cycloalkyl)alkyl,” “cycloalkyl” and “alkyl” are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylethyl.

[0060] The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

[0061] “Haloalkyl” refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0062] “Haloalkoxy” indicates a haloalkyl group as defined above attached through an oxygen bridge.

[0063] As used herein, the term “aryl” indicates aromatic groups containing only carbon in the aromatic ring(s). Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain 1 to 3 separate or fused rings, at least one of which is aromatic, and from 6 to about 18 ring atoms, without heteroatoms as ring members. Specifically preferred carbocyclic aryl groups include phenyl and napthyl, including 1-naphthyl and 2-naphthyl. When indicated, carbon atoms present within a carbocyclic ring may be optionally substituted with any of variety of ring substituents, as described above, or with specifically listed substituents.

[0064] The term “arylalkyl” refers to an aryl group is linked via an alkyl group. Certain arylalkyl groups are (C6-C18aryl)C1-C8alkyl groups (i.e., groups in which a 6- to 18-membered aryl group is linked via a C1-C8alkyl group). Such groups include, for example, groups in which phenyl or naphthyl is linked via a bond or C1-C8alkyl, preferably via C1-C4alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl.

[0065] The term “aryloxy” refers to an aryl group linked via a carbonyl (i.e., a group having the general structure —C(═O}O—aryl). Phenoxy is a representative aryloxy group.

[0066] As used herein, the term “heteroaryl” is intended to indicate a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4 heteroatoms selected from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1, 2, or 3, more typically 1 or 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.

[0067] The term “heterocyclic group” or “heterocycle” is used to indicate saturated, partially unsaturated, or aromatic groups having 1 or 2 rings, 3 to 8 atoms in each ring and in at least one ring between 1 and 3 heteroatoms selected from N, O, and S. Any nitrogen or sulfur heteroatoms may optionally be oxidized. The heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. A nitrogen atom in the heterocycle may optionally be quaternized.

[0068] Representative examples of heteroaryl groups and heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0069] “A C5a receptor” is a G-coupled protein receptor that specifically binds C5a protein.

[0070] Preferably the C5a receptor is a human C5a receptor such as the protein product of the sequence of the resulting PCR product described by Gerard and Gerard, (1991) Nature 349:614-17. The human C5a receptor may also be that described by Boulay (1991) Biochemistry, 30(12): 2993-9 (GENBANK Accension No. M62505). Non-primate C5a receptors may be a rat C5a receptor such as a rat C5a receptor, GENBANK Accension Nos. X65862, Y09613, and AB003042, a canine C5a receptor, GENBANK Accension No. X65860, or a guinea pig C5a receptor, GENBANK Accension No. U86103.

[0071] A “C5a receptor modulator” is any compound that modulates C5a receptor activation and/or activity (i.e., C5a receptor-mediated signal transduction, as measured using a C5a receptor-mediated chemotaxis, radioligand binding assay, or calcium mobilization assay as provided herein). In certain embodiments, such a modulator may be exhibit an affinity constant or IC50 for binding to a C5a receptor of less than 1 micromolar. In other embodiments the a C5a receptor modulator may exhibit an affinity constant or IC50 of less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. A modulator may be a C5a receptor agonist or antagonist, although, for certain purposes described herein, a modulator preferably inhibits C5a activation resulting from binding of C5a (i.e., the modulator is an antagonist). Preferred antagonists exhibit an antagonist IC50 (which is used herein interchangeably with EC50) of less than 1 micromolar, preferably less than 100 nanomolar, in an assay of C5a receptor-mediated chemotaxis, radioligand binding, and/or calcium mobilization. In addition, or alternatively, a modulator may act as an inverse agonist of C5a receptor. In certain embodiments, modulators provided herein modulate activation and/or activity of a primate C5a receptor, such as human C5a receptor, which may be a cloned, recombinantly expressed receptor or a naturally expressed receptor. For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.

[0072] An “inverse agonist” of the C5a receptor is a compound which inhibits the activity of C5a at the C5a receptor, and reduces the activity of the C5a receptor below its basal activity level in the absence of added C5a. Inverse agonists of the C5a receptor may also inhibit binding of C5a to the C5a receptor. The ability of a compound to inhibit the binding of C5a to the C5a receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 51. The basal activity of the C5a receptor may be determined from a GTP binding assay, such as the assay of Example 52. The reduction of C5a activity may also be determined from a GTP binding assay such as the assay of Example 52 or a calcium mobilization assay such as the assay of Example 53.

[0073] A “neutral antagonist” of the C5a receptor is a compound which inhibits the activity of C5a at the C5a receptor, but does not significantly change the basal activity of the C5a receptor. Neutral antagonists of the C5a receptor may inhibit the binding of C5a to the C5a receptor.

[0074] A “partial agonist” of the C5a receptor elevates the activity of the C5a receptor above the basal activity level of the receptor in the absence of C5a, but does not elevate the activity of the C5a receptor to the level brought about by saturating levels of the natural agonist, C5a. Partial agonist compounds may inhibit the binding of C5a to the C5a receptor. Partial agonists of the C5a receptor usually elevate the active of the C5a receptor from 5% to 90% of the activity level brought about by saturated concentrations of the natural agonist, C5a.

[0075] A “C5a receptor modulatory amount” of a compound is an amount that is sufficient to yield a plasma concentration of the compound (or its active metabolite, if a prodrug) high enough to detectably alter (modulate) C5a receptor activity and/or ligand binding, when that concentration is used in an in vitro assay. Suitable in vitro assays include the standard in vitro C5 receptor-mediated chemotaxis assay (described in Example 46 herein); C5a receptor-mediated calcium mobilization assay (described in Example 53 herein); and/or radioligand binding assay such as the assay provided in Example 51.

[0076] A “therapeutically effective amount” of a compound is an amount that is sufficient to result in a discernible patient benefit. For example, a therapeutically effective amount may reduce symptom severity or frequency. Alternatively, or in addition, a therapeutically effective amount may improve patient outcome and/or prevent or delay disease or symptom onset.

[0077] As used herein, a “pharmaceutically acceptable salt” is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC—(CH2)n—COOH where n is 0-4 and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). Accordingly, the present disclosure should be construed to include all pharmaceutically acceptable salts of the compounds specifically recited. A wide variety of synthetic procedures is available for the preparation of pharmaceutically acceptable salts. In general, a pharmaceutically acceptable salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0078] A “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound of Formula I. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Preferred prodrugs include acylated derivatives. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved to the parent compounds. Those of ordinary skill in the art will recognize various synthetic methods that may be employed to prepare prodrugs of the compounds provided herein.

[0079] A “patient” is any individual treated with a C5a modulator as provided herein. Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to C5an receptor modulation, or may be free of such symptom(s) (i.e., treatment may be prophylactic).

[0080] C5a Receptor Modulators

[0081] As noted above, the present invention provides C5a receptor modulators (i.e., compounds that modulate C5a receptor-mediated signal transduction; preferably compounds that also detectably bind to C5a receptor). C5a receptor modulators may be used to modulate C5a receptor activity in a variety of contexts, including in the treatment of patients suffering from diseases or disorders responsive to C5a receptor modulation, such as autoimmune disorders and inflammatory conditions. C5a receptor modulators may also be used within a variety of in vitro assays (e.g., assays for receptor activity), as probes for detection and localization of C5a receptor and as standards in assays of ligand binding and C5a receptor-mediated signal transduction.

[0082] C5a receptor modulators provided herein are aryl imidazoles and related compounds of Formula I (as well as pharmaceutically acceptable salts and prodrugs thereof) that detectably alter, preferably decrease, C5a receptor activation and/or signal transduction activity at submicromolar concentrations. Such an alteration in C5a receptor activity may be measured using a standard in vitro C5a receptor-mediated chemotaxis assay (Example 46), a C5a receptor-mediated calcium mobilization assay (Example 53) and/or a radioligand binding assay (Example 51). The present invention is based, in part, on the discovery that small molecules of Formula I act as antagonists and/or inverse agonists of C5a receptors.

[0083] Thus, an embodiment of the invention is directed to compounds and the pharmaceutically acceptables salts of Formula I

[0084] wherein the ring system represented by

[0085] is a 5 membered heteroaryl ring system, in which x is 0, A is chosen from carbon and heteroatoms nitrogen, oxygen, and sulfur, and E and G are independently carbon or nitrogen, provided that the 5 membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom, or a 6 membered heteroaryl ring system, in which x is 1, and A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6 membered heteroaryl ring system does not contain more than 3 nitrogen atoms.

[0086] R and R1, in this embodiment are independently chosen from:

[0087] i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, C1-C6haloalkoxy,

[0088] ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkanoyl, C1-C6alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- and di-C1-C6alkylamino, mono- and di-C1-C6alkylaminoC1-C6alkyl, mono- and di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —NHSOnC1-C6alkyl,

[0089] —SOn(C1-C6alkyl), —(C1-C6alkyl)SO,(C1-C6alkyl), —SOnN(C1-C6alkyl) (C1-C6alkyl), and phenyl-SOn—, each of which is substituted with from 0 to 3 substituents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, oxo, C1-C4alkyl, C1-C4alkoxy, and C1-C2alkoxycarbonyl, and

[0090] iii) naphthyl, phenyl, phenylC1-C4carbhydryl, pyridyl, thiazolyl, pyrimidinyl, thienyl, pyridylC1-C4carbhydryl, thiazolylC1-C4carbhydryl, pyrimidinylC1-C4carbhydryl, and thienylC1-C4carbhydryl, each of which is substituted with from 0 to 3 substitutuents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, 1,3-dioxol-5-yl, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone; C1-C6alkanoyl; C2-C6alkyl ether; C1-C6 alkanoyloxy; C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0091] R2, when E is Nitrogen, is chosen from C1-C7alkyl, substituted with from 0 to 3 substitutents independently chosen from hydroxy, halogen, amino, cyano, oxo, C1-C4alkyl, C1-C4alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy.

[0092] R2, when E is Carbon, is chosen from (i) hydrogen; halogen, and hydroxy; and (ii) C1-C7alkyl substituted with from 0 to 3 substitutents independently chosen from hydroxy, halogen, amino, cyano, oxo, C1-C4alkyl, C1-C4alkoxy, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy; C1-C7alkylamino; C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy.

[0093] When x is 0, R1 and R3 may be joined to form a cycloalkyl ring having from 3 to 7 carbon atoms, which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy;

[0094] R4 represents C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is substituted with from 0 to 3 substitutents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, C1-C2alkyl, C1-C2alkoxy, and C1-C2alkoxycarbonyl; or

[0095] R4 represents:

[0096] (i) arylC0-C4alkyl having 1 ring or 2 fused or pendant rings,

[0097] (ii) benzyl fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy,

[0098] (iii) heterocycloalkyl(C0-C4alkyl), or

[0099] (iv) heteroarylC0-C2alkyl, having 1 ring to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S,

[0100] wherein each of (i), (ii) (iii) and (iv) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, mono- and di-(C1-C6)alkylamino, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkyl ether; C1-C6 alkanoyloxy; C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0101] Ar1 represents phenyl, quinolinyl, isoquinolinyl, phthalizinayl, benzimidazolyl, indanyl, tetralinyl, chromanyl, naphthyl, pyridyl, pyrimidinyl, pyridizinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, oxazolyl, furanyl, or thienyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, C1-C6alkylamino, C1-C6alkylaminoC1-C6alkyl, cyano, nitro, C1-C6haloalkyl, C1-C6 haloalkoxy, C1-C6alkyl, and C1-C6 alkoxy.

[0102] Ar2 represents (v) C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl, (vi) aryl having 1 ring or 2 fused or pendant rings, (vii) phenyl fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy, or (viii) heteroaryl, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S; wherein each of (v), (vi), (vii) and (viii) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6haloalkyl, C1-C6 haloalkoxy, C1-C6alkyl, C1-C6alkoxy, mono- or di-C1-C6alkylamino, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkylether; C1-C6alkanoyloxy C1-C6alkoxycarbonyl, C1-C6alkylcarboxamide, C2-C6cycloalkylamino, and C2-C6cycloalkylamino(C1-C4alkyl).

[0103] The invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0; A and G are carbon; E is nitrogen; and R1 and R3 are not joined to form a cycloalkyl ring; i.e. compounds of Formula II:

[0104] The invention also includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0; A and E are carbon; G is nitrogen; and R1 and R3 are not joined to form a cycloalkyl ring, i.e. compounds of Formula III

[0105] The invention further includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0; E and G are carbon; A is nitrogen; and R1 and R3 are not joined to form a cycloalkyl ring, i.e. compounds of Formula IV

[0106] The invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0, G is carbon, A and E are nitrogen, i.e. compounds of Formula V

[0107] In yet another embodiment the invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0, A is sulfur, G and E are carbon; and R1 and R3 are not joined to form a cycloalkyl ring, i.e. compounds of Formula VI

[0108] In still another embodiment the invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 0, A is oxygen, G and E are carbon; and R1 and R3 are not joined to form a cycloalkyl ring, i.e. compounds of Formula VII

[0109] In another embodiment the invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 1, and A, E, and G are carbon, and B is nitrogen, i.e. compounds of Formula VIII

[0110] In another embodiment the invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 1, and A, B, E, and G are carbon, i.e. compounds of Formula IX

[0111] Another embodiment the invention includes compounds and pharmaceutically acceptable salts of Formula I wherein x is 1, and A is nitrogen and B E, and G are carbon, i.e. compounds of Formula X

[0112] Certain embodiments of the invention pertain to compounds and salts of Formula I (or the subformulae thereof) in which z is 1; R5 is hydrogen; and R6 is hydrogen, methyl, or ethyl.

[0113] Other embodiments of the invention pertain to compounds and salts of Formula I (or the subformulae thereof) in which z is 1; R5 is hydrogen, R6 is hydrogen, methyl, or ethyl; and Ar1 is phenyl, pyrazolyl, or thienyl, each of which is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

[0114] Still other embodiments of the invention pertain to compounds and salts of Formula I (or the subformulae thereof) in which z is 1, R5 and R6 are hydrogen, and Ar1 is unsubstituted phenyl or unsubstituted thienyl.

[0115] The Variable R1:

[0116] The invention includes compounds and pharmaceutically acceptable salts of the formulae and embodiments listed herein in which R1 is phenyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, C1-C6 haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, 1,3-dioxol-5-yl, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone; C1-C6alkanoyl; C2-C6alkyl ether; C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0117] In other embodiments the invention pertains to compounds and pharmaceutically acceptable salts of the formulae and embodiments listed herein in R1 is phenyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2alkyl, and C1-C2alkoxy.

[0118] In other embodiments R1 is unsubstituted phenyl.

[0119] The invention pertains to compounds and salts of the formulae described herein in which

[0120] R1 is thienyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2alkyl, and C1-C2alkoxy.

[0121] In certain embodiments of the formulae described described herein R1 is hydrogen.

[0122] In other certain embodiments of the formulae described described herein R1 is halogen, C1-C4alkyl, C1-C4alkoxy, cyano, trifluoromethyl, pentafluoroethyl, C1-C2alkylaminoC1-C2alkyl, hydroxymethyl, or hydroxyethyl.

[0123] In still other embodiments of the formulae described described herein R1 is halogen.

[0124] The invention further includes compounds and salts of the formulae described herein

[0125] R1 is trifluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy, or difluoromethoxy.

[0126] The Variable R2:

[0127] The invention includes compounds and salts Formula I and the subformulae therof in which R2 is propyl, butyl, pentyl, 3-methylbutyl, methoxyethyl.

[0128] The Variable R3:

[0129] The invention pertains to compounds and salts Formula I and the subformuiae therof in which

[0130] R3 is hydrogen.

[0131] The invention further pertains to compounds and salts Formula I and the subformulae therof wherein R3 is C1-C5 alkyl.

[0132] The invention includes still other compounds and salts Formula I and the subformulae therof in which

[0133] R4 represents C1-C6alkyl.

[0134] The Variable R4:

[0135] The invention pertains to compounds and salts Formula I and the subformulae therof in which

[0136] R4 represents C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2alkyl, C1-C2alkoxy, and C1-C2alkoxycarbonyl.

[0137] The includes compounds and salts Formula I and the subformulae therof in which R4 represents C1-C6alkyl, C3-C7 cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl) C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl.

[0138] The invention also pertains to compounds and salts Formula I and the subformulae therof in which R4 represents cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl, cyclohexenylmethyl, cyclhexenyl, or hexahydro-1,3-benzodioxolylmethyl.

[0139] The invention also includes compounds and salts Formula I and the subformulae therof in which R4 represents cyclohexylmethyl.

[0140] Further included in the invention are compounds and salts Formula I and the subformulae therof in which R4

[0141] R4 represents

[0142] (i) aryl or aryl(C1-C2)alkyl having 1 ring or 2 fused or pendant rings,

[0143] (ii) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1, or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy;

[0144] (iii) saturated or partially unsaturated heterocyclic(C0-C4alkyl) having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S; or

[0145] (iv) heteroaryl or heteroaryl(C0-C2alkyl), having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, wherein each of (i), (ii), (iii), and (iv) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6 haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C1-C6alkanone, C2-C6alkyl ether, C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0146] The invention pertains to compounds and salts Formula I and the subformulae therof in which R4 is benzyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, C1-C6 haloalkyl, C1-C6 haloalkoxy, mono- and di-(C1-C6)alkylamino, C1-C6 alkyl, C1-C6alkoxy, C1-C6alkanoyl, C1-C6alkylsulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkyl ether, C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0147] Also included in the invention are compounds and salts Formula I and the subformulae therof in which R4 represents benzyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, —SH, C1-C2haloalkyl, C1-C2 haloalkoxy, mono- and di-(C1-C2)alkylamino, C1-C4alkoxy, C1-C2alkanoyl, C1-C2alkylsulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C2alkylthio, C2-C3alkanone, C2-C6alkylether, C1-C4 alkanoyloxy, C1-C4alkoxycarbonyl, and C1-C2alkylcarboxamide.

[0148] Included in the invention are compounds and salts Formula I and the subformulae therof in which R4 represents benzyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, pentafluoroethyl, tetrafluoromethyl, trifluoromethyl, difluoromethyl, pentafluoroethoxy, tetrafluoroethoxy, trifluoromethoxy, difluoromethoxy, C1-C2 alkyl, C1-C4alkoxy, C1-C2alkanoyl, C1-C2alkylsulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C2alkylthio, C2-C3alkanone; C1-C4 alkanoyloxy, ethoxycarbonyl, methoxycarbonyl, and —NH2(C═O)CH3.

[0149] The invention also pertains to compounds and salts Formula I and the subformulae therof in which R4 represents pyridylmethyl, pyrimidylmethyl, thienylmethyl, napthylmethyl, indolylmethyl, benzoxadialolylmethyl, benzoxazolylmethyl, quinazolinylmethyl, benzothiazolylmethyl, or benzimidazolylmethyl, optionally substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2 alkyl, C1-C2alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, and mono- and di-(C1-C2)alkylamino.

[0150] In certain embodiments the invention pertains to compounds and salts Formula I and the subformulae therof in which R4 represents benzoxadiazol-5-ylmethyl.

[0151] The invention includes compounds and salts Formula I and the subformulae therof in which R4 represents benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1, or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6alkyl, C1-C6alkoxy, mono- and di-(C1-C6)alkylamino, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkyl ether; C1-C6 alkanoyloxy; C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0152] In yet other embodiments the invention includes compounds and salts of Formula I in which

[0153] R4 represents 1,3-benzodioxol-5-ylmethyl, 2,3-dihydro-1-benzofuran-6-ylmethyl, 2,3-dihydro-1-benzofuran-5-ylmethyl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, chroman-6-ylmethyl, chroman-7-ylmethyl, 1,3-benzothiazolylmethyl, 2,3-dihydroindol-5-ylmethyl, each of which is substituted from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkyl, C1-C2alkoxy, mono- and di-(C1-C2)alkylamino.

[0154] In certain embodiments R4 represents 1,3-benzodioxol-5-ylmethyl.

[0155] In still other embodiments R4 is a saturated or partially unsaturated heterocyclic(C0-C4alkyl) group having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon, substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6 haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, mono- and di-(C1-C6)alkylamino, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2 C6alkylether, C1-C6alkanoyloxy, C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0156] The invention also pertains to compounds and salts of Formula I and the subformulae thereof in which R4 is morpholinyl(C0-C4alkyl), azetidinyl(C0-C4alkyl), piperazinyl(C0-C4alkyl), piperidinyl(C0-C4alkyl), pyrrolidinyl(C0-C4alkyl), tetrahydropyranyl(C0-C4alkyl), or tetrahydropyridinyl(C0-C4alkyl), each of which is substituted by from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C1-C2 alkyl, C1-C2alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, mono- and di-(C1-C2)alkylamino.

[0157] Also included in the invention are compounds and salts of Formula I and the subformulae thereof in which: R4 is a heteroaryl or heteroaryl(C1-C2alkyl) group, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6 alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C1-C6alkanone, C2-C6alkyl ether, C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0158] The invention pertains to compounds and salts of Formula I and the subformulae thereof in which

[0159] R4 is pyridylmethyl, pyrimidinylmethyl, thienylmethyl, naphthylmethyl, indolylmethyl, benzoxadiazolylmethyl, benzoxazolylmethyl, quinazolinylmethyl, or benzimidazolylmethyl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2 alkyl, and C1-C2alkoxy.

[0160] The Variable Ar2

[0161] In other embodiments the invention pertains to compounds and salts of Formula I and the subformulae thereof in which Ar2 represents C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2alkyl, C1-C2alkoxy, and C1-C2alkoxycarbonyl.

[0162] The invention includes compounds and salts of Formula I and the subformulae thereof in which

[0163] Ar2 represents

[0164] (i) C1-C6cycloalkyl, C3-C7 cycloalkenyl, or hexahydro-1,3-benzodioxolyl; or

[0165] (ii) cyclopentyl, cyclohexyl, cyclohexenyl, or hexahydro-1,3-benzodioxolyl; or

[0166] (iii) phenyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6alkoxy, mono- and di-C1-C6alkylamino, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkylether; C1-C6alkanoyloxy C1-C6alkoxycarbonyl, C1-C6alkylcarboxamide, C2-C6cycloalkylamino, and C2-C6cycloalkylamino(C1-C4alkyl); or

[0167] (iv) phenyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, —SH, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2alkyl, C1-C4alkoxy, C1-C2alkanoyl, mono- and di-C1-C2alkylamino, C1-C2alkylsulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C2alkylthio, C2-C3alkanone, C2-C6alkyl ether, C1-C4 alkanoyloxy, C1-C4alkoxycarbonyl, C1-C2alkylcarboxamide, and C2-C6cycloalkylamino.

[0168] In other embodiments the invention pertains to compounds and salts of Formula I and the subformulae thereof in which Ar2 represents phenyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, pentafluoroethyl, tetrafluoromethyl, trifluoromethyl, difluoromethyl, pentafluoroethoxy, tetrafluoroethoxy, trifluoromethoxy, difluoromethoxy, C1-C2 alkyl, C1-C4alkoxy, C1-C2alkanoyl, mono- and di-C1-C2alkylamino, C1-C2alkylsulfonate, C1-C2alkylsulfonyl, C1-C2alkylsulfinyl, C1-C2alkylthio, C2-C3alkanone; C1-C4 alkanoyloxy, ethoxycarbonyl, methoxycarbonyl, —NH2(C═O)CH3, and C2-C6cycloalkylamino.

[0169] The invention also includes compounds and salts of Formula I and the subformulae thereof in which Ar2 represents pyridyl, pyrimidyl, thienyl, naphthyl, indolyl, benzoxadiazolyl, benzoxazolyl, quinazolinyl, or benzimidazolyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2 alkyl, C1-C2alkoxy, mono- and di-C1-C2alkylamino, and C2-C6cycloalkylamino.

[0170] In other embodiments the invention pertains to compounds and salts of Formula I and the subformulae thereof in which Ar2 represents benzoxadiazol-5-yl.

[0171] Further included in the invention are compounds and salts of Formula I and the subformulae thereof in which Ar2 represents

[0172] (i) phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1, or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy

[0173] (ii) a heteroaryl or heteroaryl(C1-C2alkyl) group, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, wherein each of (i) and (ii) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH2, —SO2NH2, oxo, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, C1-C6alkanoyl, C1-C6sulfonate, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C6alkylthio, C2-C6alkanone, C2-C6alkyl ether, C1-C6 alkanoyloxy; C1-C6alkoxycarbonyl, and C1-C6alkylcarboxamide.

[0174] The invention includes compounds and salts of Formula I and the subformulae thereof in which Ar2 represents 1,3-benzodioxol-5-yl, 2,3-dihydro-1-benzofuran-6-yl, 2,3-dihydro-1-benzofuran-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, chroman-6-yl, chroman-7-yl, 1,3-benzothiazolyl, or 2,3-dihydroindol-5-yl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2 alkyl, and C1-C2alkoxy.

[0175] In other embodiments the invention pertains compounds and salts of Formula I and the subformulae thereof in which Ar2 represents Ar2 represents 1,3-benzodioxol-5-yl.

[0176] Additional Embodiments

[0177] In another embodiment the invention includes compounds and salts of Formula I in which R1 and R3 are joined to form a cycloalkyl ring substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy, e.g. compounds of Formula XI:

[0178] The invention includes compounds and salts of Formula XI are those wherein z is 1, R5 is hydrogen, and R6 is hydrogen or methyl.

[0179] The invention also includes compounds and salts of Formula XI are those wherein a is 1 and XI is represents from 0 to 2 substituents chosen from 1 or 2 groups independently chosen from hydroxy, halogen, C1-C2alkyl, and C1-C2alkoxy.

[0180] The invention further includes compounds and salts of Formula XI also include those wherein a is 2 and XI is represents from 0 to 2 optional substituents chosen from 1 or 2 groups independently chosen from hydroxy, halogen, C1-C2alkyl, and C1-C2alkoxy.

[0181] The invention pertains to compounds and salts of Formula XI in which R2 is propyl, butyl, pentyl and 3-methylbutyl; butyl is preferred.

[0182] In other embodiments the invention pertains to compounds and salts of Formula XI is phenyl in which Ar1 is optionally substituted with from 1 to 3 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, C1-C2haloalkyl, and C1-C2haloalkoxy.

[0183] Values of R4 for compounds and salts of Formula XI include C3-C5 alkyl.

[0184] Other values of R4 for compounds and salts of Formula XI include benzyl optionally substituted with from 1 to 3 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, C1-C2haloalkyl, and C1-C2haloalkoxy.

[0185] Values of Ar2 for compounds and salts of Formula XI include phenyl optionally substituted with from 1 to 3 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, C1-C2haloalkyl, C1-C2alkylamino, C1-C2haloalkoxy, and C2-C6cycloalkylamino.

[0186] Additional embodiments of the invention include compounds of Formula XII-Formula XXIX as follows:

Formula XII

Formula XIII

Formula XIV

Formula XV

Formula XVI

Formula XVII

Formula XVIII

Formula XVIX

Formula XX

Formula XXI

Formula XXII

Formula XXIII

Formula XXIV

Formula XXV

Formula XXVI

Formula XXVII

Formula XXVIII

Formula XXIX

[0187] and the pharmaceutically acceptable salts thereof, wherein:

[0188] R2 is C3-C5 alkyl. Preferably R2 is butyl or methoxyethyl

[0189] R3 is hydrogen or methyl.

[0190] R4 in Formula XIV, Formula XVII, and Formula XVIX represents a straight or branched chain C3-C6 alkyl group. Preferably R4 is butyl, isobutyl, neopentyl, or cyclohexylmethyl.

[0191] R5 is hydrogen or methyl, preferably hydrogen.

[0192] R7 represents 0 to 3 groups independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R7 is absent or methyl. In certain compounds of the invention the phenyl group shown in Formula XII-XXIX as substituted with R7 (corresponding to Ar1 in Formula I, is instead a thienyl or pyrazolyl group, each of which is optionally substituted by R7). In other compounds of the invention this phenyl group is a 2,6-dimethylphenyl or a 2,6-diethylphenyl.

[0193] R8 represents 0 to 3 groups independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, —CONH2, —OC(═O)CH3, —COOH, methylthio, ethylthio, and —SO2CH3. In certain preferred compounds of the invention the phenyl group shown in Formula XII-XX and Formula XXII-XXDX as substituted with R8 (corresponding to R1 in Formula I for the imidazole compounds and R for the pyridizine compounds, is instead a thienyl group, which is optionally substituted by R8).

[0194] R9 and R10 may occur at any position on the piperonyl or benzodioxanyl group available for substitution and independently represent 0 to 3 chosen from halogen, methyl, and methoxy. Preferably R9 and R10 are absent.

[0195] R11 and R12 independently represent 0 to 3 groups chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, —CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, —OCF2CHF2, —CONH2, —C(═O)OCH3, —OC(═O)CH3, —COOH, methylthio, ethylthio, —SO2NH2, and —SO2CH3. Compounds in which R11 or R12 represents a single meta or para substituent are particularly embodied.

[0196] R13 represents 0 to 3 groups independently chosen from halogen, methyl, and C1-C4alkoxy. R13 is absent in certain embodiments of the invention.

[0197] R14 may occur at any position on the indole, indazole, or benzisoxazole group available for substitution and represents 0 to 3 groups independently chosen from halogen, methyl, cyano, and amino. R14 is absent in certain embodiments of the invention.

[0198] Additionally the invention pertains to compounds of Formulae XXX-Formula XXXVIII:

Formula XXX

Formula XXXI

Formula XXII

Formula XXXIII

Formula XXXIV

Formula XXXV

Formula XXXVI

Formula XXXVII

Formula XXXVIII

[0199] As well as compound of Formula XXXVIII-a

[0200] in Ar2 is chosen from:

[0201] and the pharmaceutically acceptable salts thereof, wherein:

[0202] R1 is selected from halogen, cyano, nitro, amino, —CHO, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalyl, C1-C2haloalkoxy, C1-C2alkoxyC1-C2allyl, mono- or di-(C1-C2)alkylaminoC1-C2alkyl, C1-C2alkoxycarbonyl, C1-C2alkylthio, C1-C2alkylsulfinyl, and C1-C2alkylsulfonyl.

[0203] Values of R1 include halogen, particularly fluoro, chloro, and bromo. Other preferred values of R1 for compounds and salts of Formula XXX-XXXVIII include cyano, C1-C2haloalkyl, C1-C2haloalkoxy, particularly, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy.

[0204] R2 is C3-C5 alkyl. Preferably R2 is butyl or methoxyethyl

[0205] R3 is hydrogen or methyl.

[0206] R4 is C3-C6alkyl. In certain embodiments R4 is butyl, isobutyl, neopentyl, and cyclohexylmethyl.

[0207] R5 is hydrogen or methyl, preferably hydrogen.

[0208] R7 represents 0 to 3 groups independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R7 is absent or methyl. In certain preferred compounds of the invention the phenyl group shown in Formula XXX-XXXVIII as substituted with R7 (corresponding to Ar1 in Formula I, is instead a thienyl or pyrazolyl group, each of which is optionally substituted by R7). In other embodiments this phenyl group is a 2,6-dimethylphenyl or 2,6-diethylphenyl

[0209] R9 and R10 may occur at any position on the piperonyl or benzodioxanyl group available for substitution and independently represent 0 to 3 chosen from halogen, methyl, and methoxy. Preferably R9 and R10 are absent.

[0210] R11 and R12 independently represent 0 to 3 groups chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, —CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, —OCF2CHF2, —CONH2, —C(═O)OCH3, —OC(═O)CH3, —COOH, methylthio, ethylthio, —SO2NH2, and —SO2CH3. Compounds in which R1, or R12 represents a single meta or para substituent are embodied.

[0211] The invention is directed to compounds of Formulae XXXIX-Formula XLII

Formula XXXIX

Formula XL

Formula XLI

Formula XLII

[0212] and the pharmaceutically acceptable salts thereof, wherein:

[0213] R1 (or R) is selected from halogen, cyano, nitro, amino, —CHO, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C2alkoxyC1-C2alkyl, mono- or di-(C1-C2)alkylaminoC1-C2alkyl, C1-C2alkoxycarbonyl, C1-C2alkylthio, C1-C2alkylsulfinyl, and C1-C2alkylsulfonyl.

[0214] Values of R1 and R include halogen, particularly fluoro, chloro, and bromo. Other preferred values of R1 and R for compounds and salts of Formula XXII-XXIV include cyano, C1-C2haloalkyl, C1-C2haloalkoxy, particularly, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy.

[0215] R2 is C3-C5 alkyl. Preferably R2 is butyl or methoxybutyl

[0216] R3 is C1-C6 alkyl.

[0217] R4 represents C1-C6alkyl, C3-C7 cycloalkenyl, (C3-C7cycloalkyl) C1-C4alkyl, (C3-C7cycloalkenyl) C1-C4alkyl. Preferably R4 is C1-C5 alkyl.

[0218] R5 is C1-C6alkyl, preferably methyl.

[0219] R7 represents 0 to 3 groups independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R7 is absent or methyl. In certain preferred compounds of the invention the phenyl group shown in Formula I-XLII as substituted with R7 (corresponding to Ar, in Formula I, is instead a thienyl or pyrazolyl group, each of which is optionally substituted by R7).

[0220] R9 and R10 may occur at any position on the piperonyl or other heterocyclic group available for substitution and independently represent 0 to 3 chosen from halogen, methyl, and methoxy. Preferably R9 and R10 are absent.

[0221] R11, represents 0 to 3 groups chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, —CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, —OCF2CHF2, —CONH2, —C(═O)OCH3, —OC(═O)CH3, —COOH, methylthio, ethylthio, —SO2NH2, and —SO2CH3. Compounds in which R1, or R12 represents a single meta or para substituent are particularly preferred.

[0222] Representative compounds of Formul I provided herein include, but are not limited to, those specifically described in Examples 141. It will be apparent that the specific compounds recited therein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a hydrate, free base or a pharmaceutically acceptable acid addition salt.

[0223] Certain substituted compounds Formulae I (and the subformula thereof) have one or more stereogenic centers. In certain embodiment thereof, such compounds may be enantiomers, and may have an enantiomeric excess of at least 55%. Within further embodiments thereof, such compounds have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99%. Certain compounds having one or more stereogenic centers have a enantiomeric excess of at least 99%.

[0224] Certain compounds of Formulae I (and the subformulae thereof) have two or more stereogenic centers. In certain embodiments thereof, such compounds have a diastereomeric excess of at least 55%. In other embodiments thereof such compounds have a diastereomeric excess of 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Certain compounds having two or more stereogenic centers have a diastereomeric excess of at least 99%.

[0225] Aryl imidazoles and related compounds provided herein detectably alter (modulate) C5a receptor activity and/or ligand binding, as determined using a standard in vitro CS receptor-mediated chemotaxis assay (described in Example 46), radioligand binding (described in Example 51), or C5a receptor-mediated calcium mobilization assay (described in Example 53). Preferred compounds exhibit an IC50 of about 500 nM or less in such a standard C5a receptor-mediated chemotaxis, radioligand binding, and/or calcium mobilization assay, more preferably an IC50 of about 250 nM or less in such an assay, still more preferably an IC50 of about 200, 150, 100, 50, 25, 10, or 5 nM or less in such an assay.

[0226] Initial characterization of compounds can be conveniently carried out using a C5a receptor binding assay or functional assay, such as set forth in the Examples, and may be expedited by applying such assays in a high throughput screening setting. Additional assays suitable for determining the effects of small molecule compounds on C5a receptor binding and receptor modulatory activity, as well as assays suitable for measuring their effects on C5a-induced neutropenia in vivo, can be found in the published literature, for example in U.S. Pat. No. 5,807,824, which is incorporated herein by reference for its disclosure in this regard in Examples 6-9, columns 19-23, as well as for its discussion of complement and inflammation at columns 1-2. Those of skill in the art will recognize that such assays can be readily adapted to the use of cells or animals of different species as deemed appropriate.

[0227] In certain embodiments, preferred compounds have favorable pharmacological properties, including oral bioavailability (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably of less than or equal to one gram, can provide a detectable in vivo effect such as a reduction of C5a-induced neutropenia), ability to inhibit leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations, low toxicity (a preferred compound is nontoxic when a C5a receptor-modulatory amount is administered to a subject), minimal side effects (a preferred compound produces side effects comparable to placebo when a C5a receptor-modulatory amount of the compound is administered to a subject), low serum protein binding, and a suitable in vitro and in vivo half-life (a preferred compound exhibits an in vitro half-life that is equal to an in vivo half-life allowing for Q.I.D. dosing, preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a-day dosing). Distribution in the body to sites of complement activity is also desirable (e.g., compounds used to treat CNS disorders will preferably penetrate the blood brain barrier, while low brain levels of compounds used to treat periphereal disorders are typically preferred).

[0228] Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, such as Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays, such as those described by Oravcová, et al. (1996) Journal of Chromatography B 677:1-27. Compound half-life is inversely proportional to the frequency of dosage of a compound required to achieve an effective amount. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26:1120-27.

[0229] Toxicity and side effects may be assessed using any standard method. In general, the term “nontoxic” as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). Toxicity may be also evaluated using the assay detecting an effect on cellular ATP production. Other assays that may be used include bacterial reverse mutation assays, such as an Ames test, as well as standard teratogenicity and tumorogenicity assays. Preferably, administration of compounds provided herein at certain doses (i.e., doses yielding effective in vivo concentrations) does not result in prolongation of heart QT intervals (i.e., as determined by electrocardiography in guinea pigs, minipigs or dogs). When administered daily for five or preferably ten days, such doses also do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 100%, preferably not more than 75%, and more preferably not more than 50% over matched controls in laboratory rodents (e.g., mice or rats). Such doses also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls in dogs or other non-rodent mammals.

[0230] Certain preferred compounds also do not promote substantial release of liver enzymes (e.g., ALT, LDH or AST) from hepatocytes in vivo. Preferably the above doses do not elevate serum levels of such enzymes by more than 100%, preferably not by more than 75%, and more preferably not by more than 50% over matched untreated controls in vivo in laboratory rodents. Similarly, concentrations (in culture media or other such solutions that are contacted and incubated with cells in vitro) equivalent to two-fold, preferably five-fold, and most preferably ten-fold the minimum in vivo therapeutic concentration do not cause detectable release of any of such liver enzymes from hepatocytes in vitro into culture medium above baseline levels seen in media from untreated cells.

[0231] In certain embodiments, preferred compounds exert their receptor-modulatory effects with high specificity. This means that they only bind to, activate, or inhibit the activity of certain receptors other than C5a receptors with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. The invention also includes highly specific C5a receptor modulatory compounds that exhibit 200-fold greater affinity for the C5a receptor that for other cellular receptors. Such receptors include neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly m1, m2 or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; as well as histamine receptors and cytokine receptors (e.g., interleukin receptors, particularly IL-8 receptors). Such receptors may also include GABAA receptors, bioactive peptide receptors (other than C5a receptors and C3a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, and hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors or melanin-concentrating hormone receptors). Compounds that act with high specificity generally exhibit fewer undesirable side effects.

[0232] Within certain embodiments, modulators provided herein do not bind detectably to receptors that do not mediate inflammatory responses, such as GABA receptors, MCH receptors, NPY receptors, dopamine receptors, serotonin receptors and VR1 receptors, with high or even moderate affinity. In addition, or alternatively, certain preferred C5a receptor modulators exhibit an affinity for C5a receptor that is substantially higher than for receptors that do not mediate inflammatory responses (e.g., at least five times higher, at least ten times higher or at least 100 times higher). Assays for evaluating binding to receptors that do not mediate inflammatory responses include, for example, those described in U.S. Pat. No. 6,310,212, which is incorporated herein by reference for its disclosure of a GABAA receptor binding assays in Examples 14, columns 16-17, in U.S. patent application Ser. No. 10/152,189 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 104-105, in U.S. Pat. No. 6,362,186, which is incorporated herein by reference for its disclosure of CRF1 and NPY receptor binding assays in Examples 19, columns 45-46, in U.S. Pat. No. 6,355,644, which is incorporated herein by reference for its disclosure of a dopamine receptor binding assay at column 10, and in U.S. Pat. No. 6,482,611, which is incorporated herein by reference for its disclosure of VR1 receptor binding assays in Examples 4-5, column 14. It will be apparent that the C5a receptor modulators provided herein may, but need not, bind to one or more other receptors known to mediate inflammatory responses, such as C3a receptors and/or A3 receptors.

[0233] Certain preferred compounds are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the C5a receptor-mediated functional assays discussed herein. Specifically, this undesired agonist activity can be evaluated, for example, in the GTP binding assay of Example 52, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a. Similarly, in a calcium mobilization assay (e.g., that of Example 53) a small molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a. The preferred extent of C5a agonist activity exhibited by compounds provided herein is less than 10%, 5% or 2% of the response elicited by the natural agonist, C5a.

[0234] Additionally, preferred C5a receptor modulators do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYPIA2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity. Preferred C5a receptor modulators also do not exhibit cytotoxicity in vitro or in vivo, are not clastogenic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) and do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells). Also preferred are C5a receptor modulators that inhibit the occurrence of C5a-induced oxidative burst (OB) in inflammatory cells (e.g., neutrophil) as can be conveniently determined using an in vitro neutrophil OB assay.

[0235] For detection purposes, compounds provided herein may be isotopically-labeled or radiolabeled. Accordingly, compounds recited in Formula I (or any other formula specifically recited herein) may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl. In addition, substitution with heavy isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.

[0236] Methods of Use

[0237] C5a modulators provided herein may be used as agonists or (preferably) antagonists of C5a receptors in a variety of contexts, both in vitro and in vivo. Within certain aspects, C5a antagonists may be used to inhibit the binding of C5a receptor ligand (e.g., C5a) to C5a receptor in vitro or in vivo. In general, such methods comprise the step of contacting a C5a receptor with a sufficient amount of one or more substituted compound of Formula I as provided herein, in the presence of C5a receptor ligand in aqueous solution and under conditions otherwise suitable for binding of the ligand to C5a receptor. The C5a receptor may be present in suspension (e.g., in an isolated membrane or cell preparation), or in a cultured or isolated cell. Within certain embodiments, the C5a receptor is expressed by a cell present in a patient, and the aqueous solution is a body fluid. In general, the amount of C5a receptor modulator contacted with the receptor should yield a concentration in the aqueous solution sufficient to inhibit C5a binding to C5a receptor in vitro as measured, for example, using a radioligand binding assay as described in Example 51, a calcium mobilization assay as described in Example 53, or a chemotaxis assay as described in Example 46. Preferably the concentration is sufficient to inhibit chemotaxis of white blood cells in an in vitro chemotaxis assay, so that the levels of chemotaxis observed in a control assay (e.g., one to which a compound provided herein has not been added) are significantly higher (significance here measured as p≦0.05 using a conventional parametric statistical analysis method such as a student's T-test) than the levels observed in an assay to which a compound as described herein has been added.

[0238] Also provided herein are methods for modulating, preferably inhibiting, the signal-transducing activity of a C5a receptor. Such modulation may be achieved by contacting a C5a receptor (either in vitro or in vivo) with an effective amount of one or more C5a receptor modulators provided herein under conditions suitable for binding of the modulator(s) to the receptor. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation or within a patient. Modulation of signal transducing activity may be assessed by detecting an effect on calcium ion conductance (also referred to as calcium mobilization or flux) or by detecting an effect on C5a receptor-mediated cellular chemotaxis. In general, an effective amount of C5a modulator(s) is an amount sufficient to yield a concentration (in an aqueous solution that is in contact with the receptor) that is sufficient to modulate C5a receptor signal transducing activity in vitro within a calcium mobilization assay as described in Example 53 or C5a receptor-mediated cellular chemotaxis within an assay as described in Example 46. C5a receptor modulator(s) provided herein are preferably administered to a patient (e.g., a human) orally or topically, and are present within at least one body fluid of the animal while modulating C5a receptor signal-transducing activity.

[0239] The present invention further provides methods for treating patients suffering from conditions responsive to C5a receptor modulation. As used herein, the term “treatment” encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms). A condition is “responsive to C5a receptor modulation” if modulation of C5a receptor activity results reduction of inappropriate activity of a C5a receptor, regardless of the amount of C5a receptor ligand present locally and/or in alleviation of the condition or a symptom thereof. Patients may include primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), with dosages as described herein.

[0240] Conditions that are responsive to C5a receptor modulation include the following:

[0241] Autoimmune disorders—e.g., rheumatoid arthritis, systemic lupus erythematosus (and associated glomerulonephritis), psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection, and hyperacute rejection of transplanted organs.

[0242] Inflammatory disorders and related conditions—e.g., neutropenia, sepsis, septic shock, Alzheimer's disease, stroke, inflammation associated with severe burns, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as acute (adult) respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS). Also included are pathologic sequellae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via, a heart-lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement) such as extracorporeal post-dialysis syndrome, or in association with contact with other artificial vessel or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like).

[0243] Cardiovascular and Cerebrovascular Disorders—e.g., myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.

[0244] In a further aspect, C5a receptor modulators may be used to perfuse a donor organ prior to transplantation of the organ into a recipient patient. Such perfusion is preferably carried out using a solution (e.g., pharmaceutical composition) comprising a concentration of the modulator that is sufficient to inhibit C5a receptor-mediated effects in vitro and/or in vivo. Such perfusion preferably reduces the severity or frequency of one or more of the inflammatory sequelae following organ transplantation when compared to that occurring in control (including, without restriction, historical control) transplant recipients who have received transplants of donor organs that have not been so perfused.

[0245] Treatment methods provided herein include in general administration to a patient an effective amount of one or more compounds of the invention. Suitable patients include those patients suffering from or susceptible to (i.e., prophylactic treatment) a disorder or disease identified herein. Typical patients for treatment in accordance with the invention include mammals, particularly primates, especially humans. Other suitable patients include domesticated companion animals such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.

[0246] In general, treatment methods provided herein comprise administering to a patient an effective amount of a compound one or more compounds provided herein. The effective amount may be an amount sufficient to modulate C5a receptor activity and/or an amount sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to yield a plasma concentration of the compound (or its active metabolite, if a pro-drug) high enough to detectably inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro. Treatment regimens may vary depending on the compound used and the particular condition to be treated; for treatment of most disorders, a frequency of administration of 4 times daily or less is preferred. In general, a dosage regimen of 2 times daily is more preferred, with once a day dosing particularly preferred. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient) and the severity of the particular disease undergoing therapy, as well as the judgment of the prescribing medical practitioner. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.

[0247] As noted above, compounds and compositions provided herein are useful as inhibitors of C5a receptor-mediated chemotaxis (e.g., they may be used as standards in assays of such chemotaxis). Accordingly, methods are provided herein for inhibiting C5a receptor-mediated cellular chemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis. Such methods comprise contacting white blood cells (particularly primate white blood cells, especially human white blood cells) with one or more compounds provided herein. Preferably the concentration is sufficient to inhibit chemotaxis of white blood cells in an in vitro chemotaxis assay, so that the levels of chemotaxis observed in a control assay are significantly higher, as described above, than the levels observed in an assay to which a compound as described herein has been added.

[0248] Within separate aspects, the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds may be labeled and used as probes for the detection and localization of C5a receptor (in samples such as cell preparations or tissue sections, preparations or fractions thereof). Compounds may also be used as positive controls in assays for C5a receptor activity, as standards for determining the ability of a candidate agent to bind to C5a receptor, or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT). Such methods can be used to characterize C5a receptors in living subjects. For example, a C5a receptor modulator may be labeled using any of a variety of well known techniques (e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e.g., determined by first assaying a time course of binding). Following incubation, unbound compound is removed (e.g., by washing), and bound compound detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups). As a control, a matched sample containing labeled compound and a greater (e.g., 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of C5a receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of C5a receptor in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York.

[0249] Modulators provided herein may also be used within a variety of well known cell separation methods. For example, modulators may be linked to the interior surface of a tissue culture plate or other support, for use as affinity ligands for immobilizing and thereby isolating, C5a receptors (e.g., isolating receptor-expressing cells) in vitro. Within one preferred embodiment, a modulator linked to a fluorescent marker, such as fluorescein, is contacted with the cells, which are then analyzed (or isolated) by fluorescence activated cell sorting (FACS).

Pharmaceutical Preparations

[0250] The present invention also provides pharmaceutical compositions comprising one or more C5a receptor modulators provided herein, together with at least one physiologically acceptable carrier or excipient. Pharmaceutical compositions may comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. As noted above, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.

[0251] A carrier is a substance that may be associated with an active compound prior to administration to a patient, often for the purpose of controlling stability or bioavailability of the compound. Carriers for use within such formulations are generally biocompatible, and may also be biodegradable. Carriers include, for example, monovalent or multivalent molecules such as serum albumin (e.g., human or bovine), egg albumin, peptides, polylysine and polysaccharides such as aminodextran and polyamidoamines. Carriers also include solid support materials such as beads and microparticles comprising, for example, polylactate polyglycolate, poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose or dextran. A carrier may bear the compounds in a variety of ways, including covalent bonding (either directly or via a linker group), noncovalent interaction or admixture.

[0252] Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilizate. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.

[0253] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents sweetening agents, flavoring agents, coloring agent, and preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

[0254] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0255] Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions may also comprise one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents, and/or coloring agents.

[0256] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oil, or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0257] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0258] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monoleate), and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate). An emulsion may also comprise one or more sweetening and/or flavoring agents.

[0259] The pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension in which the modulator, depending on the vehicle and concentration used, is either suspended or dissolved in the vehicle. Such a composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be employed are water, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.

[0260] C5a receptor modulators may also be administered in the form of suppositories (e.g., for rectal administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0261] Pharmaceutical compositions may be formulated as sustained release formulations (i.e., a formulation such as a capsule that effects a slow release of modulator following administration). Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal, or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

[0262] In addition to or together with the above modes of administration, a modulator may be conveniently added to food or drinking water (e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock). Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.

[0263] C5a receptor modulators provided herein are generally administered in an amount that achieves a concentration in a body fluid (e.g., blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to detectably inhibit the binding of C5a to C5a receptor when assayed in vitro. A dose is considered to be effective if it results in a discernible patient benefit as described herein. Preferred systemic doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (about 0.5 mg to about 7 g per patient per day), with oral doses generally being about 5-20 fold higher than intravenous doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

[0264] Pharmaceutical compositions may be packaged for treating conditions responsive to C5a receptor modulation (e.g., rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma, Alzheimer's disease, stroke, myocardial infarction, atherosclerosis, ischemic heart disease or ischemia-reperfusion injury). Packaged pharmaceutical compositions may include a container holding a effective amount of at least one C5a receptor modulator as described herein and instructions (e.g., labeling) indicating that the contained composition is to be used for treating a condition responsive to C5a receptor modulation in the patient

[0265] Preparation of Compounds

[0266] Representative methods for preparing the compounds of the invention are shown in the following Schemes. A number of abbreviations are used in the schemes and accompanying examples and are listed here.

4ABBREVIATIONS USEDDMFdimethylformamideDMAdimethylacetamideDMEethylene glycol dimethyletherTHFtetrahydrofuranDMSOdimethyl sulfoxideDCMdichloromethaneDCE1,2-dichloroethaneMeOHmethanolEtOHethanolEt2Odiethyl etherHexhexaneHOAcacetic acidAcOHacetic acidNaOAcsodium acetateAcONasodium acetateTFAtrifluoroacetic acidpTsOHp-toluenesulfonic acidHClhydrochloric acidH3O+aqueous acidHCHOformaldehydeTEAtriethylamineMsClmethanesulfonyl chlorideMeLimethyl lithiumn-BuLin-butyllithiumSAMP(S)-(−)-1-amino-2-(methoxymethyl)pyrrolidineRAMP(R)-(+)-1-amino-2-(methoxymethyl)pyrrolidineEtOAcethyl acetateNaOEtsodium ethoxideNaOHsodium hydroxideKOHpotassium hydroxideNH4OHammonium hydroxideNH3—H2Oammonium hydroxideNa2SO4sodium sulfateMgSO4magnesium sulfateK2CO3potassium carbonateCs2CO3cesium carbonateNaHsodium hydrideMeIiodomethaneBuBrn-butyl bromiden-BuIn-butyl iodideNaClsodium chlorideNaIsodium iodideCDI1,1′-carbonyldiimidazoleSOCl2thionyl chloridePOCl3phosphorous oxychlorideMe2NHdimethyl amineRB(OH)2alkyl or aryl boronic acidPd(PPh3)4tetrakis(triphenylphosphine)palladium (0)NaBH4sodium borohydrideBH3boraneNaBH(OAc)3sodiumtriacetoxyborohydrideBr2bromineNBSN-bromosuccinimdeNCSN-chlorosuccinimdeCuBr2copper (II) bromideDAST(diethylamino)sulfur trifluoride[O]oxidationAgNO3silver nitrateDDQ2,3-dichloro-5,6-dicyano-1,4-benzophenoneMnO2manganese(II) dioxideSiO2silicaLC-MSliquid chromatography/mass spectrometryHPLChigh pressure liquid chromatographyTLCthin layer chromatography1H NMRproton nuclear magnetic resonanceMHzmegahertzHzhertzδchemical shiftCDCl3deuterated chloroformMSmass spectrometrym/zmass/charge ratio(M + 1)mass + 1[α]Dspecific rotationcconcentrationeq.equivalents

[0267] Within Schemes 1-10 the variables e.g., Ar1, Ar2, R1, R2, R3 and R4, are defined as above for Formula I, unless otherwise specified.

[0268] As shown in Scheme 1, an appropriately substituted arylnitrile 10 is converted to the imidate 11 via treatment with hydrogen chloride gas in methanol followed by subsequent treatment with base to release the free base. Amidine 12 is prepared from 11 by treatment with a primary amine. 2-Arylimidazole-4-carboxaldehyde 13 is prepared from 12 by one of several methods described in the chemical literature, for instance, by treatment with 2-bromo-3-isopropoxyacrolein in the presence of base. See, for example, J. Org. Chem., 62: 8449 (Shilcrat et al., 1997).

[0269] Aldehyde 13 can then be transformed into hydroxymethylimidazole by treatment with the appropriate organometallic. The hydroxy group of 14 is converted to either a halogen or sulfonate ester leaving group. Treatment of this intermediate with an appropriate secondary amine in the presence of base provides 2-aryl-4-aminomethylimidazole 15. Alternatively, the aminoalkyl functionality of 15 may be elaborated by sequential amination-acylation-reduction steps. In situations where R1 is a halogen, it may be prepared from 15 (R1=H) by treatment with the molecular halogen, a halosuccinimide or the like.

[0270] As shown in Scheme 2, an appropriately substituted 2-aryl-4-substituted imidazole 20 can be N-alkylated by treatment with base such as sodium hydride, and an alkyl halide, or alkylsulfonate ester to provide the trisubstituted imidazole 21. Hydroxymethylation of 21 under the conditions of the Mannich reaction provides hydroxymethylimidazole 22. In examples where R3 is alkyl, the hydroxymethyl derivative 24 is prepared from 22 by oxidation to aldehyde 23 and subsequent treatment with an appropriate organometallic reagent such as an alkyl lithium or Grignard reagent. Conversion of 22 or 24 to the desired 2-aryl-5-aminomethylimidazoles is carried out by conversion of the hydroxymethyl to a halogen or sulfonate ester leaving group followed by treatment with a secondary amine. Alternatively, the aminoalkyl functionality of the 2-aryl-5-aminomethylimidazole product may be elaborated by sequential amination-acylation-reduction steps.

[0271] The 2-aryl-4-substituted imidazole 20 may be prepared by methods described in the chemical literature, for instance, via condensation of an arylamidine with a halomethyl or hydroxymethyl ketone.

[0272] An illustration of the preparation of compounds of the Cycloalkylimidazole compounds of the present invention is given in Scheme 3. Within Scheme 3 the variables Ar1, Ar2, R2, R3, and R4 are as defined previously.

[0273] As shown in Scheme 3, an appropriately substituted arylamidine 30 is condensed with an appropriately substituted 2-halo-3-alkoxyenone 31 to provide a 2-aryl-4,5-cycloalkylimidazole 32. The ketone functionality of 32 can be reduced to give the cyclic alcohol 33. Compounds of general formula 34 can be prepared from 33 by one of several methods described in the chemical literature, for instance, by treatment with thionyl chloride or by treatment with an alkyl or arylsulphonyl chloride in the presence of base.

[0274] Compounds of formula 34 can then be transformed into compounds of general Formula 35 by direct treatment with the appropriate secondary amine. Alternatively, the X functionality of 34 may be transformed into a tertiary amine in a stepwise manner. In this case, 34 would be treated with a primary amine to provide an intermediate secondary amine. This, in turn, could be alkylated to give cycloalkylimidazole compounds of the invention.

[0275] An illustration of the preparation of pyridine compounds of the present invention is given in Scheme 4. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. Within Scheme 4 the variables Ar1, Ar2, R, R1, R2, R3, and R4 are defined as previously described.

[0276] As shown in Scheme 4, an appropriately substituted 4-phenyloxazole 40 is condensed with an appropriately substituted maleic acid to provide a 2-phenylisonicotinic acid 41. The carboxylic acid functionality of 41 can be reduced directly to the primary alcohol (43, R3=H) or converted by methods known to the art to an intermediate aldehyde 42 and subsequently treated with the appropriate organometallic (for cases where R3 is alkyl) to give a secondary alcohol 43. Compounds of general formula 44 can be prepared from 43 by one of several methods described in the chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a primary amine. Compounds of formula 44 can then be transformed into compounds of formula 45 by direct treatment with the appropriate alkylating agent or, alternatively, by reductive alkylation. Alternatively, the tertiary amine functionality of formula 45 may be realized directly from compounds of formula 43 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.

[0277] An illustration of the preparation of arylpyrazole compounds of the present invention is given in Scheme 5. Within Scheme 5 the variables Ar1, Ar2, R1, R2, R3, and R4 are defined as previously described.

[0278] As shown in Scheme 5, an appropriately substituted phenylhydrazine adduct 50 is condensed with an appropriately substituted α-ketoester 51, in the presence of a Lewis acid, preferably ZnCl2, with heating at 50200° C., preferably at 125° C. to provide a 1-phenylpyrazole ester 52. The carboxylic acid functionality of 52 can be reduced directly to the primary alcohol (53, R3=H) or converted by methods known to the art to an intermediate aldehyde and subsequently treated with the appropriate the appropriate organometallic (for cases where R3 is alkyl) to give a secondary alcohol 53. Compounds of general formula 54, where LG represents a leaving group, can be prepared from 53 by one of several methods described in the chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a primary amine. Compounds of formula 54 can then be transformed into compounds of formula 58 by sequential treatment with the appropriate primary amine followed by direct alkylation or reductive alkylation of the intermediate secondary amine. Alternatively, the tertiary amine functionality of formula 58 may be realized directly from compounds of formula 53 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.

[0279] An alternative route to the preparation of compounds of Formula 58 from the 1-phenylpyrazole ester 52 may be realized by hydrolysis of 52 to a carboxylic acid of general structure 56, followed by amide formation to provide 57 and, finally, reduction of the amide functionality to the tertiary amine of 58 (R3=H).

[0280] The preparation of 6-aryl-pyridazine is shown in Scheme 6. The bromoketone 61 is prepared by treatment of the corresponding ketone 60 with two equivalents CuBr2 refluxing in CHCl3 and EtOAc. After workup and without further purification, these bromoketones are reacted with NaH and dimethyl malonate 62 to give the adduct ketodiester 63. Decarboxylation of 63 with NaCl/H2O in DMSO at 155-160° C. provides ketoester 64 cleanly. Condensation of 64 with hydrazine monohydrate refluxing in EtOH furnishes the dihydro-pyridazinone 65. Aromatization of 65 is accomplished by treatment of it with Br2 in HOAc at 80° C. The resulting pyridazinone 66 is then converted into chloropyridazine 8 by heating 66 in POCl3 at 85° C. for 3 hours. Free radical hydroxymethylation of 67 by heating with (NH4)2S208 and H2SO4 with a catalytic amount of AgNO3 in methanol and water provides the desired 5-hydroxymethyl pyridazine 68 in low to moderate yield. Subsequently treatment of 68 with SOCl2 gives the chloromethylpyridazine 69 as a hydrochloric salt. Compound 69 then is converted to secondary amine 70 by reacting with various primary amines in presence of excess K2CO3 in CH3CN. Finally, reductive amination of 70 with wide range of aldehydes provides the desired 6-aryl-pyridazine compound 71. In some cases, 71 can be prepared directly from 69 by treatment with a secondary amine and K2CO3 in refluxing CH3CN.

[0281] Scheme 7 illustrates a method for preparing pyrimidines of Formula I where R1 is hydrogen. In step 1, an appropriately substituted arylalkylketone is reacted with dimethylformamide dimethyl acetal to produce the corresponding enaminoketone. The enaminoketone intermediate is heated in a sealed tube with formamidine acetate to obtain the corresponding 4,5-disubstituted pyrimidine in step 2. In step 3, addition of methyllithium to the pyrimidine yields the corresponding 1,6-dihydropyrimidine which is oxidized in situ with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to yield the 4,5,6-trisubstituted pyrimidine which is subsequently brominated to form the 6-(bromomethyl)pyrimidine. In step 4, reaction with various appropriately substituted secondary amines provides pyrimidines of formula I. Those skilled in the art will realize that minor modifications to this synthetic route can be used to obtain differently substituted pyrimidines of Formula I. For example, use of alkylamidines in step 2 can be used to obtain compounds of Formula I where R1 is alkyl.

[0282] Scheme 8 illustrates a route for preparing pyrimidines of Formula I where R1 is alkoxy. In step 1, an appropriately substituted 1,3-ketoester is reacted with thiourea in the presence of base to obtain the corresponding 2-thioxo-2,3-dihydro-1H-pyrimidin-4-one which is hydrolyzed in step 2 to the corresponding 1H-pyrimidine-2,4-dione. In step 3, the 1H-pyrimidine-2,4-dione is reacted with phosphorous oxychloride and dimethylformamide to obtain the corresponding 2,4-dichloropyrimidine. This material is reacted under Suzuki coupling conditions in step 4 to replace the 4-chloro group with Ar1. Bromination and subsequent reaction with appropriate secondary amines in steps 5 and 6 provides 2-chloropyrimidines of Formula I. Displacement of the 2-chloro substituent in step 7 provides 2-alkoxypyrimidines of Formula I (NaOR′ represents an appropriate sodium alkoxide). Those skilled in the art will realize that minor modifications to Scheme 8 can be used to obtain differently substituted pyrimidines of Formula I. For example, displacement of the 2-chloro substituent with amines in step 7 can be used to obtain 2-aminopyrimidines of Formula I.

[0283] Scheme 9 illustrates a route for preparing imidazoles of Formula I where R1 is aryl or heteroaryl and Ar1 is a variety of aryl and heteraryl groups. In step 1, an aryl imidazole 82 is alkylated to obtain an isomeric mixture. This mixture is separarated by chromatography to provide the desired isomer 83. In step 2, imidazole 83 is lithiated at the 2-position and reacted with an electrophilic iodine or bromine source to provide 2-haloimidazole 84. In step 3, imidazole 84 is converted to the corresponding hydroxymethyl derivative by heating under pressure with aqueous formaldehyde in the presence of acetic acid and sodium acetate to yield 85. Hydroxymethylimidazole 85 is converted to the chloride and used to alkylate various amines in step 4 to obtain aminomethylimidazoles 86. Reductive amination of aminomethylimidazole 86 in step 5 provides 2-haloimidazole 87. Step 6 illustrates a particular set of conditions for conversion of 2-haloimidazole 87 to imidazoles of formula I. Those skilled in the art will recognize that the route illustrated in Scheme 8 can be modified by changing the sequence of steps or the reactants to produce a wide variety of imidazoles of Formular I. For example, 2-haloimidazole 87 can be coupled with alternative organometallics (Ar1M, M=Sn, Mg, Zn) to enhance the variety of imidazoles of Formula I accessible by this route.

[0284] Scheme 10 illustrates a route for preparing imidazoles of Formula I utilizing trihaloimidazole 90. In steps 1 and 2, 90 is prepared from dihaloimidazole 88 by alkylation with R2Y wherein Y is a suitable leaving group such as bromo, iodo or mesylate followed by electrophilic bromination. In step 3, 90 is selective coupled at the 2-position with various aryl boronic acids in the presence of palladium catalyst. In step 4, metal-halogen exchange occurs selectively at the 5-position of 91 to yield, after reaction with DMF, aldehyde 92. In steps 5 and 6, aldehyde 92 is reduced to the corresponding alchohol 93, activated as the chloride and displaced with an appropriately substitued amine to yield imdiazoles compounds of Formula I, where R1 is chloro or bromo (94). Optional subsequent steps may be employed to convert X to a variety of R1 subtituents according to the Formula I. As illustrated in Schemes 1-9 and the accompanying examples, a variety of straight-forward modifications to Scheme 10 can be employed to access a wide variety of compounds of Formua I.

[0285] Scheme 11 illustrates a route for preparing imidazoles of Formula I wherein R3 is incorporated in a stereospecific manner in a similar manner to a published procedure (Enders, D.; Thiebes, C. J. Synthesis 2000, 510-512).

EXAMPLES

[0286] The general methods given in Schemes 1 to 11 above for the preparation of compounds of the present invention are further illustrated by the following examples. Specifically, the methods given in Schemes 1 and 2 for the preparation of aryl imidazoles are illustrated by Examples 1-9, shown below. An example of the method shown in Scheme 3 for the preparation of cycloalkylimidazoles is given in example 10, an example of the method shown in Scheme 4 for the preparation of arylpyridines is given in example 11, and an example of the method shown in Scheme 5 for the preparation of arylpyrazoles is further illustrated in examples 12 and 14. Example 13 provides a method for the synthesis of aryl substituted triazoles. Methods for the synthesis of aryl substituted pyridizines are given in examples 15-18. Methods for the synthesis of compounds in which y is greater than 1 are given in examples 19 and 22. Examples 20-21 provide methods for the synthesis of 4-aryl-pyrimidines. Examples 22 and 24-26 provide supporting chemistry for the synthesis of compounds of Formula I bearing some particular funtionalized Ar2 or R4 substituents. Example 23 further illustrates the route outlined in Scheme 9. Examples 27 and 28 further illustrates the chiral synthesis of R3=alkyl compounds described in Scheme 11. Examples 29-40 are provided to illustrate the synthesis of a variety of intermediates and compounds wherein R1 is substituted alkyl. Example 41 provides for the synthesis of intermediates used in the synthesis of certain compounds prepared according to Scheme 10. Unless otherwise specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied to achieve the desired end product.

Example 1

Preparation of an Arylimidazole Compound: 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methlenedioxyphenyl Methyl])aminomethylimidazole (Compound 106)

[0287]

[0288] N-(n-butyl)-benzamidine (101). 7 ml of triethylamine is added to a solution of methyl benzimidate hydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) at 0° C. After 2 h the reaction is filtered to remove triethylamine hydrochloride. 3.68 g of 1-butylamine is added to the filtrate and the mixture is heated to 60° C. for 6 hours. After cooling the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and concentrated to provide the amidine as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).

[0289] 1-(1-Butyl)-2-phenylimidazole-5-carboxaldehyde (102). Potassium carbonate (15.5 g) and water (19 mL) are added to a solution of 101 (13.28 g) and 2-bromo-3-isopropoxyacrolein (22 g) in chloroform (150 mL). The mixture is stirred at room temperature overnight. The aqueous layer is discarded and the organic layer is washed with water (3×100 mL), dried (Na2SO4) and concentrated. The residue is purified via flash chromatography (5% MeOH/CHCl3) to provide the desired imidazole carboxaldehyde as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.90 (s, 1H), 7.55 (m, 2H), 7.45 (m, 3H), 4.38 (t, J=8 Hz, 2H), 1.75 (m, 2H), 1.22 (m, 2H), 0.91 (t, J=7 Hz, 3H).

[0290] 1-(1-Butyl)-2-phenyl-5-hydroxymethylimidazole (103). Aldehyde 102 is dissolved in methanol (150 mL). Sodium borohydride (3 g) is added in portions. After the addition is complete, the reaction is diluted with water and concentrated. The residue is dissolved in ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The product is purified by flash chromatography on silica gel (5% MeOH/CHCl3) to give 103 as a cream colored solid. 1HNMR (400 MHz, CDCl3): δ 0.79 (3H, t, J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.60 (2H, m, J=7.6 Hz), 4.03 (2H, dd, J=7.6 Hz), 4.56 (2H, s), 6.84 (1H, s), 7.39-7.50 (3H, m),7.50-7.53 (2H, m).

[0291] 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl])aminomethyl imidazole (104). Hydroxymethylimidazole 103 (0.82 g) is dissolved in chloroform (10 mL) and treated with thionyl chloride (1 mL). The solution is heated to 50° C. for 30 min, cooled and evaporated. The residue is washed with benzene and evaporated to give the intermediate chloromethyl hydrochloride as a white powder which is taken up in acetonitrile (30 mL). This is added dropwise to a solution of piperonylamine (5 mL) in acetonitrile (10 mL). The reaction is allowed to stand overnight and then evaporated. The residue is taken up in ethyl acetate and washed with water. The organic layer is dried (Na2SO4) and concentrated. Purification on silica gel (10% MeOH/CHCl3) provides the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.79 (3H, t, J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.56 (2H, m, J=7.4 Hz), 3.75 (4H, s), 4.04 (2H, dd, J=8 Hz), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H, s), 6.97 (1H, s), 7.38-7.44 (3H, m), 7.53-7.56 (2H, m).

[0292] 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl methyl]-N-(3,4-methylenedioxyphenylcarboxy]) aminomethylimidazole (105). Compound 104 (160 mg, 0.44 mmol) is dissolved in chloroform (5 ml, pentene stabilized) and treated sequentially with piperonyl chloride (100 mg) and triethylamine (1 mL). The mixture is stirred at room temperature overnight. The solution is concentrated and the residue taken up in ethyl acetate. The organic is washed with water, dried (Na2SO4) and concentrated. Purification by preparative thin layer chromatography (5% MeOH/CHCl3) provides compound 105 as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.75 (3H, br), 1.16 (2H, br), 1.49 (2H, br), 4.01 (2H, br), 4.54 (2H, br), 4.68 (2H, br), 5.97 (2H, s), 5.99 (2H, s), 6.66 (2H, d, J=7.2 Hz), 6.80 (2H, t, J=8 Hz), 6.98-7.02 (2H, m), 7.40-7.47 (3H, m), 7.56 (2H, d, J=6.8 Hz).

[0293] 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxy phenylmethyl])-aminomethylimidazole (106). Amide 105 (215 mg) in tetrahydrofuran (THF, 3 mL) is added dropwise to a solution of alane (1 M in THF, 2 mL) and the resulting solution is stirred for 2.5 h at room temperature. A solution of sodium hydroxide (15% NaOH, 1 mL) is added and the mixture is extracted with chloroform. The organic extracts are dried (Na2SO4) and concentrated. Purification by preparative thin layer chromatography (10% MeOH/CHCl3) provided compound 106 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.70 (3H, t, J=7.6 Hz), 0.98 (2H, m, J=7.6 Hz), 1.30 (2H, m), 3.44 (4H, s), 3.52 (2H, s), 3.98 (2H, dd, J=8 Hz), 5.92 (4H, s), 6.74 (4H, s), 6.69 (2H, s), 7.02 (1H, s), 7.36-7.42 (3H, m), 7.54 (2H, dd, J=1.4, 6.6 Hz). The hydrochloride salt (m.p. 187-190° C.) is prepared in isopropanol.

Example 2

Preparation of 1-(1-Butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole (Compound 108)

[0294]

[0295] 1-Butyl-2-phenyl-5-(1-hydroxyethyl)imidazole (107). A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of methyl lithium (1.4 M in THF, 1.5 mL). After 10 min, the solution is washed with ammonium chloride solution (1 M, 20 mL), dried (Na2SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl3) to provide compound 107 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).

[0296] 1-Butyl-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenylmethyl)aminoethylimidazole (108). A solution of compound 107 (80 mg) in chloroform (10 mL) is treated with thionyl chloride (10 mL) and heated to 50° C. for 30 minutes The solution is then concentrated, diluted with chloroform and reconcentrated to provide the intermediate chloromethyl hydrochloride as an oil. This material is taken up in chloroform (5 mL) and treated sequentially with N-benzylpiperonylamine (80 mg) and triethylamine. After stirring overnight, the reaction is washed with saturated potassium carbonate solution, dried (Na2SO4) and concentrated. Purification by preparative thin layer chromatography (10% MeOH/CHCl3) provides compound 108 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 1H), 7.2-7.3 (m, 9H), 6.74-6.86 (m, 4H), 5.94 (s, 2H), 4.82 (q, J=6.8 Hz, 1H), 4.33 (m, 2H), 3.78 (s, 2H), 3.53 (s, 2H), 1.83 (d, J=6.8 Hz, 3H), 1.62-1.68 (m, 2H), 1.21 (q, J=7.8 Hz, 2H), 0.82 (t, J=7.8 Hz, 3H).

Example 3

Preparation of 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])amino-methylimidazole (Compound 110)

[0297]

[0298] 1-Butyl-2-phenyl-5-(N-benzyl-N-butyl)aminomethylimidazole (109). A solution of compound 102 (115 mg) and N-butylbenzylamine (85 mg) in toluene (10 mL) is allowed to stand overnight. Treatment of the reaction with sodium borohydride (100 mg) and ethanol (2 mL) followed by aqueous workup and purification on silica gel (10% MeOH/CHCl3) provides compound 109 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.2-7.5 (m, 10H), 6.98 (s, 1H), 4.0 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.52 (s, 2H), 2.42 (t, J=8 Hz, 2H), 1.2-1.55 (m, 6H), 1.05 (in, 2H), 0.84 (t, J=7 Hz, 3H), 0.72 (t, J=7 Hz, 3H).

[0299] 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethyl imidazole (110). N-bromosuccinimide (16 mg) is added to a solution of 109 (30 mg) in acetonitrile (4 mL). The resulting mixture is heated to 60° C. and the progress of the reaction followed by TLC. The cooled reaction mixture is diluted with ethyl acetate and washed twice with water. Purification by preparative thin layer chromatography (10% MeOH/CHCl3) provides compound 110 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.2-7.5 (m, 10H), 3.98 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.46 (t, J=7 Hz, 2H), 1.52 (m, 2H), 1.3 (m, 4H), 0.98 (q, J=7 Hz, 2H), 0.84 (t, J=7 Hz, 3H), 0.70 (t, J=7 Hz, 3H).

Example 4

Preparation of 1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phenylmethyl)aminomethylimidazole. (Compound 114)

[0300]

[0301] 1-Butyl-2-phenyl-4-methylimidazole (112). Sodium hydride (4.4 g, 60% in mineral oil) is added to a solution of 4-methyl-2-phenylimidazole (111, 15.8 g) in dimethylformamide (100 mL) in small portions. After the addition is complete, the mixture is stirred for an additional 20 minutes and treated with 1-iodobutane (18.8 g). The reaction is fitted with a reflux condensor and heated at 100° C. for 12 hours. The cooled reaction mixture is partitioned between water (300 mL) and diethyl ether (300 mL). The organic layer is washed with water (3×200 mL), dried (Na2SO4) and concentrated to provide N-butylimidazoles. Analysis by 1H NMR and GC-MS revealed mixture of 1-butyl-2-phenyl-4-methylimidazole (112) and 1-butyl-2-phenyl-5-methylimidazole in a ratio of 11.5/1. The mixture is carried to the next step without purification.

[0302] 1-Butyl-2-phenyl-4-methyl-5-hydroxymethylimidazole (113). A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 hours. The reaction is then concentrated and dried by repeated reconcentration with toluene. The residue is purified by column chromatography (10% MeOH/CHCl3). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined fractions provides compound 113 (320 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.4-7.6 (m, 6H), 4.61 (s, 2H, CH2OH), 4.02 (t, J=7 Hz, 2H, NCH2), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).

[0303] 1-Butyl-2-phenyl-4-methyl-5-(N-benzyl-N-butyl)aminomethylimidazole (114). Compound 114 (23 mg) is prepared from 113 (50 mg) in a method similar to that used to obtain compound 108. 1H NMR (400 MHz, CDCl3) δ 7.5-7.55 (m,2H), 7.38-7.42 (m, 3H), 7.23-7.30 (m, 5H), 3.95 (t, J=7.5 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.40 (t, J=7 Hz, 2H), 2.22 (s, 3H), 1.25-1.40 (m, 6H), 1.05 (m, 2H), 0.82 (t, J=7 Hz, 3H). 0.70 (t, J=7 Hz, 3H); MS (LCMS) m/e 390 (M++1)

Example 5

Preparation of 1-Butyl-2,4-diphenyl-5-(N-butyl-N-benzyl)aminomethylimidazole (118)

[0304]

[0305] 1-Butyl-2,4-diphenylimidazole (116). 1-Iodobutane (1.5 g) is added to a solution of 2,4-diphenylimidazole 115 (1.76 g, 8 mmol) and cesium carbonate (2.6 g, 8 mmol) in 10 ml of DM. The resulting mixture is heated at 80° C. for 16 hours. After cooling, the reaction is partitioned between water and ether. The ether layer is dried (Na2SO4) and concentrated to provide the desired N-alkyl imidazole as an oil (2.2 g). 1H NMR (CDCl3)7.82 (d, J=5 Hz, 2H), 7.63 (d, J=4 Hz, 2H), 7.2-7.5 (m, 7H), 4.0 (t, J=7 Hz, 2H), 1.77 (m, 2H0, 1.3 (m, 2H), 0.88 (t, J=7 Hz, 3H).

[0306] 1-Butyl-2,4-diphenyl-5-hydroxymethylimidazole (117). 1-Butyl-2,4-diphenylimidazole (3 g) is dissolved in 50 ml of acetic acid with 50 ml of 37% aqueous formalin solution. The mixture is heated at reflux for 48 h, cooled and the solvents evaporated. The residue is triturated with ether and filtered. The filtrate is concentrated and partitioned between ethyl acetate (100 mL) and 5% aqueous acetic acid (100 mL). The aqueous layer is extracted with ethyl acetate (100 mL). The combined organic extracts are washed with 1N NaOH solution, brine, dried over Na2SO4, and concentrated. The crude product is triturated with ethyl acetate to give the product as a white solid. 1H NMR (CDCl3) 7.73 (d, J=5 Hz, 2H), 7.62 (d, J=4 Hz, 2H), 7.3-7.5 (m, 6H), 4.82 (s, 2H), 4.10 (t, J=7 Hz, 2H), 1.7 (m, 2H), 1.25 (m, 2H), 0.85 (t, J=7 Hz, 3H).

[0307] 1-Butyl-2,4-diphenyl-5-(N-butyl-N-benzyl)aminomethylimidazole dihydrochloride (118). Thionyl chloride (1 ml) is added to a solution of 1-butyl-2,4-diphenyl-5-hydroxymethylimidazole (0.5 g) in chloroform (10 mL) and the mixture is heated to reflux for 10 minutes The reaction is then concentrated and dried on a vacuum pump. The crude chloride is dissolved in acetonitrile (10 mL) and N-butylbenzylamine (0.27 g, 1 equiv). Potassium carbonate (1 g) is added. The reaction is heated at 60° C. for 8 h, cooled and partitioned between ether and water. The ether layer is dried (Na2SO4) and concentrated. The crude product is purified on silica (5% MeOH/CH2Cl2) to give the desired product as an oil. 1H NMR (CDCl3)7.70 (d, J=5 Hz, 2H), 7.58 (d, J=4 Hz, 2H), 7.2-7.5 (m, 11H), 4.15 (t, J=7 Hz, 2H), 3.77 (s, 2H), 3.52 (s, 2H0, 2.38 (t, J=7 Hz, 2H), 1.6 (m, 4H), 1.2 (m, 2H), 1.05 (m, 2H), 0.8 (t, J=7 Hz, 3H), 0.73 (t, J=7 Hz, 3H). The free base is converted to the hydrochloride salt C31H37N32HCl{fraction (1/2)}H2O.

[0308] C, H, N Calc: 69.78; 7.56; 7.86. Found: 69.79; 7.81; 7.46.

Example 6

Preparation of Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-trifluoromethyl-3H-imidazol-4-ylmethyl)-amine (125)

[0309]

[0310] 4-Trifluoromethyl 2-phenylimidazole (120). 1,1,1-Trifluoro-3,3-dibromoacetone is added to a solution of NaOAc (11.97 g, 145 mmol) in water (40 mL). The reaction mixture is stirred at 70-80° C. for 30 minutes. After cooling, the solution is added to benzaldehyde (4.25 g, 40 mmol) in methanol (200 mL) and concentrated ammonium hydroxide (50 mL) at room temperature. The mixture is stirred for 4 h. The reaction is monitored by TLC. The reaction mixture is evaporated in vacuo to remove the organic solvent and cooled to room temperature. The solid is collected by filtration gave desired product 120.

[0311] NMR (CDCl3, 8 ppm): 7.38-7.42 (m, 1H), 7.46 (t, J=7.2 Hz, 2H), 7.85 (d, J=1.3 Hz, 1H), 7.96-7.99 (dd, J=1.5, 7.2 Hz, 2H).

[0312] N-Butyl 4-Trifluoromethyl 2-phenylmidazole (121) Powdered KOH (3 mmol) is suspended in DMSO (4 mL). A solution of 120 (2 mmol) and n-BuI (4.5 mmol) in DMSO (4 mL) is added and the solution is stirred overnight. The reaction mixture is diluted with ether (80 mL) and water (80 mL). The aqueous phase is extracted with ether (20 ml×2). Combined organic phase are washed with water (2×100 mL), dried over MgSO4, and concentrated in vacuo to dryness to provide the product 121 as a colorless oil. NMR (CDCl3, a ppm): 0.88 (t, J=7.5 Hz, 3H), 1.26-1.31(m, 2H), 1.72-1.75 (m, 2H), 4.00 (t, J=7.5 Hz, 2H), 7.35 (s, 1H), 7.45-7.47 (m, 3H), 7.55-7.57 (m, 2H).

[0313] n-Butyl 4-Trifluoromethyl 5-formyl 2-phenylmidazole (122) n-BuLi (1.6M in hexane, 30 mL) is added to a solution of 121 (10.8 g, 40.3 mmol) in anhydrous THF (100 mL) at −78° C. under N2 over a 30 minute period The reaction mixture is stirred at −78° C. for 1 h, followed by the followed by the addition of anhydrous DMF (5 mL), and stirred at −78° C. for 3 h. 20 ml of water is added at −50° C. and the reaction-mixture is diluted with EtOAc. Organic layer are separated and washed with H2O and brine, and dried over MgSO4. Concentration in vacuo to dryness provides the desired product 122. 1H NMR (CDCl3, 6 ppm): 0.83 (t, J=7.5 Hz, 3H), 1.13-1.26 (m, 2H), 1.66-1.70 (m, 2H), 4.34 (t, J=7.5 Hz, 2H), 7.50-7.52 (m, 3H), 7.53-7.59 (m, 2H), 10.0 (s, 1H).

[0314] N-Butyl 4-trifluoromethyl 5-hydroxymethyl 2-phenylmidazole (123) NaBH4 is added to a solution of 122 (8.0 g, 27 mmol) in methanol (150 mL) in small portions at 0° C. After the addition is complete, the mixture is stirred at 0° C. for an additional 30 minutes Ice (30 g) is added slowly and the mixture is evaporated in vacuo to remove the organic solvent. Product is collected the solid by filtration, washed with water, dried in vacuo at 35° C. overnight, to give the desired product 123. 1H NMR (CDCl3, 6 ppm): 0.83 (t, J=8.0 Hz, 3H), 1.21-1.26 (m, 2H), 1.65-1.69 (m, 2H), 4.08 (t, J=8.0 Hz, 2H), 4.79 (s, 2H), 7.45-7.48 (m, 3H), 7.53-7.56 (m, 2H).

[0315] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-trifluoromethyl-3H-imidazol-4-ylmethyl)-amine (125) Mesyl chloride is added to a solution of 123 (393 mg, 1.32 mmol) and TEA (2.6 mmol) in chloroform (10 mL) at 0-5° C. The reaction mixture is stirred at room temperature for 4 h. until the reaction complete and then concentrated in vacuo to dryness. The residue is dissolved in acetonitrile (20 mL) and dipiperonylamine (376 mg, 1.32 mmol) and K2CO3 (728 mg, 5.28 mmol) are added. The reaction mixture is heated under reflux overnight. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate, washed with water, and dried over MgSO4. Concentration in vacuo gives the product 125. 1H NMR (CDCl3, 8 ppm): 0.67 (t, J=7.7 Hz, 3H), 0.88-0.94 (m, 2H), 1.18-1.22 (m, 2H), 3.44 (s, 4H), 3.68 (s, 2H), 4.04 (t, J=7.1 Hz, 2H), 5.92 (s, 4H), 6.73-6.74 (m, 4H), 6.76 (s, 2H), 7.41-7.44 (m, 3H), 7.48-7.51 (m, 2H).

Example 7

Preparation of 5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1h-imidazole-4-carbonitrile (129)

[0316]

[0317] 4-Cyano2-phenylimidazole (126), 4-Trifluoromethyl 2-phenylimidazole (20 g, 94 mmol) is added to a 5% ammonium hydroxide solution (200 mL). The mixture is then warmed to 60-65° C. and stirred for 2 h, extracted with ethyl acetate (300 ml×3), and dried over MgSO4. Evaporation to dryness gives the desired product 126 (14 g).

[0318]

1
H NMR (CDCl3, o ppm): 7.40-7.45 (m, 3H), 7.73 (s, 1H), 7.82-7.85 (m, 2H).

[0319] N-Butyl 4-Cyano2-phenylimidazole (127). N-Butyl 4-Cyano2-phenylimidazole is synthesized by the procedure given for compound 121. 1H NMR (CDCl3, o ppm): 0.73 (t, J=7.6 Hz, 3H), 1.11-1.16 (m, 2H), 1.57-1.61 (m, 2H), 3.93 (t, J=7.6 Hz, 2H), 7.34-7.37 (m, 3H), 7.42-7.45 (m, 2H). 7.51 (s, 1H).

[0320] N-Butyl 4-cyano-5-formyl 2-phenylmidazole (128). N-Butyl 4-cyano-5-formyl 2-phenylmidazole is synthesized by the procedure given for compound 121. 1H NMR (CDCl3, o ppm): 0.82 (t, J=7.5 Hz, 3H), 1.19-1.26 (m, 2H), 1.63-1.68 (m, 2H), 4.34 (t, J=15=7.5 Hz, 2H), 7.49-7.57 (m, 5H), 9.99 (s, 11H).

[0321] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-cyano-3H-imidazol-4-ylmethyl)-amine (129) Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-cyano-3H-imidazol-4-ylmethyl)-amine is synthesized by the procedure given for compound 125. 1H NMR (CDCl3, S ppm): 0.68 (t, J=7.4 Hz, 3H), 0.84-0.96 (m, 2H), 1.18-1.26 (m, 2H), 3.49 (s, 4H), 3.68 (s, 2H), 3.99 (t, J=7 Hz, 2H), 5.90 (s, 4H), 6.73 (s, 4H), 6.77 (s, 2H), 7.44 (brs, 5H).

Example 8

Preparation of Bis-benzo[1,3]dioxol-5-yethyl-[3-butyl-5-(5-methyl-thiophen-2-yl)-2-phenyl-3H-imidazol-4-ylmethyl]-amine

[0322]

[0323] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-3H-imidazol-4-ylmethyl)-amine (136) is synthesized via the procedure given for compound 125.

[0324]

1
H NMR (CDCl3, o ppm): 0.69 (t, J=7.4 Hz, 3H), 0.95-1.00 (m, 2H), 1.22-1.31 (m, 2H), 3.44 (s, 4H), 3.54 (s, 2H), 3.98 (t, J=7. Hz, 2H), 5.91 (s, 4H), 6.73 (s, 4H), 6.79 (s, 2H), 7.01 (s, 1H), 7.38-7.42 (m, 3H), 7.51-7.54 (m, 2H).

[0325] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-bromo-3H-imidazol-4-ylmethyl)-amine (137). 1H NMR (CDCl3, 8 ppm): 0.69 (t, J=7.4 Hz, 3H), 0.89-0.96 (m, 2H), 1.24-1.28 (m, 2H), 3.45 (s, 4H), 3.54 (s, 2H), 4.00 (t, J=7. Hz, 2H), 5.90 (s, 4H), 6.73 (s, 4H), 6.77 (s, 2H), 7.38-7.42 (m, 3H), 7.48-7.51 (m, 2H).

[0326] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-bromo-3H-imidazol-4-ylmethyl)-amine (138). 1H NMR (CDCl3, 8 ppm): 0.69 (t, J=7.4 Hz, 3H), 0.89-0.96 (m, 2H), 1.24-1.28 (m, 2H), 2.52 (s, 3H), 3.48 (s, 4H), 3.80 (s, 2H), 4.06 (t, J=7. Hz, 2H), 5.91 (s, 4H), 6.73 (m, 5H), 6.77 (s, 2H), 7.17 (d, J=3.3 Hz, 1H), 7.38-7.46 (m, 3H), 7.55-7.58 (m, 2H).

Example 9

Preparation of 4-fluoroimidazole Compounds

[0327]

[0328] 1-Butyl-2-phenyl-5-hydroxymethylimidazole (139). Sodium borohydride (1.135 g, 30 mmol) is added to a solution of aldehyde 138 (6.849 g, 30 mmol) in 100 ml of methanol cooled to 0° C. The resulting solution is stirred at 0° C. for 30 min, evaporated and the residue dissolved in 150 ml of ethyl acetate, washed with water and brine, dried over Na2SO4, concentrated and taken to dryness under high vacuum to give the product 139 as an oil. MS (+VE) m/z 231 (M+1).

[0329] 1-Butyl-2-phenyl-4-bromo-5-hydroxymethylimidazole (140). N-bromo succinimide (3.56 g, 20 mmol) is added to a solution of alcohol 139 (4.60 g, 20 mmol) in 100 ml of anhydrous acetonitrile cooled to 0° C., in portions over 15 minutes. The resulting mixture is stirred at 0° C. for 60 min, water is added to quench the reaction, the acetonitrile is evaporated, and the residue dissolved in 100 ml of ethyl acetate, washed with water and brine, and dried over Na2SO4 The solvent is evaporated and the residue purified by silica gel flash chromatography (hexanes/ethyl acetate, from 6:1 to 3:1) to give 3.15 g of product 140. 1H NMR (300 MHz, CDCl3) δ 7.48-7.56 (2H, m), 7.40-7.47 (3H, m), 4.67 (2H, s), 4.07 (2H, t, J=7.60 Hz), 1.65 (2H, m), 1.24 (2H, m), 0.83 (3H, t, J=7.5 Hz). MS (+VE) m/z 309 (M+), 311 (M+2).

[0330] Compound (141). 3,4-Dihydro-2H-pyran (1.41 g, 16.8 mmol, 5 eq.) is added to a solution of alcohol 140 (1.04 g, 3.36 mmol) in 20 ml of anhydrous dichloromethane cooled to 0° C., followed by addition of p-toluenesulfonic acid monohydrate (10 mg). The mixture is stirred at room temperature overnight. The solution is diluted with 20 ml of ether and washed with a solution made up of 5 ml of NaHCO3-5 ml brine-10 ml water. The aqueous phase is extracted with ether and the combined organic solutions are dried with Na2SO4. The solvent is evaporated and the residue purified by silica gel flash chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) to give compound 141 as a sticky oil. 1H NMR (300 MHz, CDCl3) δ 7.54-7.58 (2H, m), 7.72-7.47 (3H, m), 4.75 (1H, d, J=13 Hz), 4.73 (1H, m), 4.58 (1H, d, J=13 Hz), 4.06 (2H, m), 3.94 (1H, m), 3.61 (1H, m), 1.45-1.88 (8H, m), 1.23 (2H, m), 0.83 (3H, t, J=7.5 Hz). MS (+VE) m/z 393 (M+), 395 (M+2).

[0331] Compound (142). A solution of butyl lithium in hexanes (1.6M, 1.02 ml, 1.64 mmol) is added to a solution of compound 141 (537 mg, 1.37 mmol) in 10 ml of anhydrous THF at −78° C. under nitrogen. The resulting mixture is stirred at −78° C. for 60 min; a solution of N-fluorobenzenesulfonimide (516 mg, 1.64 mmol) in 10 ml of THF is then added dropwise. The resulting solution is stirred at −78° C. for 30 min, warmed to room temperature, and then stirred overnight. 10 ml of saturated NaHCO3 is added to quench the reaction. The mixture is diluted with 50 ml of ethyl acetate, the organic layer is separated, washed with water and brine, and dried over Na2SO4 Concentration and purification through silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords compound 142. 1H NMR (400 MHz, CDCl3) δ 7.52-7.55 (2H, m), 7.37-7.44 (3H, m), 4.70 (1H, d, J=13 Hz), 4.69 (1H, m), 4.51 (1H, d, J=13 Hz), 3.95-4.07 (2H, m), 3.88 (1H, m), 3.56 (1H, m), 1.48-1.82 (8H, m), 1.22 (2H, m), 0.82 (3H, t, J=7.2 Hz). MS (+VE) m/z 333 (M+1).

[0332] 1-Butyl-4-fluoro-5-hydroxymethyl-2-phenylimidazole (143). 1-Butyl-2-phenyl-4-fluoro-5-hydroxymethylimidazole 142 (100 mg, 0.30 mmol) is dissolved in a solution made up of 1.0 ml acetic acid-1.0 ml THF-1.0 ml water. The solution is heated to 55-60° C. and stirred for 2 h. The acetic acid and THF are evaporated, the residue basified with sodium hydroxide solution, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. The product is concentrated and taken to dryness under high vacuum to give compound 143. MS (+VE) m/z 249 (M+1).

[0333] Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-fluoro-2-phenyl-3H-imidazol-4-yl methyl)-amine (144). Compound 143 (76 mg, 0.30 mmol) is dissolved in 2 ml dichloromethane and cooled to 0° C. Thionyl chloride (0.05 mL) is added and the resulting solution is stirred at room temperature for 2 h. The solvent and excess thionyl chloride are evaporated. The residue is dissolved in 1.0 ml DMF and added to a solution of piperonyl amine (227 mg, 1.5 mmol) in DMF (2 mL) containing 100 mg potassium carbonate. The resulting mixture is stirred at room temperature for 2 h, then diluted with 20 ml of ethyl acetate, washed with water and brine, dried, and concentrated. The resulting residue is purified with silica gel chromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to provide compound 144. MS (+VE) m/z 382 (M+1).

[0334] Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-fluoro-2-phenyl-3H-imidazol-4-ylmethyl)-(3-ethoxy-benzyl)-amine (145) Compound 144 (0.079 mmol) is dissolved in 2 ml 1,2-dichloroehane. 3-Ethoxybenzaldehyde (28 mg, 2.0 eq) is added followed by one drop of acetic acid. The solution is stirred at room temperature for 2 hr; sodium triacetoxyborohydride (50 mg, 0.236 mmol, 3.0 eq.) is then added. The resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with 10 ml of dichloromethane, washed with water and brine, dried, and concentrated. The residue is purified by silica gel flash chromatography (hexanes/ethyl acetate, from 8:1 to 4:1) to afford compound 1451H NMR (400 MHz, CDCl3) δ 7.47-7.52 (2H, m), 7.38-7.44 (3H, m), 7.21 (1H, t, J=8 Hz), 6.82-6.90 (3H, m), 6.7-6.78 (3H, M), 5.93 (2H, s), 4.01 (2H, q, t=7.2 Hz), 3.92 (2H, t, J=7.6 Hz), 3.52 (2H, s), 3.51 (2H, s), 3.48 (2H, s), 1.41 (3H, t, J=6.8 Hz), 1.34 (2H, m), 0.99 (2H, m), 0.71 (3H, t, J=7.2 Hz). MS (+VE) m/z 516.3 (M+1).

Example 10

Preparation of Cycloalkylimidazole Compounds: 4-{[butyl(1-butyl-2-phenyl(4,5,6-triihydrocyclopenta[3,2-d]imidazol-6-yl)amino]methyl}-3-chlorophenol (156)

[0335]

[0336] N-(n-butyl)-benzamidine (150). 7 ml of triethylamine is added to a solution of methyl benzimidate hydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) at 0° C. After 2 h the reaction is filtered to remove triethylamine hydrochloride. 1-Butylamine (3.68 g) is added to the filtrate and the mixture is heated to 60° C. for 6 hours. After cooling the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate and concentrated to provide the amidine as a yellow oil. 1H NMR (CDCl3) 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).

[0337] 2-Bromo-3-methoxycyclopentenone (151) is prepared via the method of Curran et al JACS, vol 112, page 5601. N-Bromosuccinimide (18.2 g) is added to a suspension of 1,3-cyclopentanedione (10 g) in chloroform (700 mL). The mixture is refluxed for 2 h, cooled and concentrated. Methanol (700 mL) and p-toluenesulfonic acid (1 g) are added and the solution is refluxed overnight. The mixture is concentrated to 100 ml, diluted with methylene chloride (500 mL), and poured into water. The aqueous layer is discarded and the organic layer is washed with water (3×100 mL), dried (Na2SO4) and concentrated. The residue is crystallized from ethyl acetate to give 151 as tan crystals (1.67 g).

[0338] 1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-one (152). Solid potassium carbonate (3.32 g, 24 mmol) is added to a mixture of amidine 150 (3.52 g, 20 mmol) and enone 13 (4.58 g, 24 mmol) in chloroform (40 mL) and water (5 mL). The resulting mixture is refluxed overnight. After cooling, the mixture is washed with water, dried (Na2SO4), and concentrated. Purification on silica gel eluting with 25% ethyl acetate/hexane gives the desired product 152 (3.0 g) LC-MS (M++1): 255. 1H NMR (6, CDCl3): 0.84 (t, J=7.6 Hz, 3H), 1.23 (dt, J=7.0, 7.6 Hz, 2H), 1.81 (m, 2H), 2.95 (m, 4H), 4.13 (t, J=7.6 Hz, 2H) 7.5-7.45 (m, 3H), 7.76-7.6 (m, 2H) ppm.

[0339] 1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-ol (153). Sodium borohydride (1.5 equiv) is added to a solution of 152 (2.68 g) in methanol (20 mL) and the mixture is stirred overnight. The mixture is concentrated, diluted with chloroform, and washed with 0.5 N NH4Cl solution. The organic layer is dried (Na2SO4) and concentrated to provide the desired product 153. LC-MS (M+1) 257.

[0340] Butyl(1-butyl-2-phenyl-4,5,6-trihydrocyclopentyl[3,2-d]imidazol-6-yl))amine (155). Compound 153 (2 g) is dissolved in chloroform (20 mL) and thionyl chloride (5 mL); the resulting solution is stirred at room temperature overnight. The solvent and excess thionyl chloride are evaporated and the crude chloride 154 dissolved in n-butylamine (10 mL). After 2 h, the excess butylamine is evaporated, the residue dissolved in ethyl acetate and the organic solution washed with 5% NaOH solution and water. The organic layer is dried and concentrated. The organic residue is purified by column chromatography on silaica gel eluting with 10% CH3OH in CHCl3 to provide the desired secondary amine 155. LC-MS (M+1) 312 1H NMR (chemical shift, CDCl3): 0.83 (t, J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H), 1.23 (q, J=7.2 Hz, 2H), 1.35 (q, J=7.2 Hz, 2H), 1.46 (m, 2H), 1.70 (m, 2H), 2.24 (m, 1H), 2.55-2.66 (m, 4H), 2.73-2.80 (m, 2H), 3.97-4.04 (m, 2H), 4.30 (d, J=5.6 Hz, 1H), 7.37-7.44 (m, 3H), 7.55-7.57 (m, 2H).

[0341] 4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))amino]methyl}-3-chlorophenol (156). Sodium triacetoxyborohydride (100 mg) is added to a solution of 155 (50 mg) in 1,2-dichloroethane (2 mL) and 2-chloro-4-hydroxybenzaldehyde (30 mg) is added The resulting mixture is allowed to stir overnight. After washing with 0.5 ammonium chloride solution, the organic layer is dried (Na2SO4) and concentrated. Purification using preparative thin layer chromatography eluting with 5% CH3OH/CHCl3 provides the desired product 156 as an oil (21 mg). LC-MS (M+1) 452, (M−1) 450. 1H NMR (chemical shift, CDCl3): 0.74 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.2 Hz, 3H), 1.11 (q, J=7.2 Hz, 2H), 1.21-1.33 (m, 2H), 1.41-1.51 (m, 4H), 2.34-2.44 (m, 3H), 2.51-2.57 (m, 1H), 2.60-2.67 (m, 1H), 2.69-2.75 (m, 1H), 3.38 (d, J=7.6 Hz, 1H), 3.47 (d, J=13.6 Hz, 1H), 3.65 (d, J=13.6 Hz, 1H), 3.78-3.96 (m, 1H), 6.62 (dd, J=8, 2 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 7.07.(d, J=8 Hz, 1H), 7.35-7.41 (m, 3H), 7.45-7.48 (m, 2H).

Example 11

Preparation of 2-phenyl-4-(N,N-di{2H-benzo[3,4-D]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine (161)

[0342]

[0343] 4-Phenyl-5-butyloxazole (157). A mixture of α-bromohexanophenone (25.5 g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110 mL) is refluxed with stirring for 3 hours. The reaction mixture is poured onto ice, made basic with 10 N NaOH, and extracted with ether. The organic layer is washed with water, dried over sodium sulfate, and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to provide the desired compound as an oil. 1H NMR (6, CDCl3, 400 MHz) 7.55 (m, 2H), 7.40 (s, 1H), 7.34 (dd, J=7, 7 Hz, 2H), 7.22 (dd, J=7, 7 Hz, 1H), 2.74 (m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J=7 Hz, 3H) ppm.

[0344] 2-Phenyl-3-butylisonicotinic acid (158). A mixture of 4-phenyl-5-butyloxazole (12, 5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100° C. for 30 minutes After cooling, the semisolid mass is triturated with ether and the solid collected by filtration. 1H NMR (6, CDCl3, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H), 0.68 (t, J=7.6 Hz, 3H). MS (M+1): 256, (M—1) 254.

[0345] 2-Phenyl-4-hydroxymethyl-3-butylpyridine (159). Lithium aluminum hydride (4 ml of 1M in tetrahydrofuran) is added to a solution of 2-phenyl-3-butylisonicotinic acid (510 mg, 2 mmol) in tetrahydrofuran (20 mL). The reaction is stirred overnight and then quenched with 5 ml of 15% aqueous NaOH. The resulting mixture is extracted with ether, dried (Na2SO4), and concentrated to provide the desired hydroxymethylpyridine as an oil. LC-MS (M+1): 242; 1H NMR (6, CDCL3) 8.35 (1H, d, J=5.2 Hz), 7.30-7.39 (6H, m), 4.59 (2H, s), 2.43 (2H, t, J=8.0 Hz), 1.23 (2H, m), 1.13 (2H, m), 0.70 (3H, t, J=7.2 Hz).

[0346] 2-Phenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine (160). Thionyl chloride (200 mg, 1.67 mmol) is added to a solution of 2-phenyl-4-hydroxymethyl-3-butylpyridine (400 mg, 1.66 mmol) in pentene stabilized chloroform (8 mL) and the mixture is heated to 50° C. for 2 hours. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na2SO4) and concentrated. The resulting crude chloride is taken up in dimethylformamide (10 mL) and added dropwise to a refluxing solution of piperonylamine (1.0 g, 4 equiv) in dimethylformamide (30 mL) containing 3 g of powdered potassium carbonate. After the addition is complete, the resulting mixture is refluxed for an additional 3 h, cooled and partitioned between water (200 mL) and ether (100 mL). The ether layer is washed 2 times with water, dried (Na2SO4), and concentrated. The resulting material is purified by chromatography on silica eluting with 10% CH3OH/CHCl3 to give the desired secondary amine 160. LC-MS (M+1): 375.3; 1H NMR (6, CDCl3): 0.73 (3H, t, J=7.2 Hz), 1.15 (2H, m J=7.2 Hz), 1.30 (2H, m), 2.58 (2H, t, J=8.0 Hz), 3.79 (2H, s), 3.83 (2H, s), 5.93 (2H, s), 6.75-6.82 (2H, m), 6.89 (1H, d, J=1.2 Hz), 7.36-7.42 (6H, m), 8.45 (1H, d, J=4.8 Hz) ppm.

[0347] 2-Phenyl-4-(N,N-di {2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine (161). Piperonal (30 mg) is added to a solution of 160 (38 mg) in dichloroethane (5 mL). The resulting mixture is stirred for 3 h after which time sodium triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight. The reaction mixture is quenched with 10% ammonium hydroxide solution (5 mL). The organic layer is washed with water and extracted with 1N HCl solution. The acidic extract is made basic with 1N NaOH solution and extracted with chloroform. The organic extract is dried (Na2SO4) and concentrated. The resulting oil is purified on preparative thin layer chromatography eluting with 10% CH3OH/CHCl3 to give the desired tertiary amine 161 as an oil. LC-MS (M+1): 509.4; 1H NMR (6, CDCl3): 0.71 (3H, t, J=7.2 Hz), 1.10 (2H, m, J=7.2 Hz), 2.60 (2H, t, J=8.0 Hz), 3.48 (4H, s), 3.58 (2H, s), 5.94 (4H, s), 6.75 (1H, d, J=8.0 Hz),6.80 (1H, dd, J=0.8, 8.0 Hz), 6.91 (1H, d, J=0.8 Hz), 7.36-7.43 (5H, m), 7.56 (1H, d, J=5.2 Hz), 8.47 (1H, d, J=5.2 Hz) ppm.

Example 12

Preparation of Arylpyrazole: 1,3-diphenyl-4-(N-{2H-benzo[3,4-D]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole (167)

[0348]

[0349] N′-Phenyl-N-phenylhydrazone (162). Benzaldehyde (9.81 g, 9.25 mmol) is added at 0-5° C. to a solution of phenyl hydrazine (10 g, 9.25 mmol) in ethanol (100 mL). A cream colored solid forms and the reaction mixture is allowed to stand for 2 hours. The solid is collected by filtration, washed with ice-cold ethanol and dried under vacuum to provide the desired compound, 162; LC-MS m/z 197.2.

[0350] Ethyl 1,3-diphenyl-5-propylpyrazole-4-carboxylate (164). A mixture of 162 (5 g, 25.5 mmol) and ethyl butyrylacetate (20.2 g, 128 mmol) and a catalytic amount of zinc chloride is heated at 125° C. under an air atmosphere for 3 hours. The reaction vessel is fitted with a short path distillation head and excess ethyl butyrylacetate is distilled away under vacuum. The resulting material is purified by column chromatography on silica eluting with 10% ethyl acetate in hexanes to provide the desired ester 164 as a yellow oil which crystallizes upon standing. Recrystallization from diisopropyl ether provides a white solid. MS (M+1): 335.2.

[0351] 1,3-Diphenyl-4-hydroxymethyl-5-propylpyrazole (165). 4 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran is added to a solution of ester 164 (670 mg, 2 mmol) in tetrahydrofuran (20 mL). The reaction is stirred overnight and then quenched with 5 ml of 15% aqueous NaOH. The resulting mixture is extracted with ether, dried (Na2SO4), and concentrated to provide the desired hydroxymethylpyrazole as an oil. LC-MS (M+1): 293.3; 1H NMR (6, CDCL3) 7.86 (dd, J=8.4 Hz, 2H), 7.34-7.52 (m, 8H), 4.65 (s, 2H), 2.72 (t, J=8.0 Hz, 2H), 1.52 (m, 2H), 0.87 (t, J=7.6 Hz, 3H).

[0352] [(1,3-Diphenyl-5-propylpyrazol-4-yl)methyl]butylamine (166). Thionyl chloride (1 mL) is added to a solution of 165 (289 mg) in pentene stabilized chloroform (8 mL) and the mixture heated to 60° C. for 2 hours. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na2SO4), and concentrated. The resulting crude chloride is taken up in dimethylformamide (3 mL) and added dropwise to a solution of butylamine (1.0 g) in dimethylformamide (10 mL) containing 2 g of powdered potassium carbonate. After the addition is complete, the resulting mixture is stirred for an additional 3 h and partitioned between water (20 mL) and ether (10 mL). The ether layer is washed 2 times with water, dried (Na2SO4), and concentrated. The resulting material is purified by chromatography on silica eluting with 10% CH3011/CHCl3 to give the desired secondary amine 166. LC-MS (M+1): 348.3; 1H NMR (6, CDCl3): 7.87 (dd, J=8.0, 1.6 Hz, 2H), 7.32-7.48 (m, 8H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91 (t, J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.

[0353] 1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole (167). Piperonal (30 mg) is added to a solution of 166 (35 mg) in dichloroethane (5 mL). The resulting mixture is stirred for 3 h after which time sodium triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight. The reaction mixture is quenched with 10% ammonium hydroxide solution (5 mL). The organic layer is washed with water and extracted with 1N HCl solution. The acidic extract is made basic with 1N NaOH solution and extracted with chloroform. The organic extract is dried (Na2SO4) and concentrated. The resulting oil is purified on preparative thin layer chromatography eluting with 10% CH3OH/CHCl3 to give the desired tertiary amine (167) as an oil. LC-MS (M+1): 482.5; 1H NMR (6, CDCl3): 7.87 (d, J=7.2 Hz, 2H), 7.47 (d, J=4.4 Hz, 4H), 7.33-7.43 (m, 4H), 6.77 (s, 1H), 6.70 (s, 2H), 5.92 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.42 (m, 4H), 1.21 (m, 2H), 0.83 (t, J=7.6 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H) ppm.

Example 13

Preparation of an Aryltriazole: Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-amine (171)

[0354]

[0355] N-Butyl-oxalamic acid ethyl ester (168). Ethyl oxalyl chloride (1.1 eq.) is added slowly to a mixture of n-butylamine (7.31 g, 0.1 mol) and triethylamine (1.2 eq.) in DCM (60 mL) at 0° C., stirred at 0° C. for 2 hours. The reaction mixture is quenched with water, washed with 2N NaOH, 2N HCl and brine, dried with anhydrous Na2SO4, and concentrated. The residue is taken up in ether and the solid removed. The filtrate is concentrated and the residue is taken up in ether, and filtered to remove a slight amount of solid. The filtrate is concentrated to give the product (168). 1HNMR(CDCl3): δ=4.32(2H, q, —OCH2—), 3.32(2H, q, —NHCH2—), 1.30-1.60(7H, m), 0.92(3H, t, —OCH2CH3)

[0356] 4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169). Starting material (168) is taken up in 35 ml thionyl chloride, refluxed for 2.5 hours, cooled to room temperature, and the excess thionyl chloride removed. The residue is taken up in 50 ml toluene, benzoic hydrazide (1.0 eq.) is added, the mixture is stirred at room temperature overnight and then refluxed for 2.5 hours. The reaction mixture is cooled to room temperature, mixed with water, and washed with water and brine. Purification by column chromatography with hexane/ethyl acetate gives the product (169). 1HNMR(CDCl3): δ=7.52-7.60(5H, m, phenyl-H), 4.50(2H, q, J=7.2 Hz, —OCH2CH3), 4.34(2H, t, J=7.5 Hz, N—CH2-n-C3H7), 1.60-1.80 (2H, m, —CH2—), 1.47(3H, t, J=7.2 Hz, —CH3), 1.18-1.38(2H, m, —CH2—), 0.83(3H, t, J=7.5 Hz, —CH3)

[0357] (4-Butyl-5-phenyl-4H-[1,2,4]triazol-3-yl)-methanol (170). 4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169) (1.38 g, 5 mmol) is taken up in 50 ml anhydrous THF. LAH is added (3 eq.). The reaction is refluxed for 12 hours and then quenched carefully with water. Purification by column with 2.5% MeOH/DCM gives the desired product (170). 1HNMR(CDCl3): δ=7.40-7.60(5H, m, phenyl-H), 4.88(2H, s, —CH2OH), 4.26(1H, br, —OH), 4.10(2H, t, J=7.8 Hz, —CH2—), 1.58-1.70(2H, m, —CH2—), 1.08-1.30(2H, m, —CH2—), 0.82(3H, t, J=7.5 Hz, —CH3)

[0358] Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-amine (171) (4-Butyl-5-phenyl-4H-[1,2,4]triazol-3-yl)-methanol (170) (174 mg, 0.75 mmol) is taken up in 5 ml anhydrous DCM, triethylamine (1.2 eq.) is added, MsCl (1.1 eq.) is added at 0° C., and the reaction is then stirred at room temperature for 2 hours, concentrated, and the residue dried on high vacuum for 2 hours. The residue is mixed with amine (1.0 eq.) and K2CO3(2.0 eq.) in 5 ml anhydrous CH3CN and refluxed for 15 hours. The reaction mixture is filtered and washed with ethyl acetate. Purification by column chromatography with hexane/ethyl acetate yields the desired product (171). Treatment with 1.0M HCl in ether gives a white solid HCl salt. 1HNMR(For free amine, CDCl3): δ=7.40-7.60(5H, m, phenyl-H), 6.79(1H, s, phenyl-H), 6.74(1H, s, phenyl-H), 6.73(1H, s, phenyl-H), 5.90(2H, s, —OCH2O—), 3.98(2H, t, J=7.6 Hz, triazole-N—CH2—), 3.75(2H, s, triazole-CH2—N—), 3.50(s, 2H, phenyl-CH2N—), 2.49(2H, t, J=7.2 Hz, —CH2-nC3H7), 1.40-1.58(2H, m, —CH2—), 1.20-1.40(4H, m, —CH2—), 0.84(3H, t, J=7.2 Hz, —CH3), 0.72(3H, t, J=7.2 Hz, —CH3) LC-MS: RT=2.76 min, M+1: 421.21

Example 14

Preparation of a Mixture of 5-Arylpyrazoles: Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-1-methyl-5-phenyl-1H-pyrazol-3-ylmethyl)-amine and benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-2-methyl-5-phenyl-11H-pyrazol-3-ylmethyl)-amine (179)

[0359]

[0360] 3-Benzoyl-2-oxo-heptanoic acid ethyl ester (172). Diethyl oxalate (7.31 g, 0.05 mol) is added to freshly made sodium ethoxide (1.05 eq.) in ethanol. Hexanophenone (8.81 g, 0.05 mol) is added dropwise, and the resulting mixture is stirred at room temperature overnight. After concentration the residue is partitioned between 3N HCl and ethyl acetate, extracted with ethyl acetate. Combined organic layers are washed with brine and dried with anhydrous Na2SO4. Purification by column chromatography with hexane/ethyl acetate gives the product (172).

[0361] 4-Butyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (173). Diketone and hydrazine hydrochloride (1.05 eq.) are taken up in 50 ml ethanol and refluxed overnight. Purification by column with hexane/ethyl acetate provides the product (173). 1HNMR(CDCl3): δ=10.6(1H, br, pyrazole-NH), 7.40-7.60(5H, m, phenyl-H), 4.42(2H, q, J=7.2 Hz, —COOCH2—), 2.83(2H, t, J=7.8 Hz, pyrazole-CH2—), 1.20-1.70(4H, m, —CH2CH2—), 0.89(3H, t, J=7.2 Hz, —CH3)

[0362] 4-Butyl-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (175) and 4-Butyl-2-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (174). Starting material (173) (795 mg, 2.92 mmol) is dissolved in 30 ml anhydrous DMF. Potassium carbonate (3 eq.) is added followed by the addition of iodomethane (5 eq.). The resulting mixture is stirred at room temperature for 15 hours, until TLC shows the reaction is complete. The reaction is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried with anhydrous Na2SO4. Purification by column chromatography with hexane/ethyl acetate gives the 1-methyl substituted (175) and 2-methyl substituted products (174).

[0363] 1-methyl Substituted Pyrazole:

[0364]

1
H NMR(CDCl3): δ=7.50-7.60(2H, m, phenyl-H), 7.30-7.50(3H, m, phenyl-H), 4.40(2H, q, J=7.2 Hz, —COOCH2—), 4.18(3H, s, —NCH3), 2.77(2H, t, J=7.8 Hz, pyrazole-CH2—), 1.30-1.60(7H, m, —CH2CH2CH3), 0.89(3H, t, J=7.2 Hz, —CH3)

[0365] 2-methyl Substituted Pyrazole:

[0366]

1
H NMR(CDCl3): δ=7.40-7.60(3H, m, phenyl-H), 7.20-7.30(2H, m, phenyl-H), 4.43(2H, q, J=7.2 Hz, —COOCH2—), 3.78(3H, s, —NCH3), 2.59(2H, t, J=7.8 Hz, pyrazole-CH2—), 1.38-1.50(5H, m, —CH2 and —CH3), 1.18-1.30(2H, m, —CH2—), 0.79(3H, t, J=7.2 Hz, —CH3)

[0367] (4-Butyl-1-methyl-5-phenyl-1H-pyrazol-3-yl)-methanol (177). 1-methyl substituted pyrazole compound (175) (380 mg) is dissolved in 30 ml anhydrous THF.1.0 M DIBAL-H (13 ml, 10 eq.) is added dropwise at −78° C. The resulting mixture is warmed naturally to room temperature and stirred overnight. The reaction is quenched with saturated Na2SO4. The resulting mixture is filtered and dried with anhydrous Na2SO4. Concentration provides the crude product (177). 1H NMR(CDCl3): δ=7.50-7.60(2H, m, phenyl-H), 7.30-7.50(3H, m, phenyl-H), 4.63(2H, d, —CH2OH), 3.95(3H, s, —NCH3), 2.58(2H, t, pyrazole-CH2—), 1.30-1.60(4H, m, —CH2CH2—), 0.90(3H, t, —CH3) LC-MS: RT=2.57 min, M+1: 245.23

[0368] Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-2-methyl-5-phenyl-1H-pyrazol-3-ylmethyl)-amine (179). 1-methyl substituted pyrazole alcohol (177) (110 mg) is dissolved in anhydrous DCM (4 mL) and triethylamine (1.2 eq.) is added. MsCl is added at 0° C. and the mixture is stirred at room temperature for 2 hours, concentrated, and dried on high vacuum for 30 minutes The residue is dissolved in 5 ml anhydrous CH3CN followed by the addition of amine (1.2 eq.) and potassium carbonate (5 eq.). The resulting mixture is refluxed for 12 hours. The reaction solution is filtered and washed with ethyl acetate. Purification by column chromatography with hexane/ethyl acetate provides product (179). Treated with 2M HCl in ether to give a white solid. 1H NMR(For free amine, CDCl3): δ=7.58-7.60(2H, m, phenyl-H), 7.26-7.40(3H, m, phenyl-H), 6.81(1H, s, phenyl-H), 6.74(2H, s, phenyl-H), 5.94(2H, s, —OCH2O—), 3.87(3H, s, —NCH3), 3.48(2H, s, pyrazole-CH2—), 3.42(2H, s, —CH2Ph), 2.55(2H, t, J=8.0 Hz, —NCH2—C3H7), 2.37(2H, t, J=7.2 Hz, pyrazole-CH2—), 1.20-1.60(8H, m, 4×(—CH2—)), 0.78-0.90(6H, m, 2×(—CH3))

[0369] LC-MS: RT=2.89 minutes, M+1: 434.28

Example 15

Preparation of Benzo[1,3]dioxol-5-ylmethyl-butyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine (180)

[0370]

[0371] 2-Bromo-1-phenyl-hexan-1-one. CuBr2 (26.6 g, 119.2 mmol) is added in small portions to a solution of 1-phenyl-hexan-1-one (10.5 g, 59.6 mmol) in CHCl3 (80 mL) and EtOAc (80 mL) of over a period of 1 h while the temperature maintained at 75-80° C. Heating is continued for 6 h until the green color disappears. The solid is filtered and washed with EtOAc (80 mL). The combined filtrate is evaporated and the residue is dissolved in EtOAc (200 mL), washed with water (200 mL) and brine (200 mL), and dried over Na2SO4. Evaporation of the solvent in vacuo provides a light yellow oil. LC-MS (M+1) 255. 1H NMR (8, CDCl3) 7.92-8.07 (m, 2H), 7.40-7.61 (m, 3H), 5.13 (t, J=7.2 Hz, 1H), 2.02-2.23 (m, 2H), 1.33-1.57 (m, 4H), 0.92 (t, J=7.4 Hz, 3H).

[0372] 2-(1-Benzoyl-pentyl)-malonic acid dimethyl ester. Small portions of NaH (60%, 7.92 g, 198 mmol) are added to a solution of dimethyl malonate (22.6 ml, 198 mmol) in DMSO (100 mL) at 0 C. The ice bath is removed and the mixture stirred at room temperature for 2 hours. The solution is rechilled to 0° C. and a solution of 2-bromo-1-phenyl-hexan-1-one (2-1) (16.8 g, 66 mmol) in DMSO (50 mL) is added slowly. The ice bath is removed and the mixture stirred overnight. Water (500 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provide the product as a light yellow oil. LC-MS (M+1) 307. 1H NMR (8, CDCl3) 7.98-8.02 (m, 2H), 7.46-7.60 (m, 3H), 4.18-4.28 (m, 1H), 4.03-4.12 (m, 1H), 3.80 (s, 3H), 3.6.1 (s, 3H), 1.55-1.63 (m, 2H), 1.02-1.20 (m, 4H), 0.76 (t, J=0.72 Hz, 3H).

[0373] 3-Benzoyl-heptanoic acid methyl ester. Water (3 ml, 166 mmol) and NaCl (5.3 g, 90.2 mmol) are added to a solution of 2-(1-benzoyl-pentyl)-malonic acid dimethyl ester (25.0 g, 81.7 mmol) in DMSO (150 mL). The mixture is heated at 150° C. for 6 hours. Water (450 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provides 3-Benzoyl-heptanoic acid methyl ester as a light yellow oil. LC-MS (M+1) 249. This compound without further purification is used directly to the next step.

[0374] 5-Butyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one. A solution of 3-benzoyl-heptanoic acid methyl ester (4.72 g, 19 mmol) and hydrazine monohydrate (4.6 ml, 95 mmol) in ethanol (50 mL) is reflux for 12 hours. The solvent and excess hydrazine monohydrate is removed in vacuo and the residue is partitioned with EtOAc (80 mL) and water (80 mL). The layers are separated and the organic phase is washed with brine (60 mL), dried (Na2SO4) and evaporated in vacuo. Flash column chromatography of the residue (silica gel, 2:1 hexane, EtOAc) provides a creamy solid. LC-MS (M+1) 231. 1H NMR (5, CDCl3) 8.84 (s, 1H), 7.72-7.79 (m, 2H), 7.37-7.43 (m, 3H), 3.19-3.30 (m, 1H), 2.62 (d, J=6.8 Hz, 2H), 1.52-1.62 (m, 2H). 1.21-1.43 (m, 4H), 0.87 (t, J=7.8 Hz, 3H).

[0375] 5-Butyl-6-phenyl-2H-pyridazin-3-one. A solution of bromine (0.94 ml, 18.2 mmol) in HOAc (10 mL) is added dropwise to a solution of 5-butyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one (3.8 g, 16.5 mmol) in HOAc (40 mL) at 80° C. After the addition is complete, the heating is continued for 30 minutes and the solvent is evaporated in vacuo. The residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL) and the organic layer washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the desired product as a yellow solid. LC-MS (M+1) 229. 1H NMR (5, CDCl3) 12.39 (s, 1H), 7.39-7.48 (m, 5H), 6.83 (s, 1H), 2.41 (t, J=7.2 Hz, 2H), 1.20-1.43 (m, 4H), 0.77 (t, J=7.7 Hz, 3H).

[0376] 5-Butyl-3-chloro-6-phenyl-pyridazine. 5-butyl-6-phenyl-2H-pyridazin-3-one (3.6 g, 15.8 mmol)) is dissolved in POCl3 (40 mL) and the solution is heated at 85° C. for 3 hours. The excess POCl3 is evaporated in vacuo and the residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL). The organic layer is washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatograph (silica gel, 4:1 hexane, EtOAc) provides a light yellow oil. LC-MS (M+1) 247. 1H NMR (5, CDCl3) 7.47 (s, 5H), 7.42 (s, 1H), 2.62 (t, J=7.2 Hz, 2H), 1.43-1.53(m, 2H), 1.18-1.31 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).

[0377] 5-Butyl-3-chloro-4-hydroxymethyl-6-phenyl-pyridazine. Concentrated H2SO4 (0.17 ml, 3.2 mmol), (NH4)2S2O8 (0.575 g, 2.52 mmol) and AgNO3 (4 mg) are added to a solution of 4-butyl-6-chloro-3-phenyl-pyridazine (0.526 g, 2.1 mmol) in MeOH (12 mL) and water (6 mL). The mixture is heated at 75° C. for 3 h and the solvent is then evaporated in vacuo. The residue is partitioned between saturated aqueous NaHCO3 solution (30 mL) and EtOAc (30 mL) and the organic layer is washed with water (25 mL), brine (25 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatography (silica gel, 2:1 hexane, EtOAc) provides the product as a light yellow solid. LC-MS (M+1) 277. 1H NMR (o, CDCl3) 7.42-7.50 (m, 5H), 4.87 (s, 2H), 2.75 (t, J=8.1 Hz, 2H), 2.40 (s, 1H), 1.34-1.43 (m, 2H), 1.17-1.25 (m, 2H), 0.74 (t, J=7.5 Hz, 3H).

[0378] 5-Butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride. To a solution of 4-butyl-6-chloro-5-hydroxymethyl-3-phenyl-pyridazine (0.32 g, 1.16 mmol) in CH2Cl2 (5 mL) is added SOCl2 (2 mL). The resulting clear solution is stirred at room temperature for 3 hours. The solvent is removed in vacuo and the residue is dissolved in toluene (5 mL) and evaporated to remove the remaining SOCl2. The resulting semi-solid is used directly for the next step. LC-MS (M+1) 295.

[0379] Benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine. Piperonylamine (0.37 ml, 3 mmol) and K2CO3 (0.69 g, 3 mmol) are added to a solution of 5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride (0.176 g, 0.6 mmol) in CH3CN (12 mL). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatography (silica gel, 10:0.5:0.05 CH2Cl2, MeOH, NH4OH) of the residue provides a light yellow oil. LC-MS (M+1) 410. 1H NMR (6, CDCl3) 7.41-7.49 (m, 5H), 6.87 (s, 1H), 6.74-6.82 (m, 2H), 5.94 (s, 2H), 3.87 (s, 2H), 3.81 (s, 2H), 2.59 (t, J=7.8 Hz, 2H), 1.81 (s, 1H), 1.25-1.35 (m, 2H), 1.07-1.17 (m, 2H), 0.70 (t, J=7.2 Hz, 3H).

[0380] Benzo[1,3]dioxol-5-ylmethyl-butyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine. PrCHO (0.036 ml, 0.4 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine (0.04 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 min, NaBH(OAc)3 (0.127 g, 0.6 mmol) is then added and the mixture is stirred overnight. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Preparative TLC (10:0.5:0.05 CH2Cl2, MeOH, NH4OH) provides the purified product as a light yellow oil. LC-MS (M+1) 466. 1H NMR (6, CDCl3) 7.39-7.47 (m, 5H), 6.77 (s, 1H), 6.70 (s, 2H), 5.90 (s, 2H), 3.76 (s, 2H), 3.49 (s, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 1.45-1.54 (m, 2H), 0.92-1.32 (m, 6H), 0.82 (t, J=7.2 Hz, 3H), 0.63 (t, J=7.2 Hz, 3H).

Example 16

Preparation of Bis-benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine (181)

[0381]

[0382] Piperonyl (0.06 g, 0.4 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine (0.042 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 minutes, NaBH(OAc)3 (0.127 g, 0.6 mmol) is then added and the mixture is stirred overnight. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), and the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the compound shown above as a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil. LC-MS (M+1) 544. 1H NMR (8, CDCl3) 7.37-7.48 (m, 5H), 6.77 (s, 2H), 6.72 (s, 4H), 5.91 (s, 4H), 3.78 (s, 2H), 3.49 (s, 4H), 2.69 (t, J=7.2 Hz, 2H), 0.85-1.02 (m, 4H), 0.59 (t, J=7.0 Hz, 3H).

Example 17

Preparation of Benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-(3-ethoxy-benzyl)-amine (182)

[0383]

[0384] 3-Ethoxybenzaldehyde (0.062 ml, 0.44 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine) (0.045 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 minutes, NaBH(OAc)3 (0.140 g, 0.66 mmol) is then added and the mixture is stirred over night. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the product shown above as a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides purified product as a light yellow oil. LC-MS (M+1) 544. 1H NMR (6, CDCl3) 7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.70-6.87 (m, 6H), 5.91 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.52 (s, 2H), 2.70 (t, J=7.5 Hz, 2H), 1.41 (t, J=7.2 Hz, 2H), 0.84-1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).

Example 18

Preparation of (5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (183)

[0385]

[0386] (2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (0.211 g, 0.7 mmol) and K2CO3 (0.69 g, 3 mmol) is added to a solution of 5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride (0.175 g, 0.6 mmol) in CH3CN (15 mL). The mixture is stirred at 80° C. overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The organic layer is washed with water (15 mL), brine (15 mL), then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil. LC-MS (M+1) 558 1H NMR (8, CDCl3) 7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.72-6.89 (m, 6H), 4.21 (s, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.50 (s, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.41 (t, J=6.9 Hz, 3H), 0.84-1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).

Example 19

Preparation of Bis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine (191)

[0387]

[0388] (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187). Triethylamine (1.0 ml, 7.18 mmol) and methanesulfonyl chloride (0.37 ml, 4.89 mmol) are added to a stirred solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-methanol (1.0 g, 3.26 mmol)(185) in anhydrous acetonitrile (30 mL) at 0° C. After proceeding for 1 hour the reaction is concentrated at 60° C. to remove all solvent and excess MsCl. Cold acetonitrile is added to precipitate triethylammonium chloride, which is then removed by filtration. The remaining solution of mesylate product is reduced to a 30 ml volume; tetraethylammonium cyanide (1.53 g, 9.79 mmol) is added to the solution, and the reaction is heated at 60° C. overnight. Solvent is removed in vacuo and the crude product dissolved in ethyl acetate (100 mL). The organic layer is washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL) and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) as a light orange oil.

[0389] (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188). Hydrogen chloride gas is bubbled into solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03 mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirring for 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and the reaction refluxed at 80° C. for 2 hours. The methanol is then removed in vacuo, the reaction crude is dissolved in ethyl acetate (100 mL) and the organic layer is washed with saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 ethyl acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) as a colorless oil.

[0390] (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (189) 5N sodium hydroxide (100 mL) is added to a solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) (460 mg, 1.32 mmol) in ethanol (100 mL). The mixture is stirred at 85° C. for 4 hours. All ethanol is removed in vacuo and the crude extracted with ethyl ether (2×50 mL). The aqueous fraction is then acidified to pH 2 using 1M HCl and the product extracted into ethyl acetate (100 mL). The organic fraction is washed with water (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. Concentration in vacuo affords (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (189) as a white foam.

[0391] N,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide (190). Triethylamine (0.23 ml, 1.64 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (330 mg, 0.748 mmol) are added to a solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (250 mg, 0.748 mmol) (189) in N,N-dimethylformamide (15 mL) and the reaction mixture is allowed to stir overnight at room temperature. The reaction is diluted with ethyl ether (100 mL) and the organic layer washed with saturated sodium bicarbonate (3×100 mL), brine (1×100 mL), and is dried over magnesium sulfate. The crude is filtered, concentrated in vacuo, and flash chromatographed on SiO2 using an eluent of 1:1 ethyl ether:hexane to afford N,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide (190) as a colorless waxy solid.

[0392] Bis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine (191). A solution of N,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide (150 mg, 0.249 mmol) in tetrahydrofuran (25 mL) is cooled to 0° C. under a nitrogen atmosphere. Lithium aluminum hydride (95%, 30 mg, 0.747 mmol) is added in one portion and the reaction allowed to stir overnight warming to room temperature. Water (0.03 mL), sodium hydroxide (15% solution, 0.03 mL), and water (0.09 mL) are added and the reaction mixture is allowed to stir at 0° C. for 15 minutes. Magnesium sulfate is then added and the crude solution is filtered through a bed of Celite washing with 2% methanol in dichloromethane (100 mL). The crude sample is concentrated in vacuo and flash chromatographed on SiO2 using an eluent of dichloromethane:methanol 95:5 to afford bis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine as a colorless syrup.

Example 20

Preparation of (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine

[0393]

[0394] Step 1. Preparation of 2-Butyl-3-dimethylamino-1-phenyl-propenone

[0395] A solution of hexanophenone (1.76 g, 10.0 mmol) in dimethylformamide dimethyl acetal (DMF-DMA) (7.07 ml, 50.0 mmol) is stirred at 150° C. in a sealed tube for 16 hours. After cooling, the solution is concentrated in vacuo. EtOH is added and then removed in vacuo in order to aid in the removal of DMF and DMF-DMA. 2-Butyl-3-dimethylamino-1-phenyl-propenone is obtained as an orange oil and is used directly in the next reaction. 1H NMR (CDCl3, 300 MHz) δ 7.42-7.39 (m, 2H), 7.36-7.32 (m, 3H), 6.80 (s, 1H), 3.01 (s, 6H), 2.61-2.56 (m, 2H), 1.48-1.36 (m, 4H), 0.93 (t, J=7.2 Hz, 3H) ppm.

[0396] Step 2. Preparation of 5-butyl-4-phenyl-pyrimidine

[0397] Crude 2-butyl-3-dimethylamino-1-phenyl-propenone is dissolved in EtOH (5-6 mL) and treated with formamidine acetate (3.12 g, 30.0 mmol). The reaction mixture is then stirred at 120° C. in a sealed tube for 6 hours. After cooling, the reaction mixture is partitioned between EtOAc and H2O (50 mL). The layers are separated, and the organic layer is washed with additional H2O (50 mL) and brine (50 mL). The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 3:1 EtOAc-hexanes affords pure 5-butyl-4-phenyl-pyrimidine as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 9.11 (s, 1H), 8.64 (s, 1H), 7.55-7.46 (m, 5H), 2.73-2.68 (m, 2H), 1.56-1.45 (m, 2H), 1.27 (sext, J=7.2 Hz, 2H), 0.83 (t, J=7.2 Hz, 3H) ppm. MS: m/z 213 [M+1].

[0398] Step 3. Preparation of 5-butyl-4-methyl-6-phenyl-pyrimidine

[0399] 1.4 M MeLi in Et2O (1.54 ml, 2.16 mmol) is slowly added to a solution of 5-butyl-4-phenyl-pyrimidine (436 mg, 2.05 mmol) in Et2O (6 mL) at −30° C. under N2. The reaction mixture is stirred at −30° C. for 30 minutes and then at 0° C. for 45 minutes. Next, a solution of AcOH (0.12 mL) and H2O (0.02 mL) in THF (2 mL) is added, followed by a solution of 2,3-dichloro-5,6-dicyano-1,4-benzophenone (DDQ) (466 mg, 2.05 mmol) in THF (5 mL). The resulting mixture is stirred at room temperature for 5 minutes, recooled to 0° C., and then treated with 3.0 M aqueous NaOH. The mixture is stirred at 0° C. for 5 minutes, diluted with H2O, and extracted twice with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The dark residue is purified by flash chromatography on silica gel. Elution with 2:1 Hex-EtOAc followed by 1:1 hexanes-EtOAc affords 5-butyl-4-methyl-6-phenyl-pyrimidine as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.95 (s, 1H), 7.45 (m, 5H), 2.67-2.62 (m, 2H), 2.61 (s, 3H), 1.48-1.40 (m, 2H), 1.25 (sext, J=7.2 Hz), 0.82 (t, J=7.2 Hz, 3H) ppm. MS: m/z 227 [M+1].

[0400] Step 4. Preparation of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine

[0401] A solution of 5-butyl-4-methyl-6-phenyl-pyrimidine (320 mg, 1.14 mmol) and Br2 (0.08 ml, 1.48 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is then partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 3:1 hexanes-EtOAc affords 4-bromomethyl-5-butyl-6-phenyl-pyrimidine and a small amount of an unidentified impurity. 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 1H), 7.47 (s, 5H), 4.57 (s, 2H), 2.79-2.74 (m, 2H), 1.52-1.42 (m, 2H), 1.38-1.20 (m, 2H), 0.80 (t, J=7.4 Hz, 3H) ppm.

[0402] Step 5. Preparation of (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine

[0403] A mixture of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine (86 mg), (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (93 mg, 0.310 mmol), and K2CO3 (195 mg, 1.4 mmol) in CH3CN (2.0 mL) is stirred at reflux for 1 h and at room temperature for 16 hours. The reaction mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the residue purified by preparative TLC, developing with 2:1 hexanes-EtOAc (+0.5% Et3N). The band containing product affords pure (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine. 1H NMR (CDCl3, 300 MHz) δ 8.98 (s, 1H), 7.42 (m, 5H), 7.19 (t, J=8.0 Hz, 1H), 6.92-6.73 (m, 6H), 4.22 (s, 4H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s, 2H), 3.60 (s, 2H), 3.54 (s, 2H), 2.70-2.64 (m, 2H), 1.41 (t, J=6.9 Hz, 3H), 1.09-0.99 (m, 2H), 0.91 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 524 [M+1].

Example 21

Preparation of 4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic Acid

[0404]

[0405] Step 1. Preparation of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

[0406] Sodium metal (1.85 g, 80.5 mmol) is dissolved in EtOH (50 mL). Next, thiourea (5.11 g, 67.1 mmol) is added to the NaOEt solution, followed by ethyl 2-n-butylacetoacetate (2.5 g, 13.4 mmol). The reaction mixture is stirred at reflux for 3 hours and then allowed to cool to room temperatute overnight. The EtOH is removed in vacuo. The residue is then suspended in H2O (50 mL) and the resulting mixture carefully treated with concentrated HCl (7.5 mL) just until pH 4 is reached. After stirring for 15 minutes, the suspension is filtered, and the solid thoroughly washed with H2O. Drying affords pure 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a slightly off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.28 (br s, 1H), 12.05 (br s, 1H), 2.21 (m, 2H), 2.18 (s, 3H), 1.30-1.21 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 199 [M+1].

[0407] Step 2. Preparation of 5-butyl-6-methyl-1H-pyrimidine-2,4-dione

[0408] A suspension of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one in 10% aqueous chloroacetic acid (100 mL) is stirred at reflux for 3 hours and then allowed to cool to room temperature. The suspension is cooled in an ice bath for a few minutes and then filtered. The solid is thoroughly washed with H2O and dried, yielding pure 5-butyl-6-methyl-1H-pyrimidine-2,4-dione as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 10.86 (br s, 1H), 10.57 (br s, 1H), 2.17 (m, 2H), 2.01 (s, 3H), 1.25 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 183 [M+1 ].

[0409] Step 3. Preparation of 5-Butyl-2,4-dichloro-6-methyl-pyrimidine

[0410] A mixture of 5-butyl-6-methyl-1H-pyrimidine-2,4-dione (1.76 g, 9.66 mmol) in POCl3 (15 mL), containing DMF (0.065 mL) is stirred at reflux for 4 hours. After cooling, the yellow solution is concentrated in vacuo. The flask is placed in an ice bath, and crushed ice (−50-100 g) is added to the residue. The mixture is stirred vigorously until the ice melts. The mixture is then extracted with EtOAc. The extract is washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to provide pure 5-butyl-2,4-dichloro-6-methyl-pyrimidine as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.74-2.57 (m, 2H), 2.56 (s, 3H), 1.55-1.40 (m, 4H), 0.97 (t, J=7.1 Hz, 3H) ppm. MS: m/z 219 [M+1].

[0411] Step 4. Preparation of 5-Butyl-2-chloro-4-methyl-6-phenyl-pyrimidine

[0412] A mixture of 5-butyl-2,4-dichloro-6-methyl-pyrimidine (711 mg, 3.24 mmol), phenylboronic acid (475 mg, 3.89 mmol), Na2CO3 (1.03 g, 9.73 mmol), and Pd(PPh3)4 (187 mg, 0.162 mmol) in toluene-EtOH—H2O (4 ml-0.5 ml-2 mL) is stirred at relux for 6 hours. After cooling, the reaction mixture is diluted with H2O and extracted with EtOAc. The extract is then washed with brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 8:1 hexanes-EtOAc followed by 7:1 hexanes-EtOAc affords 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.45 (m, 5H), 2.65-2.62 (m, 2H), 2.60 (s, 3H), 1.46-1.36 (m, 2H), 1.25 (sext, J=7.2 Hz, 2H), 0.81 (t, J=7.2 Hz, 3H) ppm.

[0413] Step 5. Preparation of 4-Bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine

[0414] A solution of the 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine (215 mg, 0.825 mmol) and Br2 (0.042 ml, 0.825 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated to 305 mg of crude 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine, which also contains small amounts of SM and dibromo material. This material is used without further purification.

[0415] Step 6. Preparation of 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic Acid Methyl Ester

[0416] A solution of impure 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (288 mg) and 4-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (190 mg, 0.606 mmol) in CH3CN containing K2CO3 (300 mg) is stirred at room temperature. The reaction is monitored by TLC until complete consumption of 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (24 hours). The mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the resulting residue is purified by flash chromatography on silica gel. Elution with 5:1 hexanes-EtOAc followed by 4:1 hexanes-EtOAc affords 215 mg of pure 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, J=8.1 Hz, 2H), 7.44-7.33 (m, 7H), 6.84 (s, 1H), 6.79 (s, 2H), 4.22 (s, 4H), 3.90 (s, 3H), 3.74 (s, 2H), 3.72 (s, 2H), 3.55 (s, 2H), 2.64-2.56 (m, 2H), 1.01 (m, 2H), 0.90 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 572 [M+1].

[0417] Step 7. Preparation of 4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo [1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic Acid

[0418] NaH (60% dispersion in mineral oil) (40 mg) is added to a solution of 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (46 mg, 0.0804 mmol) in THF (3 mL) containing isobutyl alcohol (0.5 mL) at room temperature. The mixture is stirred at room temperature for 5 minutes and then at reflux for 2 hours. Next, H2O (0.5 mL) is added and heating is continued for an additional 30 minutes. After cooling to room temperature, the reaction mixture is treated with a few drops of AcOH until pH 4-5. The mixture is then diluted with H2O and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by preparative TLC, eluting with 20:1 CHCl3-MeOH. The band containing the product affords 28.4 mg 4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid as a colorless gum. 1H NMR (CDCl3, 300 MHz) δ 8.02 (br, 2H), 7.39 (br, 7H), 6.87 (br s, 1H), 6.78 (br s, 2H), 4.21 (br s, 4H), 4.12 (br d, J=6.3 Hz, 2H), 3.70 (br, 4H), 3.54 (br s, 2H), 2.54 (br m, 2H), 2.13 (br, 1H), 1.02 (d, J=6.3 Hz, 6H), 0.94 (br 4H), 0.60 (br, 3H) ppm. MS: m/z 596 [M+1].

Example 22

Preparation of 5-{3-[(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-ol and 5-{3-[(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo [1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol

[0419]

[0420] Step 1. Preparation of 5-(3-benzyloxy-isoxazol-5-yl)-propenal (Major) and 5-(3-benzyloxy-isoxazol-5-yl)-penta-2,4-dienal

[0421] (Triphenylphosphoranylidene)acetaldehyde (785 mg, 2.58 mmol) is added in one portion to a solution of 3-benzyloxy-isoxazole-5-carbaldehyde (403 mg, 1.98 mmol) (prepared according to Eur. J. Org. Chem. 1998, 473-479) in 5:1 toluene-CH3CN (12 mL) at room temperature. The reaction mixture is stirred at room temperature overnight. The dark solution is then concentrated in vacuo, and the residue purified by flash chromatography on silica gel. Elution with 4:1 hexanes-EtOAc affords an approximately 2:1 mixture of 3-(3-benzyloxy-isoxazol-5-yl)-propenal (major) and 5-(3-benzyloxy-isoxazol-5-yl)-penta-2,4-dienal (minor). Diagnostic 1H NMR signals: Major: 1H NMR (CDCl3, 300 MHz) δ 9.72 (d, J=7.8 Hz, 1H), 6.24 (s, 1H), 5.31 (s, 2H) ppm. Minor: 1H NMR (CDCl3, 300 MHz) δ 9.66 (d, J=7.8 Hz, 1H), 6.04 (s, 1H), 5.30 (s, 2H) ppm.

[0422] A solution of the enal mixture in 10 ml of EtOAc containing a catalytic amount of 10% Pd/C is stirred under an atmosphere of H2 (double-stuffed balloon) for 6 hours. The reaction mixture is then filtered through a pad of Celite. The filtrate is concentrated to a colorless oil, which is used without further purification.

[0423] Step 2. Preparation of of [3-(3-benzyloxy-isoxazol-5-yl)-propyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine (Major) and [5-(3-benzyloxy-isoxazol-5-yl)-pentyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine (Minor)

[0424] 5 drops of AcOH is added to a solution of (3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine (134 mg, 0.325 mmol) and the crude aldehyde mixture from the previous reaction (75 mg) in 1,2-dichloroethane (5 mL). The mixture is stirred at rt for 15 min., and then NaBH(OAc)3 (103 mg, 0.488 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 60 hours. Next, half saturated NaHCO3 is added. The resulting mixture is stirred for 15 minutes, and then extracted two times with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by preparative TLC, to afford an inseparable mixture of [3-(3-benzyloxy-isoxazol-5-yl)-propyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine (major) and [5-(3-benzyloxy-isoxazol-5-yl)-pentyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine (minor). Diagnostic 1H NMR signals: Major: 1H NMR (CDCl3, 300 MHz) δ 5.52 (s, 1H), 5.21 (s, 2H) ppm. Minor: 1H NMR (CDCl3, 300 MHz) δ 5.61 (s, 1H), 5.23 (s, 2H) ppm. MS: m/z 627 [M+1] (major) and 655 [M+1] (minor).

[0425] Step 3. Preparation of 5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-ol and 5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol

[0426] A solution of the amine mixture from the previous reaction in 30% HBr in AcOH (5 mL) is stirred at room temperature overnight. The solution is concentrated in vacuo, and the residue is purified by reversed phase HPLC in order to separate the two amines. The pure fractions are concentrated to approximately 10% of their original volume. The remaining mixtures are treated with a few drops of AcOH in order to adjust the pH to approximately 4. The mixtures are then extracted three times with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated to the pure amines as colorless gums.

[0427] 5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-ol: 1H NMR (CDCl3, 300 MHz) δ 7.52-7.49 (m, 2H), 7.44-7.40 (m, 3H), 6.81-6.73 (m, 3H), 5.50 (s, 1H), 4.22 (s, 4H), 3.95 (m, 2H), 3.52 (s, 2H), 3.46 (s, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.51 (t, J=6.8 Hz, 2H), 1.83 (pent, J=7.2 Hz, 2H), 1.40-1.28 (m, 2H), 1.99 (sext, J=7.2 Hz, 2H), 0.71 (t, J=7.2 Hz, 3H) ppm. MS: m/z 537 [M+1].

[0428] 5-{5-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol: 1H NMR (CDCl3, 300 MHz) δ 7.52-7.49 (m, 2H), 7.44-7.39 (m, 3H), 6.81-6.72 (m, 3H), 5.60 (s, 1H), 4.21 (s, 4H), 3.97 (m, 2H), 3.51 (s, 2H), 3.44 (s, 2H), 2.57 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.61-1.25 (m, 8H), 1.02 (sext, J=7.2 Hz, 2H), 0.73 (t, J=7.2 Hz, 3H) ppm. MS: m/z 565 [M+1].

Example 23

Preparation of Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-phenyl-2-o-tolyl-3H-imidazol-4-ylmethyl)-amine

[0429]

[0430] To the suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in 30 ml of anhydrous DMF is added a solution of 4-phenylimidazole (7.21 g, 50 mmol) in 30 ml of DMF at room temperature, the resulting mixture is stirred at 70° C. 1 h, and then cooled to room temperature followed by the dropwise addition of iodobutane (9.66 g, 52.5 mmol, 1.05 eq.). The mixture is stirred at room temperature for 1 h, heated to 70° C. and stirred for an additional 8 h. The reaction mixture is cooled to room temperature, poured into 200 ml of ice-water, extracted with ethyl acetate (100 ml×3). The combined organics are washed with water, brine, dried over anhydrous sodium sulfate, filtered, evaporated at reduced pressure and purified by flash chromatography on silica gel to obtain 9.08 g of 1-butyl-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d, J=7.6 Hz), 7.49 (1H, s), 7.36 (2H, t, J=7.6 Hz), 7.23(1H, m), 7.20 (1H, s), 3.95 (2H, t, J=7.2 Hz), 1.80 (2H, m), 1.36 (2H, m), 0.96 (3H, t, J=7.2 Hz); MS (+VE) m/z 201 (M+1).

[0431] To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml of anhydrous THF at −78° C. under nitrogen is added a solution of n-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 h follwed by dropwise addition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml of THF. The resulting solution is stirred at −78° C. for 30 min. and then warmed to room temperature. Saturated ammonium chloride (30 mL) is added to quench the reaction. The resulting mixture is evaporated a reduced pressure to remove THF, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords 5.73 g of 1-butyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24 (1H, m), 3.92 (2H, t, J=7.2 Hz), 1.79 (2H, m), 1.41 (2H, m), 0.98 (3H, t, J=7.2 Hz); MS (+VE) m/z 327 (M+1).

[0432] To a 60 ml sealed flask is added 1-butyl-2-iodo-4-phenylimidazole (3.26 g, 10 mmol) followed by the addition of 5.5 ml of acetic acid, 16 ml of 37% formaldehyde and 7 g of sodium acetate. The resulting mixture is stirred at 115° C. for 10 h, cooled to room temperature and diluted 50 ml of water. The reaction mixture is adjusted to pH=9, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 2:1) affords 3.24 of 1-butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.59 (2H, dd, J=1.6, 6.8 Hz), 7.39 (2H, m), 7.31 (1H, m), 4.78 (2H, s), 4.00 (2H, t, J=8.0 Hz), 1.78 (2H, m), 1.46 (2H, m), 1.00 (3H, t, J=7.2 Hz); MS (+VE) m/z 357(M+1).

[0433] 1-Butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole (1.96 g, 6.1 mmol) is dissolved in 20 ml dichloromethane and cooled to 0° C. To the solution is added 5 equivalents of thionyl chloride and the resulting solution is stirred at room temperature for 2 h. The reaction mixture is evaporated at reduced pressure and 20 ml of toluene is added to the residue and evaporated to remove any residual thionyl chloride. The crude product is dissolved in 20 ml of anhydrous acetonitrile and added to an ice-cooled solution of piperonyl amine (2.0 eq.) in acetonitrile (10 mL) containing potassium carbonate (2 eq.). The resulting mixture is stirred at room temperature for 4 h, diluted with 100 ml of ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated at reduced pressure. The residue is purified by silica gel chromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to give 2.28 g of 1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole. MS (+VE) m/z 490 (M+1).

[0434] To a solution of 1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole (1.22 g, 2.5 mmol) in 1,2-dichloroehane (10 mL) is added piperonal (750 mg, 5.0 mmol, 2.0 eq) followed by 10 drops of acetic acid. The solution is stirred at room temperature for 2 h, sodium triacetoxyborohydride (1.1 g, 5.0 mmol, 2.0 eq.) is added and the resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with 50 ml of dichloromethane, washed with water and brine, dried and concentrated. The residue is purified by silica gel flash chromatography (hexanes/ethyl acetate, from 8:1 to 4:1) to afford bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine. 1H NMR (400 MHz, CDCl3) δ 7.57 (2H, m), 7.39 (2H, m), 7.31 (1H, m), 6.70-6.73 (4H, m), 6.64 (2H, d, J=8.0 Hz), 5.94 (4H, s), 4.01 (2H, t, J=6.8 Hz), 3.71 (2H, s), 3.32 (4H, s), 1.41 (2H, m), 1.15 (2H, m), 0.88 (3H, t, J=7.6 Hz); MS (+VE) m/z 624 (M+1).

[0435] To a solution of bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine (62 mg, 0.1 mmol) and Pd(PPh3)4 (6 mg) in 1 ml of toluene is added aqueous sodium carbonate (0.4 ml of 2.0 N) and 2-methylphenyl boronic acid (18 mg, 0.13 mmol, 1.3 eq.) in 0.3 ml of ethanol under nitrogen, the resulting mixture is stirred at 100° C. for 8 h. After being cooled to room temperature, the reaction mixture is diluted with 10 ml of ethyl acetate, washed with water and brine and dried over sodium sulfate. Concentration and purification by flash chromatography affords 43 mg of bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-phenyl-2-o-tolyl-3H-imidazol-4-ylmethyl)-amine 1H NMR (400 MHz, CDCl3) δ 7.70 (2H, d, J=7.2 Hz), 7.43-7.24 (7H, m), 6.776.67 (6H, m), 5.94 (4H, s), 3.87 (2H, t, J=7.6 Hz), 3.78(2H, s), 3.37 (4H, s), 2.20 (3H,s), 1.17 (2H, m), 0.88 (2H, m), 0.63 (3H, t, J=7.2 Hz); MS (+VE) m/z 588 (M+1).

Example 24

Preparation of 4-({[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-hydroxy-benzamide

[0436]

[0437] To a solution of benzamidine hydrochloride (31.22 g, 0.2 mmol, 1.17 eq.) in 250 ml of DMF is added potassium carbonate (69 g, 0.5 mol). 2-bromo-4′-methoxyacetophnone is dissolved in 200 ml of DMF and added to the reaction flask dropwise at 55° C. After the addition, the reaction mixture is stirred at 60° C. for 3 h, then cooled to room temperature and poured into 1000 ml of ice-water, the mixture is extracted with ethyl acetate (150 ml×4), washed with water and brine, dried over sodium sulfate, purified through flash chromatography to give 30 g of 2-phenyl-4-(4-methoxyphenyl)imidazole. 1H NMR (400 MHz, CDCl3) δ 7.86 (2H, d, J=6.8 Hz), 7.43-7.25 (5H, m), 6.93(2H, d, J=8.8 Hz), 3.83 (3H, s); MS (+VE) m/z 251 (M+1).

[0438] Potassium hydroxide (4.36, 76 mmol, 1.3 eq.) is suspended in 40 ml of anhydrous DMSO, to the suspension is added a solution 2-phenyl-4-(4-methoxyphenyl)imidazole (15.02, 60 mmol) and bromobutane (8.63 g, 63 mmol, 1.05 eq.) in 80 ml of DMSO at room temperature over 2 h, the resulting mixture is stirred over 24 h, and then poured into 400 ml of ice-water, extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified through flash chromatography to give 16.73 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole. MS (+VE) m/z 307 (M+1).

[0439] To a 150 ml sealed flask is added 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole (10.72, 35 mmol) followed by the addition of 24 ml of acetic acid and 24 ml of 37% formaldehyde, the resulting mixture is stirred at 70° C. for 8 h, then cooled to room temperature. The organic solvents is evaporated, the residue is diluted 100 ml of water and basified with sodium hydroxide solution, the mixture is extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over Na2SO4 Concentration and purification through silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 1:1) affords 10.0 of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol as white solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, dd, J=8.7 Hz), 7.354-7.51(2H, m), 7.44-7.38 (3H, m), 6.87 (2H, d, J=8.7 Hz), 4.59 (2H, s), 3.95 (2H, t, J=7.5 Hz), 3.784 (3H, s), 1.60 (2H, m), 1.16 (2H, m), 0.77 (3H, t, J=7.2 Hz); MS (+VE) m/z 337(M+1).

[0440] 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol (6.72 g, 20 mmol) is dissolved in 30 ml dichloromethane and cooled to 0° C., to the solution is added 5 equivalent of thionyl chloride. The resulting solution is stirred at room temperature for 2 h, the solvent and excess of thionyl chloride is evaporated. 20 ml of toluene is added to the residue and evaporated again to remove the remained thionyl chloride. The residual crude product is dissolved in 30 ml of anhydrous acetonitrile and added to an ice-cooled solution of cyclohexanemethyl amine (2.0 eq.) in 20 ml of acetonitrile containing 2 equivalent of potassium carbonate. The resulting mixture is stirred at room temperature for 4 h, then diluted with 200 ml of ethyl acetate, washed with water and brine, dried and concentrated, the residue is purified through silica gel chromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to give 11.26 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl-cyclohexylmethyl-amine. 1H NMR (400 MHz, CDCl3) δ 7.64-7.60 (4H, m), 7.477.40 (3H, m), 6.94 (2H, d, J=8.8 Hz), 4.11 (2H, m), 3.87 (2H, s), 3.84 (3H,s), 2.52 (2H, d, J=6.4 Hz), 0.91-1.77 (15H, m), 0.84 (3H, t, J=7.2 Hz); MS (+VE) m/z 432 (M+1).

[0441] To a solution of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amine (4.0 g, 9.31 mmol) and 3-acetoxy]-4-tert-butoxycarbonyl-benzyl bromide (3.37 g, 10.24 mmol, 1.1 eq.) in 50 ml anhydrous acetonitrile is added anhydrous potassium carbonate (2.82 g, 20.5 mmol, 2.2 eq.), the resulting mixture is stirred at room temperature for 1 h, then raised to 50° C., stirred overnight. The solid precipitate is filtered off, washed with ethyl acetate, the combined organics is concentrated to dryness, purified through silica gel flash chromatography to give 3.99 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoic acid tert-butyl ester MS (+VE) m/z 680 (M+1).

[0442] 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoic acid tert-butyl ester (3.99 g, 5.87 mmol) is dissolved in 50 ml of dichloromethane, to the solution is added 10 ml of Trifluoroacetic acid at 0° C., after stirring at room temperature for 8 h, the solvent is evaporated under house vacuum and the residue is dissolved in 30 ml of toluene (containing 5 ml of THF), to the solution is added 6 equivalent of thionyl chloride at 0° C., and then the reaction mixture is heated to 60° C., stirred overnight. The solvent and the remained thionyl chloride is evaporated, the residue is dissolved in 50 ml of chloroform and added to concentrated aqueous ammonium hydroxide solution with vigorous stirring slowly, stirred for 4 h. The chloroform layer is collected, and the aqueous phase is extracted with chloroform (50 ml×2), the combined organics is evaporated to dryness, and the residue is dissolved in 60 ml of methanol followed with addition of 30 ml of saturated aqueous sodium bicarbonate solution and 30 ml of water, the mixture is stirred at 40-45° C. overnight. The methanol is evaporated, and the residue is extracted with dichloromethane (50 ml×3), dried over sodium sulfate. Concentration and purification through silica gel flash chromatography affords 2.74 g of 4-({[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amno}-methyl)-2-hydroxy-benzamide. 1H NMR (400 MHz, CDCl3) δ 7.57 (2H, d, J=8.7 Hz), 7.39-7.51 (5H, m), 7.27 (H, d, J=8.1 Hz), 6.95 (2H, d, J=9.0 Hz), 6.88 (1H,d, J=1.5Ha), 6.57 (1H, dd, J=1.5, 8.4 Hz), 4.15 (2H, m), 3.84 (3H, s), 3.71 (2H, s), 3.36 (2H, s), 2.19 (2H, d, J=6.9 Hz), 0.77-1.80 (15H, m), 0.70 (3H, t, J=6.9 Hz); MS (+VE) m/z 581 (M+1).

Example 25

Preparation of (3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1h-indol-5-ylmethyl)-(3-methyl-butyl)-amine

[0443]

[0444] To a solution of (3-Butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine (150 mg, 0.31 mmol) in 5 ml of anhydrous acetonitrile cooled to 0° C. is added NCS (44 mg, 0.33 mmol, 1.05 eq.), the resulting mixture is stirred at 40° C. overnight. The solvent is evaporated; the residue is purified through flash chromatography to give 112 mg of (3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (1H, s), 7.52 (1H, S), 7.117.36 (6H, m), 6.98 (1H, d, J=2.4 Hz), 3.67 (2H, m), 3.65 (2H, s), 3.54 (2H, s), 2.52 (2H, t, J=7.2 Hz), 2.11 (3H, s), 1.62 (1H, m), 1.45 (2H, q, J=6.9 Hz), 1.10 (2H, m), 0.84 (6H, d, J=6.6 Hz), 0.73 (2H, m), 0.47 (3H, t, J=6.9 Hz); MS (+VE) m/z 511 (M+1).

Example 26

Preparation of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1h-indole-3-carbonitrile

[0445]

[0446] To an ice-cooled solution of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole (173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen is added a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35 eq.) in 1 ml of acetonitrile, after stirring for 20 min, a solution of DMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred for additional 1 h. The reaction mixture is poured into ice water and basified with diluted ammonium hydroxide solution; the mixture is extracted with dichloromethane, dried over sodium sulfate. The solvent is evaporated; the residue is purified through flash chromatography to give 11 mg of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.38 (1H, d, J=3 Hz), 7.15-7.36 (4H, m), 7.07 (1H, dd, J=1.2, 8.4 Hz), 6.896.93 (2H, m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d, J=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H,m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS (+VE) m/z 502 (M+1).

Example 27

Preparation of (R)-[1-(3-butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-cyclohexylmethyl-(4-methoxy-benzyl)-amine

[0447]

[0448] (R)-(3-Butyl-2-phenyl-3H-imidazole-4-ylmethylene)-(2-methoxymethyl-pyrrolidin-1-yl)-amine (192). A solution of aldehyde 138 (4.05 g, 14 mmol) and SAMP (2 g, 15 mmol) in benzene is refluxed for 15 h with Dean-Stark trap under argon. The solvent is then removed and the residue is used for the next step without further purification. LC-MS (MH+): 341.

[0449] (R,S)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-(2-methoxymethyl-pyrrolidin-1-yl)-amine (193). To a solution of BuLi (2.5 M in hexane, 12.5 ml, 31 mmol) under argon in anhydrous THF (15 mL) at −78° C. is slowly added a solution of crude 192 (14 mmol) in THF (15 mL). The mixture is allowed to warm to oom temperature over a period of 15 h and quenched with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate and the combined organic phases were washed with water and dried over sodium sulfate. Removal of solvents under reduced pressure and purification of the residue by column chromatograpy affords the desired product as a colorless syrup. Yield: 5.1 g; [α]D-72 (c=1.2, CHCl3); LC-MS (MH+): 399.

[0450] (R)-1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentylamine (194). To a solution of 193 (1.43 g, 3.6 mmol) under argon in anhydrous THF (25 mL) at room temperature is slowly added borane-THF complex (1 M in THF, 54 ml, 54 mmol). The mixture is then refluxed under argon for 16 h. After cooling to room temperature, 10% HCl (20 mL) is added very slowly and the mixture is stirred for 2 h at room temperature. The organic solvent is removed under reduced pressure and the residue is extracted with ether. The aqueous phase is saturated with solid potassium carbonate and extracted with sthyl acetate. The residue obtained after removal of the solvent is purified by column chromatography to afford the desired product as a colorless oil. Yield: 0.6 g; LC-MS (MH+): 286.

[0451] (R)-[1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethylene-amine (196) and [1-(3-butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethyl-amine (197). A solution of amine 194 (440 mg, 1.54 mmol) and cyclohexylmethylaldehyde (173 mg, 1.6 mmol) in benzene is refluxed for 16 h with Dean-Stark trap under argon. The solvent is then removed and the residue 196 is used for the next step without further purification. LC-MS (MH+): 380. The crude 196 is dissolved in anhydrous methanol (10 mL) and cooled to 0° C. To this solution, sodium borohydride (80 mg) is added slowly and the mixture is stirred at room temperature for 4 h. The reaction is quenched with water (10 mL) and most methanol is removed under reduced pressure. The residue is extracted with ethyl acetate, and the organic phase is washed with saturated sodium bicarbonate and brine. Evaporation of the solvent and purification of the residue affords a colorless oil. Yield: 560 mg; [α]D-5.8 (c=1, CHCl3); LC-MS (MH+): 382.

[0452] (R)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-cyclohexylmethyl-(4-methoxy-benzyl)-amine (199). This compound is prepared from amine 197 and aldehyde 198 in the manner as described in Example 9 for preparation of compound 145. The enantiomer excess value of 199 is greater than 97.5% indentifed by chiral column. [α]D-14.4 (c=1, CHCl3); LC-MS (MH+): 502; 1H NMR (400 MHz, CDCl3) δ 7.46-7.37 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 6.99 (s, 1H), 6.89-6.84 (m, 2H), 3.80 (s, 2H), 3.78 (s, 2H), 3.76-3.61 (m, 5H), 2.38-2.32 (m, 1H), 2.17-2.12 (m, 1H), 1.98-1.94 (m, 2H), 1.70-1.52 (m, 5H), 1.46-1.34 (m, 4H), 1.26-0.99 (m, 6H), 0.95 (t, J=7.2 Hz, 3H), 0.82-0.71 (m, 2H), 0.58 (t, J=7.2 Hz, 3H).

Example 28

Preparation of (S)-[1-(3-butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-cyclohexylmethyl-(4-methoxy-benzyl)-amine

[0453]

[0454] The title compound 200 is prepared in the same manner as in Example 20 using RAMP. The analytical data is intentical to that of compound 199 except for the optical rotation.

Example 29

Preparation of (R)-4({butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzamide

[0455]

[0456] (R)-4({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzoic acid (202). This compound is prepared in the same manner as in Example 20 using aldehyde 201 as the starting material. 4-formylbenzoic acid is employed for the reductive amination step. LC-MS (MH+): 510.

[0457] (R)-4({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzamide (204). A solution of compound 202 (110 mg, 0.2 mmol) in anhydrous chloroform is treated with thionyl chloride (0.2 mL) under reflux for 2 h. The solvent and excess of thonyl chloride were evaporated under reduced pressure and the residue is dried in vacuo to yield acid chloride 203 which is used for the next step without further purification. To a vigorously stirred solution of ammonium hydroxide (30% in water, 2 mL) and chloroform (4 mL) is added a solution of 203 in chloroform (2 mL) in one portion at room temperature. The mixture is continued stirring at room temperature overnight. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is washed with water, saturated sodium bicarbonate and brine. Removal of the solvent and purification of the residue by column chromatography yields the desired product 204. Yield: 98 mg. LC-MS (MH+): 509; 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=7.8 Hz, 2H), 7.60 (d, J=7.8 Hz, 2H), 7.50-7.48 (m, 2H), 7.40-7.38 (m, 4H), 7.32 (d, J=7.5 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 6.12 (br s, 1H), 5.75 (br s, 1H), 4.55-4.45 (m, 1H), 4.27 (q, J=6.9 Hz, 1H), 4.14-4.03 (m, 1H), 3.71 (d, J=14.7 Hz, 1H), 3.52 (d, J=14.7 Hz, 1H), 2.53 (d, J=7.4 Hz, 2H), 2.05-1.96 (m, 2H), 1.49 (d, J=6.9 Hz, 3H), 1.44-1.13 (m, 4H), 0.88-0.75 (m, 6H).

Examples 29-40

Preparation of Various 4-substituted Imidazole Derivatives

[0458]

Example 29

Preparation of Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine (212)

[0459] 3-Bromo-1,1-dimethoxy-propan-2-one (206). Bromine (80 g, 0.5 mol) is added dropwise to a solution of 1,1-dimethoxy-propan-2-one 205 (59 g, 0.5 mol) in anhydrous methanol (400 mL) at 0° C. and the solution is continued stirring at room temperature for 48 h. The sovent is removed under reduced pressure and the residue is dried in vacuo and used without further purification.

[0460] 4-Dimethoxymethyl-2-phenyl-1H-imidazole (208). To a solution of benzamidine 207 (1.44 g, 12 mmol) and potassium carbonate (4.1 g, 30 mmol) in anhydrous DMF (25 mL) is slowly added a solution of 3-bromo-1,1-dimethoxy-propan-2-one 206 (1.97 g, 10 mmol) in anhydrous DMF (10 mL) over 30 min. The mixture is then heated at 50-60° C. for 2 h. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added. The organic phase is separated and the aqueous phase is extracted with ethyl acetate twice and the combined organic phase is washed with water (3×20 mL) and brine. Removal of solvents under reduced pressure and purification of the residue by column chromatography affords the desired product as a white solid. Yield: 2.08 g; LC-MS (MH+): 219.11H NMR (300 MHz, CDCl3) δ 7.88-7.85 (m, 2H), 7.37-7.46 (m, 4H), 5.49 (s, 1H), 3.36 (s, 6H).

[0461] 1-Butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole (209). A solution of 4-dimethoxymethyl-2-phenyl-1H-imidazole 208 (2.18 g, 10 mmol) and n-butyl bromide (2.74 g, 20 mmol) in anhydrous DMSO (15 mL) is added to a suspension of powdered potassium hydroxide (0.96 mg, 15 mmol) in DMSO (20 mL) at room temperature over 3 h. The mixture is then stirred at rt for 16 h. The mixture is diluted with ether and washed with water (three times), brine, and dried over anhydrous sodium sulfate. Removal of the solvent and purification of the residue affords the desired product. Yield: 2.5 g; LC-MS (MH+): 275.

[0462] 3-Butyl-5-dimethoxymethyl-2-phenyl-3H-imidazole-4-carbaldehyde (210). To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous THF under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 min. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60-7.56 (m, 2H), 7.51-7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73-1.63 (m, 2H), 1.28-1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

[0463] Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)-amine (211). A solution of 3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazole-4-carbaldehyde (2.1 g, 7 mmol) and piperalamine (7 mmol) in anhydrous methanol (35 mL) is stirred at room temperature overnight. After cooling to 0° C., sodium borohydride (7 mmol) is added slowly in 30 min. The reaction is quenched by addition of water (20 mL) and most methanol is removed under reduced pressure. The residure is extracted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a colorless syrup. Yield: 2.62 g; LC-MS (MH+): 438.

[0464] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine (212). This compound is prepared according to the procedure as preparation of 129 in Example 7. LC-MS (MH+): 572.

Example 30

Preparation of 5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde (213)

[0465] Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine 212 (571 mg, 1 mmol) in THF (5 mL) is treated with p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) at room temperature overnight. The solvent is removed and the residue is diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The solvent is removed under reduced pressure and the redure is purified by column chromatography to yield the desired product. Yield: 510 mg; LC-MS (MH+): 526.

Example 31

5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylic Acid (214)

[0466] To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (263 mg, 0.5 mmol) in actone (10 mL) and water (5 mL) is added sulfamic acid (107 mg, 1.11 mmol) at room temperature and the mixture is stirred for 30 min. Sodium chlorite (63 mg, 0.7 mmol) is added and the mixture is stirred for additional 30 min at room temperature. Evaporation of most actone and the residure is extracted with chloroform. The organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed and the product is dried in vacuo. Yield: 281 mg; LC-MS (MH+): 542.

Example 32

5-[(Bis-benzo[1,3]Dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylic Acid Methy Easter (215).

[0467] To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylic acid 214 (54 mg, 0.1 mmol) in methanol (5 mL) at 0° C. is added freshly prepared diazomethane ether solution. The mixture is stirred for 1 h and concentrated to provide the desired methyl ester. LC-MS (MH+): 556.

Example 33

2-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-propan-2-ol (216)

[0468] To a solution of 5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylic acid methy easter 215 (40 mg, 0.08 mmol) in anhydrous THF (2 mL) at −78° C. under argon is added methyl lithium (1M solution in ether, 0.2 ml, 0.2 mmol). The mixture is then stirred at room temperature for 1 h and the reaction is quenched with saturated ammonium chloride. The residure is extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography to yield the desired product. Yield: 35 mg; LC-MS (MH+): 556.

Example 34

{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-methanol (217)

[0469] To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (52 mg, 0.1 mmol) in anhydrous methanol (5 mL) at room temperature is added sodium borohydride (10 mg) and the mixture is stirred for 30 min. Water is added to quench the reaction and the residure is extracted with ethyl acetate. The organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed and the residue is purified by column chromatogaraphy to yield the desired product. Yield: 51 mg; LC-MS (MH+): 528.

Example 35

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-methoxymethyl-2-phenyl-1H-imidazol-4-ylmethyl)-amine (218)

[0470] To a solution of {5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl j-methanol 217 (52 mg, 0.1 mmol) and NaH (5 mg) in anhydrous THF (5 mL) at 0° C. under argon is added iodomethane (0.05 mL) and the mixture is stirred for 1 h. Evaporation of the solvent and excess of MeI and the residue is purified by column chromatogaraphy to yield the desired product. Yield: 41 mg; LC-MS (MH+): 542.

Example 36

Bis-benzo[1,3]dioxol-5-ylmethyl-(1′-butyl-2′-phenyl-1′H-[1,4′]biimidazolyl-5′-ylmethyl)-amine (219)

[0471] To a solution of {5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-methanol 217 (52 mg, 0.1 mmol) in anhydrous acetonitrile (5 mL) at room temperature is added CDI (21 mg, 0.13 mmol) and the mixture is stirred for 1 h. Evaporation of the solvent and excess of MeI and the residue is purified by column chromatogaraphy to yield the desired product. Yield: 561 mg; LC-MS (MH+): 578.

Example 37

1-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-yl}-ethanol (220)

[0472] This compound is prepared in the manner as described for the preparation of 216 to yield the desired product; LC-MS (MH+): 542.

Example 38

1-{5-[(Bis-benzo [1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-yl}ethnone (221)

[0473] A solution of 1-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-yl}-ethanol 220 (54 mg, 0.1 mmol) in anhydrous THF (5 mL) is oxidized with MnO2 (100 mg) under reflux for 5 h. After cooling to room temperature, the residue is filtered though celite and concentrated. The residue is purified by column chromatogaraphy to yield the desired product. Yield: 38 mg; LC-MS (MH+): 540.

Example 39

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethylaminomethyl-2-phenyl-3H-imidazol-4-yl}-amine (222)

[0474] This compound is prepared in the manner as described for the preparation of 212 to yield the desired product; LC-MS (MH+): 542.

Example 39

5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazole-4-carboxylic Acid Dimethylamide (223)

[0475] To a solution of 5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylic acid 214. (50 mg, 0.1 mmol) in anhydrous dichloromethane (3 mL) is added dimethylamine (1M solution in THF, 0.4 ml, 0.4 mmol) and DCC (0.2 mmol) and the mixture is stirred for 48 h. Evaporation the solvent and the residue is purified by column chromatogaraphy to yield the desired product. Yield: 25 mg; LC-MS (MH+): 569.

Example 40

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-difluoromethyl-2-phenyl-1H-imidazol-4-ylmethyl)-amine (224)

[0476] To a solution of 5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (42 mg, 0.8 mmol) in anhydrous dichloromethane (2 mL) at −78° C. under argon is added DAST (0.11 ml, 8.1 mmol). The mixture is stirred at room temperature for 16 h and concentrated. The residue is purified by column chromatogaraphy to yield the desired product. Yield: 33 mg; LC-MS (MH+): 548.

Example 41

Preparation of 2-(2,6-diethylphenyl)-4-chloroimidazole-5-carboxyaldehyde

[0477] Synthesis of 2,6-diethylphenylboronic Acid

[0478] 2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise through an additional funnel over a 1 hour period to a solution of n-BuLi (2.0 M in cyclohexane, 99.1 ml, 198.2 mmol) in THF (380 mL) at −75° C. After addition, the reaction mixture is stirred at −75° C. for 30 minutes; trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minute period. The reaction mixture is warmed to room temperature overnight. 2N HCl (250 mL) is added slowly and the resulting mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ether (2×200 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvents are removed in vacuo. Hexane (400 mL) is added to the residue and a white precipitate is formed. Filtration and drying in vacuo gives 19.0 g of 2,6-diethylphenyl boronic acid as a white solid. 1H NMR: (CDCl3) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64 (q, 4H), 1.22 (t, 6H).

[0479] Synthesis of 1-methoxyethyl-3,4-dichloroimidazole

100

[0480] A solution of 1 mmol of 3,4-dichloroimidazole in anhydrous DMF (5 mL) is treated with sodium hydride (1.05 mmol) at 0° C. under nitrogen with magnetic stirring. After 30 min., 2-chloroethyl methyl ether (1 mmol) is added and the reaction mixture is warmed to 60° C. for 2 h. The reaction mixture is cooled, portioned between water and ethyl acetate. The organic layer is separated, washed with water, brine and dried over sodium sulfate. The reaction mixture is filtered, evaporated and purified by chromatography on silica gel to obtain 1-methoxyethyl-3,4-dichloroimidazole.

[0481] Synthesis of 2-bromo-1-methoxyethyl-3,4-dichloroimidazole

101

[0482] To a solution of 1-methoxyethyl-3,4-dichloroimidazole (1.95 g, 10 mmol) in acetonitrile (50 mL) is added NBS (1.86 g, 1.05 mmol) at room temperature in portions. The reaction mixture is stirred at rt for 30 min. Ethyl acetate (100 mL) is added and washed with water, brine, dried over MgSO4, filtered and evaporated in vacuo to dryness. The crude product is purified by flash chromatography (hexane/ethyl acetate 100/5) to obtain 2-bromo-1-methoxyethyl-3,4-dichloroimidazole.

[0483] Synthesis of 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole

102

[0484] A solution containing 2-bromo-1-methoxyethyl-3,4-dichloroimidazole (2.74 g, 10 mmol), 2,6-diethylphenylboronic acid (2.14 g, 12 mmol.) and Pd(PPh3)4 (0.23 mg, 0.2 mmol) in toluene/2M Na2CO3 (30 ml/15 mL) in a sealed tube is degassed, then allowed to heat to 110° C. overnight. The organic layer is separated and concentrated in vacuo to dryness. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 100/5) to obtain the 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole.

[0485] Synthesis of 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde

103

[0486] To a solution of N-methoxyethyl 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole (3.27 g, 10 mmol.) in anhydrous THF is added n-BuLi (1.6M in hexane) (9.4 ml, 15 mmol) dropwise at −78° C. After the reaction mixture is stirred at −78° C. for 2 h, anhydrous DMF (3 equiv.) is added in one portion. The mixture is stirred at −78° C. for 30 min, then allowed to warm to room temperature slowly. The reaction mixture is quenched with water and extracted with ethyl acetate, dried over MgSO4, filtered, concentrated in vacuo and purified by chromatography on silica gel to give 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde. This material is used to make various compounds of Formula I as depicted in Scheme 10 and futher illustrated in Examples 4-9 and related examples.

Example 42

Pharmaceutical Preparations of Oral and Intravenous Administration

[0487] A. Tablets containing a C5a antagonist and an anti-arthritic agent which is not a C5a receptor antagonist can be prepared as illustrated below:

5IngredientAmountC5a receptor antagonist5 mg-500 mgC5a receptor-inactive therapeutic1 mg-500 mgagentdiluent, binder, distigrant, lubricant excipientsq.s. 200-400 mg.

[0488] B. Tablets containing a C5a receptor antagonist as the only active ingredient can be prepared as illustrated below:

6IngredientmgmgC5a receptor antagonist1050Microcrystalline Cellulose70.4352Grannular Mannitol15.175.5Croscarmellose Sodium3.015.0Colloidal Silicon Dioxide0.52.5Magnesium Stearate (Impalpable Powder)1.05.0Total (mg)100500

[0489] C. Tablets containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:

7IngredientmgmgC5a receptor antagonist1025C5a receptor inactive therapeutic agent1025Microcrystalline Cellulose40100Modified food corn starch1.054.25Magnesium sterate1.250.5

[0490] D. Intravaneous formulations containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:

8IngredientAmountC5a receptor antagonist0.5-10 mgC5a receptor inactive therapeutic agent0.5-10 mgSodium Citrate 5-50 mgCitic Acid 1-15 mgSodium Chloride 1-8 mgWater for Injectionto 1.0 liter

[0491] E. Oral suspensions containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:

9IngredientAmount per 5 ml doseC5a receptor antagonist5-100 mgC5a receptor inactive therapeutic agent5-100 mgPolyvinylpyrrolidone 150 mgPoly oxyethylene sorbitan monolaurate 25 mgBenzoic Acid10 mg to 5 mL with sorbitolsolution (70%)

Example 43

[0492] Additional C5a Modulators

[0493] Additional compounds of the invention, shown in Tables I-IV are prepared via the methods provided in Scheme 1-11 and further illustrated in Examples 1-41. Compounds which have an asterisk in the column labeled Ca Mobilization Assay Ki<1 uM, were tested in the standard assay of C5a receptor mediated calcium mobilization given in Example 35 and found to exhibit a Ki of less than 1 uM.

[0494] The LC/MS data presented in Tables I-IV were obtained using the following instrumentation and methods. MS spectroscopy data is Electrospray MS, obtained in positive ion mode, with a 15V Cone voltage, using a WATERS ZMD 2000 Mass Spec Detector, equipped with a WATERS 600 pump, WATERS 2487 Dual Wavelength Detector, GILSON 215 Autosampler, and a GILSON 841 Microinjector. MassLynx version 3.4 software was used for data collection and analysis.

[0495] Sample, 2-20 uL, was injected onto a 33×4.6 mm YMC ProPack C18;5u column, and eluted using a 2-phase linear gradient at a 4 mL/minute flow rate. Sample was detected at 220 and 254 nm. The elution conditions were as follows: Mobile Phase A-95/5/0.1 Water/Methanol/TFA, Mobile Phase B-5/95/0.1 Water/Methanol/TFA.

10Gradient-time(min)% B0100.01102.01003.51003.51103.52

[0496] The total run time for the gradient was 4.0 minutes.

11TABLE ICa2+Ret.CMP #STRUCTUREMob.IUPAC NameMASSTime225

104

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(methylthio)-2-phenyl-1H- imidazol-5- yl]methyl}methanamine543.221.22226

105

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(methylsulfonyl)-2-phenyl-1H- imidazol-5- yl]methyl}methanamine575.211.27227

106

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(methylsulfonyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine597.211.27228

107

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine675.271.23229

108

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine603.311.24230

109

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine689.291.24231

110

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(methylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine691.251.24232

111

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(ethylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine233

112

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine675.271.23234

113

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine689.291.24235

114

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[3-(methylthio)phenyl]-2- phenyl-1H-imidazol-5-yl)methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine691.251.24236

115

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine659.281.24237

116

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine659.281.22238

117

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-dimethylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine673.291.25239

118

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-dimethylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl]-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine673.291.27240

119

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methoyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine663.251.23241

120

*1-(1,3-benzodioxol-5-yl)-N-{(1- butyl-4-(4-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine663.251.22242

121

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine681.241.24243

122

*1-(1,3-benzodioxol-5-yl)-N-{(1- butyl-4-(3,5-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine681.241.26244

123

*1-(1,3-benzodioxol-5-yl)-N-{(1- butyl-4-(4-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine617.331.26245

124

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(methylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine619.291.26246

125

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(ethylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine633.31.26247

126

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine603.311.23248

127

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine617.331.26249

128

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[3-(methylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine619.291.25250

129

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine587.311.25251

130

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine587.311.25252

131

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-dimethylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine601.331.29253

132

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-dimethylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine601.331.28254

133

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine591.291.24255

134

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine591.291.24256

135

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine609.281.26257

136

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine609.281.28258

137

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-(3- ethoxybenzyl)methanamine641.291.27259

138

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-(3- ethoxybenzyl)methanamine641.291.27260

139

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-(3- ethoxybenzyl)methanamine657.281.27261

140

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-(3- ethoxybenzyl)methanamine657.281.29262

141

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[(1E)-pent-1-enyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine565.331.27263

142

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine264

143

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine265

144

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine266

145

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine267

146

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[(1E)-pent-1-enyl]-2- phenyl-1H-imidazol-5-yl}methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine637.291.25268

147

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine607.261.27269

148

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine607.261.27270

149

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-isopropylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine615.351.29271

150

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(2,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine609.281.25272

151

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine679.221.25273

152

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy) benzyl]methanamine679.221.26274

153

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-isopropylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine687.311.26275

154

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(2,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine681.241.25276

155

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-isopropylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine615.311.27277

156

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3,4-dimethylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine278

157

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(2,4-difluorophenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine609.241.23279

158

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3,5-difluorophenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine609.241.26280

159

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[(E)-2- phenylethenyl]-1H-imidazol-5- yl}methyl)methanamine599.281.23281

160

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[(E)-2- phenylethenyl]-1H-imidazol-5- yl}methyl)-N-(3- ethoxybenzyl)methanamine599.311.27282

161

*1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[(E)-2- phenylethenyl]-1H-imidazol-5- yl}methyl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine283

162

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]butan-1-amine453.221.15284

163

*4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl) methyl]amino}methyl)benzamide530.211.26285

164

*4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl) methyl]amino}methyl) benzenesulfonamide566.181.24286

165

*methyl 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl) methyl]amino}methyl)benzoate545.211.37287

166

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- methoxybenzyl)methanamine517.211.35288

167

*6-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}-3,4-dihydroquinolin- 2(1H)-one552.311.37289

168

*6-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-3,4- dihydroquinolin-2(1H)-one512.281.19290

169

*6-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-3,4- dihydroquinolin-2(1H)-one590.251.3291

170

*6-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one554.31.18292

171

*6-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one520.321.13293

172

*6-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one598.291.17294

173

*6-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](cyctohexylmethyl) amino]methyl}-3,4-dihydroquinolin- 2(1H)-one560.351.23295

174

*6-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino) methyl)-3,4-dihydroquinolin-2(1H)- one620.31.16296

175

*1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N,N-bis(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)methanamine525.261.18297

176

*1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N,N-bis(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)methanamine298

177

*1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)methanamine601.291.21299

178

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- dihydro-1,4-benzodioxin-6- ylmethyl)methanamine300

179

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1-benzofuran-5- ylmethyl)methanamine529.211.28301

180

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amine559.221.28302

181

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)methanamine579.231.37303

182

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1-benzofuran-5- ylmethyl)methanamine563.241.35304

183

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-phenyl-2-(1H-pyrazol-1-yl)- 1H-imidazol-5- yl]methyl}methanamine305

184

*4-[(butyl{[1-butyl-4-(5-methylthien- 2-yl)-2-phenyl-1H-imidazol-5- yl]methyl}amino)methyl]benzamide514.281.17306

185

*N-{[1-butyl-4-(5-methylthien-2-yl)- 2-phenyl-1H-imidazol-5-yl]methyl}- N-(3-ethoxybenzyl)butan-1-amine515.31.25307

186

*N-{[1-butyl-4-(5-methylthien-2-yl)- 2-phenyl-1H-imidazol-5-yl]methyl}- N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]butan- 1-amine587.261.26308

187

*N-(1,3-benzodioxol-5-ylmethyl)-N- {[1-butyl-4-(5-methylthien-2-yl)-2- phenyl-1H-imidazol-5- yl]methyl}butan-1-amine515.261.2309

188

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4- butyl-5-phenyl-4H-1,2,4-triazol-3- yl)methyl]methanamine498.231.23310

189

*1-(1,3-benzodioxol-5-yl)-N-[(4- butyl-5-phenyl-4H-1,2,4-triazol-3- yl)methyl]-N- (cyclohexylmethyl)methanamine460.281.28311

190

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-5-phenyl-4H-1,2,4-triazol- 3-yl)methyl]butan-1-amine420.251.14312

191

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-2-morpholin-4- ylethanamine313

192

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzoxazol-2-ylmethyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine570.261.19314

193

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(tetrahydro-2H-pyran- 4-ylmethyl)methanamine537.31.17315

194

N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-2-piperidin-1- ylethanamine550.331.06316

195

N˜1˜-(1,3-benzodioxol-5- ylmethyl)-N˜1˜-[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]- N˜2˜,N˜2˜-diethylethane-1,2- diamine538.331.06317

196

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-2-thiomorpholin-4- ylethanamine318

197

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(2S)-tetrahydrofuran- 2-ylmethyl]methanamine523.281.18319

198

*523.281.18320

199

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- methylchroman-4-amine451.261.19321

200

*N,N-bis(1,3-benzodioxol-5- ylmethyl)-2-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)acetamide601.261.17322

201

*N,N-bis(1,3-benzodioxol-5- ylmethyl)-2-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethanamine587.281.1323

202

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4- butyl-1-methyl-3-phenyl-1H- pyrazol-5-yl)methyl]methanamine511.251.34324

203

N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-1-methyl-3-phenyl-1H- pyrazol-5-yl)methyl]butan-1-amine511.251.34325

204

1-(1,3-benzodioxol-5-yl)-N-[(4- butyl-1-methyl-3-phenyl-1H- pyrazol-5-yl)metbyl]-N-(3- ethoxybenzyl)methanamine433.271.18326

205

1-(1,3-benzodioxol-5-yl)-N-benzyl- N-[(4-butyl-1-methyl-3-phenyl-1H- pyrazol-5-yl)methyl]methanamine511.281.34327

206

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4- butyl-1-methyl-5-phenyl-1H- pyrazol-3-yl)methyl]methanamine467.261.38328

207

N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-1-methyl-5-phenyl-1H- pyrazol-3-yl)methyl]butan-1-amine433.271.16329

208

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(1,4- dioxaspiro[4.5]dec-8- ylmethyl)methanamine330

209

*4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl) cyclohexanone331

210

*4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)-1- methylcyclohexanol332

211

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(2-methyl-1,3- benzoxazol-5- yl)methyl]methanamine333

212

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-methylethanamine334

213

*4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl) cyclohexanol335

214

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(5-butyl-1,3-diphenyl-1H-pyrazol- 4-yl)methyl]butan-1-amine495.291.15336

215

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5- butyl-1,3-diphenyl-1H-pyrazol-4- yl)methyl]methanamine573.261.19337

216

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(2-methyl-1,3- benzothiazol-5- yl)methyl]methanamine600.261.22338

217

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(1-ethyl- 3,5-dimethyl-1H-pyrazol-4- yl)methyl]butan-1-amine339

218

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(3,5- dimethyl-1H-pyrazol-4- yl)methyl]butan-1-amine340

219

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H- imidazol-5-yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine651.221.22341

220

*methyl 2-amino-4-[(butyl{[1-butyl- 4-(3-methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]benzoate554.331.2342

221

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)methanamine587.281.21343

222

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1- benzofuran-5- ylmethyl)methanamine571.281.22344

223

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine579.261.23345

224

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-(4-fluorophenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine346

225

*1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)-N-(2,3-dihydro-1- benzofuran-5- ylmethyl)methanamine509.271.16347

226

*1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)-N-(3- ethoxybenzyl)methanamine511.281.2348

227

*1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(2,3-dihydro-1- benzofuran-5- ylmethyl)methanamine577.261.36349

228

*1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine579.271.4350

229

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{(1- butyl-2-(4-methylphenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine587.281.24351

230

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-(2-methylphenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine587.281.23352

231

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-(3-fluorophenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine591.251.22353

232

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]butan-1- amine354

233

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine355

234

*1-(1,3-benzodioxol-5-yl)-N-benzyl- N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5- yl)methyl]methanamine356

235

*N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N- (cyclohexylmethyl)-N-(1H-indol-5- ylmethyl)amine472.31.16357

236

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N- (cyclohexylmethyl)methanamine535.321.26358

237

*N-{(1-butyl-4-phenyl-2-(1H- pyrazol-1-yl)-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine359

238

*4-(2-{(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}ethyl)phenol559.281.18360

239

*methyl 2-amino-4-[((1,3- benzodioxol-5-ylmethyl){[1-butyl-2- phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoate594.251.34361

240

*7-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]quinazolin-4-ol589.231.27362

241

*methyl 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)-2- nitrobenzoate632.261.18363

242

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(4-fluorophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine591.251.22364

243

*7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)quinazolin- 4-ol597.271.15365

244

*7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)quinazolin- 4-amine596.291.08366

245

*7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)-N,N- diethylquinazolin-4-amine367

246

*7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl) methyl]amino}methyl)-N- ethylquinazolin-4-amine624.321.1368

247

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(4-ethoxyquinazolin- 7-yl)methyl]methanamine625.311.22369

248

*1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N- methylmethanamine370

249

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- (cyclohexylmethyl)butan-1-amine371

250

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-1-cyclohexyl- N-methylethanamine372

251

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine373

252

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]butan-1- amine374

253

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)butan-1-amine375

254

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- methoxybenzyl)butan-1-amine376

255

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{(1- butyl-2-phenyl-4-(phenylsulfonyl)- 1H-imidazol-5- yl]methyl)methanamine637.221.31377

256

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine515.261.29378

257

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-4-fluoro-2-phenyl-1H- imidazol-5- yl)methyl]methanamine515.221.23379

258

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-methylmethanamine453.241.11380

259

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]ethanamine467.261.12381

260

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]propan-1-amine481.271.16382

261

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-3-ethoxypropan-1- amine525.31.17383

262

*1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(2,3- dihydro-1-benzofuran-5- ylmethyl)methanamine585.31.22384

263

*1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine587.311.25385

264

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N- methylmethanamine411.171.09386

265

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]ethanamine425.191.09387

266

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]propan-1- amine439.21.12388

267

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-3- ethoxypropan-1-amine389

268

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)-N-(2,3-dihydro-1- benzofuran-5-ylmethyl)amine390

269

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)amine391

270

*1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-phenyl-2-(1H-pyrazol-1-yl)- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine392

271

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-(2,6-dimethylphenyl)-4- phenyl-1H-imidazol-5- yl]methyl}methanamine393

272

*N-[(1-butyl4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1-benzofuran-5- ylmethyl)butan-1-amine394

273

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[3- (difluoromethoxy)benzyl]butan-1- amine395

274

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5- butyl-1-phenyl-1H-pyrazol-4- yl)methyl]methanamine396

275

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(1,1- dioxidotetrahydro-2H-thiopyran-4- yl)methyl]methanamine397

276

*N-[1-(1,3-benzodioxol-5-yl)ethyl]- N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]butan-1- amine398

277

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[1-(3- ethoxyphenyl)ethyl]butan-1-amine399

278

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-{1-[4- (difluoromethoxy)phenyl]ethyl}butan-1-amine400

279

*N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[1-(2,3- dihydro-1,4-benzodioxin-6- yl)ethyl]butan-1-amine401

280

*4-(1-{butyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}ethyl)benzoic acid402

281

*N-{[3-(benzyloxy)isoxazol-5- yl]methyl}-N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]butan-1- amine403

282

*1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(2-methyl- 1,3-benzothiazol-5- yl)methyl]methanamine404

283

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(2-methyl- 1,3-benzothiazol-5- yl)methyl]butan-1-amine405

284

*1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5- butyl-3-chloro-6-phenylpyridazin-4- yl)methyl]methanamine406

285

*N-(1,3-benzodioxol-5-ylmethyl)-N- [(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl]butan- 1-amine407

286

*N-[1-(1,3-benzodioxol-5-yl)ethyl]- N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]propan-1- amine408

287

*N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[1-(2,3- dihydro-1,4-benzodiodn-6- yl)ethyl]propan-1-amine409

288

*1-(1,3-benzodioxol-5-yl)-N-[(5- butyl-3-chloro-6-phenylpyridazin-4- yl)methyl]-N-(3- ethoxybenzyl)methanamine

[0497]

12

TABLE II

CMP

Ca2+

RT

#
STRUCTURE
Mob.
IUPAC Name
MASS
(min.)

410

289

4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-4-(4- imidazol-5- yl]methyl}amino)methyl]benzamide

411

290

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine

412

291

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2,6- dichlorophenol
570.25
1.21

413

292

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- chlorophenol
536.30
1.18

414

293

*
4-({(1,3-benzodioxol-5-ylmethyl)[1- (1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)ethyl]amino}methyl)-2,6- dimethylphenol
588.42
1.21

415

294

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,4- dichlorobenzyl)butan-1-amine
520.31
1.26

416

295

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)pentan-1- amine

417

296

(1R)-N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)pentan-1-amine

418

297

*

419

298

*

420

299

*
(1R)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(2,3-dihydro- 1-benzofuran-6-ylmethyl)pentan-1- amine

421

300

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(2,3-dihydro- 1-benzofuran-6-ylmethyl)pentan-1- amine
628.48
1.27

422

301

*

423

302

*

628.48
1.27

424

303

*
4-{[[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)pentyl](cyclohexylmethyl)amino]methyl}-2,6-dimethylphenol

425

304

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)pentyl]amino}methyl)-2,6- dimethylphenol
630.50
1.26

426

305

*

427

306

*

630.50
1.26

428

307

(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)ethanamine

429

308

(1R)-N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethanamine

430

309

*
(1S)-N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethanamine

431

310

*
(1R)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(2,3-dihydro- 1-benzofuran-6- ylmethyl)ethanamine

432

311

(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(2,3-dihydro- 1-benzofuran-6- ylmethyl)ethanamine

433

312

*
(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(2,3- dihydro-1-benzofuran-6- ylmethyl)ethanamine

434

313

*
4-{[[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)ethyl](cyclohexylmethyl)amino]methyl}-2,6-dimethylphenol

435

314

*
4-{[[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl](cyclohexylmethyl)amino]methyl}-2,6-dimethylphenol

436

315

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3-fluoro- 4-methoxybenzyl)butan-1-amine
500.31
1.19

437

316

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3-fluoro-4- methoxybenzyl)methanamine
534.30
1.21

438

317

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4- methoxy-3-methylbenzyl)butan-1- amine
496.34
1.18

439

318

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(4-methoxy-3- methylbenzyl)methanamine
530.32
1.24

440

319

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3-chloro- 4-fluorobenzyl)butan-1-amine
540.27
1.24

441

320

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3-chloro-4- fluorobenzyl)methanamine
538.26
1.25

442

321

methyl 4-({butyl[1-(1-butyl-2- phenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoate
448.31
1.19

443

322

methyl 4-({benzyl[1-(1-butyl-2- phenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoate
482.29
1.19

444

323

methyl 4-({butyl[1-(1-butyl-2- phenyl-1H-imidazol-5- yl)pentyl]amino}methyl)benzoate
490.35
1.23

445

324

*
5-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methoxyphenol
532.36
1.18

446

325

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methoxyphenol
498.38
1.1

447

326

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methoxyphenol
532.37
1.17

448

327

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)benzene- 1,2-diol
428.32
1

449

328

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(4- methoxybenzyl)methanamine
546.39
1.21

450

329

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(3,4- dihydroxybenzyl)methanamine

451

330

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-fluoro- 5-(trifluoromethyl)benzyl]butan-1- amine
538.31
1.24

452

331

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4- methoxy-3,5- dimethylbenzyl)butan-1-amine
510.37
1.2

453

332

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,5- dichloro-4-methoxybenzyl)butan-1- amine
550.28
1.26

454

333

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3-chloro- 4-methoxybenzyl)butan-1-amine
516.31
1.21

455

334

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(4-methoxy- 3,5-dimethylbenzyl)methanamine
544.36
1.25

456

335

*
4-({butyl[(1-butyl-2-phenyl-1H- imidazol-5- yl)methyl]amino}methyl)benzamide
419.31
1.08

457

336

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3,5-dichloro- 4-methoxybenzyl)methanamine
584.26
1.25

458

337

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3-chloro-4- methoxybenzyl)methanamine
550.30
1.23

459

338

4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1-benzofuran-5- ylmethyl)amino]methyl}benzene- sulfonamide
607.39
1.12

460

339

N-(1,3-benzodioxol-5-ylmethyl)-N- [(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)ethyl]butan-1-amine
510.39
1.21

461

340

N-[(1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
524.41
1.2

462

341

*
4-({butyl[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoic acid
510.39
1.19

463

342

N-(1,3-benzodioxol-5-ylmethyl)- N-[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]butan-1- amine
510.40
1.21

464

343

N-[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
524.41
1.21

465

344

4-({butyl[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoic acid
510.40
1.18

466

345

methyl 4-({butyl[(1S)-1-(1-butyl- 2,4-diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoate
524.41
1.22

467

346

methyl 4-({butyl[(1R)-1-(1-butyl- 2,4-diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzoate
524.41
1.22

468

347

*
4-({butyl[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzamide
509.42
1.15

469

348

4-({butyl[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzamide
509.43
1.15

470

349

4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2,6- dichlorophenol
536.27
1.22

471

350

*
5-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methoxyphenol
498.38
1.11

472

351

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methylphenol
516.37
1.21

473

352

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methylphenol
482.38
1.12

474

353

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- chlorophenol
502.33
1.16

475

354

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-fluoro-3- (trifluoromethyl)benzyl]methanamine
572.32
1.24

476

355

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-fluoro- 3-(trifluoromethyl)benzyl]butan-1- amine
539.36
1.25

477

356

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-3- (trifluoromethyl)benzyl]methanamine
578.38
1.29

478

357

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2-fluoro-3- (trifluoromethyl)benzyl]methanamine
616.32
1.22

479

358

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-fluoro-4- (trifluoromethyl)benzyl]methanamine
573.35
1.25

480

359

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-fluoro- 4-(trifluoromethyl)benzyl]butan-1- amine
538.33
1.25

481

360

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-4- (trifluoromethyl)benzyl]methanamine
579.40
1.29

482

361

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2-fluoro-4- (trifluoromethy)benzyl]methanamine
616.32
1.24

483

362

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-fluoro-5- (trifluoromethyl)benzyl]methanamine
573.35
1.24

484

363

*
1-(1-butyl-2,4-diphenyl-1H- imidazo-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-5- (trifluoromethyl)benzyl]methanamine
579.40
1.28

485

364

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2-fluoro-5- (trifluoromethyl)benzyl]methanamine
617.35
1.23

486

365

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]methanamine
553.36
1.22

487

366

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]butan-1- amine
518.35
1.2

488

367

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]methanamine
559.41
1.26

489

368

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
596.34
1.21

490

369

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3-fluoro-4- (trifluoromethyl)benzyl]methanamine
572.32
1.24

491

370

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-fluoro- 4-(trifluoromethyl)benzyl]butan-1- amine
538.33
1.25

492

371

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-fluoro-4- (trifluoromethyl)benzyl]methanamine
579.40
1.28

493

372

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[3-fluoro-4- (trifluoromethyl)benzyl]methanamine
616.32
1.23

494

373

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]methanamine
552.29
1.22

495

374

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3- (trifluoromethyl)benzyl]butan-1- amine
518.30
1.2

496

375

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]methanamine
558.33
1.26

497

376

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[3- (trifluoromethyl)benzyl]methanamine
596.28
1.21

498

377

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (methylthio)benzyl]methanamine
532.31
1.24

499

378

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (methylthio)benzyl]butan-1-amine
498.33
1.2

500

379

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(2,2-dimethyl- 3,4-dihydro-2H-chromen-6- yl)methyl]methanamine
570.39
1.27

501

380

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(2,2- dimethyl-3,4-dihydro-2H-chromen- 6-yl)methyl]butan-1-amine
536.42
1.21

502

381

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(4- isopropylbenzyl)methanamine
528.37
1.28

503

382

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4- isopropylbenzyl)butan-1-amine
494.38
1.24

504

383

*
2-{[1-(2,3-dihydro-1H-inden-2-yl)- 2-phenyl-1H-imidazol-5-yl]methyl)- 1-(2-methylphenyl)-1,2,3,4- tetrahydroisoquinoline
496.30
1.24

505

384

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4-fluoro-3- (trifluoromethyl)benzyl]methanamine
616.30
1.23

506

385

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-fluoro- 5-(trifluoromethyl)benzyl]butan-1- amine
538.30
1.26

507

386

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-fluoro-5- (trifluoromethyl)benzyl]methanamine
578.34
1.28

508

387

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[3-fluoro-5- (trifluoromethyl)benzyl]methanamine
616.29
1.24

509

388

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4-chloro-3- (trifluoromethyl)benzyl]methanamine
588.28
1.26

510

389

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-chloro- 3-(trifluoromethyl)benzyl]butan-1- amine
554.30
1.25

511

390

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-chloro-3- (trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
594.33
1.3

512

391

1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4-chloro-3- (trifluoromethyl)benzyl]methanamine
632.28
1.24

513

392

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-chloro- 3-(trifluoromethyl)benzyl]butan-1- amine
554.28
1.26

514

393

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-chloro-3- (trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
594.32
1.3

515

394

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2-chloro-3- (trifluoromethyl)benzyl]methanamine
632.27
1.24

516

395

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-chloro-5- (trifluoromethyl)benzyl]methanamine
588.28
1.25

517

396

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-chloro- 5-(trifluoromethyl)benzyl]butan-1- amine
554.28
1.26

518

397

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-chloro-5- (trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
594.34
1.29

519

398

1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2-chloro-5- (trifluoromethyl)benzyl]methanamine
632.27
1.25

520

399

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2,3-difluoro- 4- (trifluoromethyl)benzyl]methanamine
590.28
1.24

521

400

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2,3- difluoro-4- (trifluoromethyl)benzyl]butan-1- amine
557.33
1.26

522

401

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2,3-difluoro- 4- (trifluoromethyl)benzyl]methanamine
596.34
1.29

523

402

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2,3-difluoro-4- (trifluoromethyl)benzyl]methanamine
634.28
1.23

524

403

N-benzyl-1-[2,4- bis(trifluoromethyl)phenyl]-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
622.30
1.27

525

404

N-[2,4-bis(trifluoromethyl)benzyl]- N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]butan-1- amine
589.34
1.28

526

405

1-[2,4-bis(trifluoromethyl)phenyl]- N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
628.34
1.31

527

406

N-benzyl-1-[2,5- bis(trifluoromethyl)phenyl]-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
622.32
1.26

528

407

*
1-(1,3-benzodioxol-5-yl)-N-[2,5- bis(trifluoromethyl)benzyl]-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
666.31
1.25

529

408

N-[3,5-bis(trifluoromethyl)benzyl]- N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]butan-1- amine
588.32
1.27

530

409

1-[3,5-bis(trifluoromethyl)phenyl]- N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
628.39
1.32

531

410

*
1-(1,3-benzodioxol-5-yl)-N-[3,5- bis(trifluoromethyl)benzyl]-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
667.33
1.25

532

411

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methylphenyl acetate
558.35
1.22

533

412

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methylphenyl acetate
524.37
1.19

534

413

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2,6- dimethylphenyl acetate
572.37
1.23

535

414

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2,6- dimethylphenyl acetate
538.38
1.2

536

415

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-fluoro-4- (trifluoromethyl)benzyl]-N-(4- methoxybenzyl)methanamine
602.35
1.25

537

416

*
N,N-dibenzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methanamine
486.35
1.23

538

417

4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2,6- dimethylphenyl methanesulfonate
608.37
1.21

539

418

*
N-butyl-N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]butan-1- amine
418.37
1.12

540

419

4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2,6- dimethylphenyl methanesulfonate
574.38
1.21

541

420

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (trifluoromethyl)benzyl]amino}methyl)- 2,6-dimethylphenol
598.37
1.25

542

421

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[4- (trifluoromethyl)benzyl]methanamine
620.34
1.23

543

422

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
620.28
1.22

544

423

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (trifluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
639.30
1.26

545

424

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
618.28
1.2

546

425

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[4- (trifluoromethoxy)benzyl]methanamine

547

426

4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][3- (trifluoromethyl)benzyl]amino}methyl)- 3-chlorophenol
604.25
1.22

548

427

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[2- fluoro-4- (trifluoromethyl)benzyl]methanamine
638.26
1.23

549

428

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3,4- dimethoxybenzyl)methanamine
546.32
1.19

550

429

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,4- dimethoxybenzyl)butan-1-amine
512.33
1.13

551

430

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,4- dimethoxybenzyl)methanamine
552.37
1.24

552

431

1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3,4- dimethoxybenzyl)methanamine
590.31
1.18

553

432

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3,5- dimethoxybenzyl)methanamine
546.32
1.23

554

433

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,5- dimethoxybenzyl)butan-1-amine
512.32
1.2

555

434

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,5- dimethoxybenzyl)methanamine
552.36
1.27

556

435

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3,5- dimethoxybenzyl)methanamine
590.31
1.21

557

436

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3,4- diethoxybenzyl)methanamine
574.35
1.23

558

437

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,4- diethoxybenzyl)butan-1-amine
540.36
1.17

559

438

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,4- diethoxybenzyl)methanamine
581.42
1.28

560

439

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3,4- diethoxybenzyl)methanamine

561

440

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(3,4- dimethoxybenzyl)methanamine
612.32
1.19

562

441

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,5- dimethoxybenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
614.30
1.23

563

442

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(3,5- dimethoxybenzyl)methanamine
612.31
1.21

564

443

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,4- diethoxybenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
640.34
1.22

565

444

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][3- (trifluoromethyl)benzyl]amino}methyl)benzenesulfonamide
633.27
1.15

566

445

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)benzenesulfonamide

567

446

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (trifluoromethoxy)benzyl]amino}methyl)benzenesulfonamide
649.27
1.16

568

447

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]pentan-1- amine
652.43
1.26

569

448

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]ethanamine
611.40
1.21

570

449

(1R)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]ethanamine
572.41
1.26

571

450

*
(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]pentan-1- amine
615.50
1.3

572

451

*
(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]ethanamine
572.41
1.26

573

452

*

610.37
1.22

574

453

*

652.42
1.26

575

454

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-chloro- 4-(difluoromethoxy)benzyl]butan- 1-amine
552.27
1.25

576

455

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-chloro-4- (difluoromethoxy)benzyl]methanamine
586.26
1.24

577

456

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][2-chloro-4- (difluoromethoxy)benzyl]amino}methyl)benzenesulfonamide
665.25
1.15

578

457

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)-3- methylbenzyl]butan-1-amine
533.35
1.21

579

458

*
N-benzyl-3-butyl-N-[4- (difluoromethoxy)benzyl]-2-phenyl- 3,4,5,6- tetrahydrocyclopenta[d]imidazol-4- amine
502.28
1.19

580

459

N-benzyl-3-butyl-2-phenyl-N-[3- (trifluoromethyl)benzyl]-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4- amine
504.27
1.22

581

460

*
N,3-dibutyl-N-[4- (difluoromethoxy)benzyl]-2-phenyl- 3,4,5,6- tetrahydrocyclopenta[d]imidazol-4- amine
468.33
1.2

582

461

*
N,3-dibutyl-2-phenyl-N-[3- (trifluoromethyl)benzyl]-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4- amine
470.30
1.23

583

462

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)-3- methylbenzyl]methanamine
566.31
1.24

584

463

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)-3,5- dimethylbenzyl]methanamine
580.37
1.25

585

464

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)-3,5- dimethylbenzyl]butan-1-amine
546.38
1.24

586

465

*
N,1-dibutyl-5,5-dimethyl-2-phenyl- N-[3-(trifluoromethyl)benzyl]- 4,5,6,7-tetrahydro-1H- benzimidazol-7-amine
281.21
1.23

587

466

*
1-butyl-N-[4- (difluoromethoxy)benzyl]-5,5- dimethyl-2-phenyl-N-[3- (trifluoromethyl)benzyl]-4,5,6,7- tetrahydro-1H-benzimidazol-7- amine
281.21
1.23

588

467

*
bis(1,3-benzodioxol-5-ylmethyl)(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methylamine oxide
590.29
1.22

589

468

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)-3- fluorobenzyl]butan-1-amine
590.29
1.23

590

469

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)-3- fluorobenzyl]methanamine
537.36
1.22

591

470

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)-3- fluorobenzyl]amino}methyl)benzenesulfonamide
570.33
1.22

592

471

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)-3,5-dimethyl benzyl]amino}methyl)benzenesulfonamide
649.33
1.13

593

472

*
(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]pentan-1- amine
659.36
1.17

594

473

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]pentan-1- amine
616.43
1.33

595

474

*
(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]ethanamine
654.38
1.28

596

475

*
(1R)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]ethanamine
612.33
1.23

597

476

*
(1R)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]pentan- 1-amine
574.37
1.28

598

477

*
(1S)-1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]ethanamine
616.42
1.32

599

478

*
(1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]ethanamine
574.37
1.29

600

479

*
(1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]pentan- 1-amine
612.33
1.24

601

480

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(4- ethoxybenzyl)methanamine
654.37
1.27

602

481

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4- ethoxybenzyl)butan-1-amine
530.32
1.25

603

482

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(4- ethoxybenzyl)methanamine
496.33
1.18

604

483

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(4- ethoxybenzyl)methanamine
536.37
1.29

605

484

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3- ethoxybenzyl)methanamine
574.32
1.23

606

485

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)butan-1-amine
530.32
1.25

607

486

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3- ethoxybenzyl)methanamine
496.33
1.21

608

487

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3- ethoxybenzyl)methanamine
536.36
1.29

609

488

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
574.32
1.23

610

489

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]butan-1- amine
602.29
1.22

611

490

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
568.30
1.23

612

491

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
608.33
1.27

613

492

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]methanamine
646.28
1.22

614

493

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3- (difluoromethoxy)benzyl]butan-1- amine
518.30
1.21

615

494

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3- (difluoromethoxy)benzyl]methanamine
559.36
1.26

616

495

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[3- (difluoromethoxy)benzyl]methanamine
596.29
1.21

617

496

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
620.27
1.23

618

497

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)benzyl]methanamine
618.28
1.21

619

498

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2- (difluoromethoxy)benzyl]methanamine
552.29
1.22

620

499

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2- (difluoromethoxy)benzyl]butan-1- amine
519.33
1.21

621

500

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2- (difluoromethoxy)benzyl]methanamine
559.37
1.26

622

501

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[2- (difluoromethoxy)benzyl]methanamine
596.28
1.21

623

502

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2- (difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
620.28
1.23

624

503

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)benzyl]methanamine
619.32
1.2

625

504

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)-3,5- dimethylbenzyl]methanamine
586.37
1.3

626

505

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4-(difluoromethoxy)- 3,5-dimethylbenzyl]methanamine
625.35
1.25

627

506

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)-3,5- dimethylbenzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
649.35
1.27

628

507

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3,5- dimethylbenzyl]methanamine
647.35
1.24

629

508

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4- (difluoromethoxy)-3- fluorobenzyl]methanamine
577.36
1.26

630

509

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4-(difluoromethoxy)- 3-fluorobenzyl]methanamine
614.28
1.21

631

510

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)-3-fluorobenzyl]- N-[3- (trifluoromethyl)benzyl]methanamine
638.27
1.23

632

511

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3- fluorobenzyl]methanamine
636.28
1.21

633

512

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)-3-methylbenzyl]- N-[3- (trifluoromethyl)benzyl]methanamine
634.29
1.25

634

513

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3- methylbenzyl]methanamine
632.31
1.23

635

514

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
588.33
1.24

636

515

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4-ethoxybenzyl)- N-[3- (trifluoromethyl)benzyl]methanamine
598.32
1.26

637

516

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(4- ethoxybenzyl)methanamine
596.32
1.23

638

517

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3-ethoxybenzyl)- N-[3- (trifluoromethyl)benzyl]methanamine
599.34
1.26

639

518

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
596.31
1.23

640

519

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
670.27
1.24

641

520

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[3- (1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
668.28
1.22

642

521

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4-methoxy-3- methylbenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
598.31
1.27

643

522

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(4- methoxy-3- methylbenzyl)methanamine
596.32
1.24

644

523

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1- benzofuran-5-ylmethyl)-N-[3- (trifluoromethyl)benzyl]methanamine
596.30
1.24

645

524

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(2,3- dihydro-1-benzofuran-5- ylmethyl)methanamine
594.31
1.22

646

525

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4-methoxy-3,5- dimethylbenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
613.36
1.27

647

526

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(4- methoxy-3,5- dimethylbenzyl)methanamine
611.37
1.24

648

527

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5- yl]methyl}methanamine
566.28
1.36

649

528

*
1-butyl-N-[4- (difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3-fluorobenzyl]- 5,5-dimethyl-2-phenyl-4,5,6,7- tetrahydro-1H-benzimidazol-7- amine
281.23
1.21

650

529

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4- (difluoromethoxy)benzyl]ethanamine
482.23
1.2

651

530

*
methyl 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-2- methoxybenzoate
540.36
1.18

652

531

*
methyl 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-methoxybenzoate
580.39
1.25

653

532

*
methyl 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methoxybenzoate
619.37
1.18

654

533

*
methyl 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl](isopentyl)amino]methyl}- 2-methoxybenzoate
554.37
1.21

655

534

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methoxybenzamide
525.36
1.14

656

535

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- hydroxybenzamide
511.34
1.16

657

536

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methoxybenzamide
604.37
1.15

658

537

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[4-(ethylthio)phenyl]-2- phenyl-1H-imidazol-5- yl}methyl)methanamine
634.40
1.25

659

538

*
5-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)- 1,3-benzoxazol-2(3H)-one
601.35
1.28

660

539

*
1-(1,3-benzodioxol-5-yl)-N-(1-3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[2-(methylthio)phenyl]-2- phenyl-1H-imidazol-5- yl}methyl)methanamine
620.39
1.22

661

540

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[(E)-2-(4- fluorophenyl)ethenyl]-2-phenyl-1H- imidazol-5- yl}methyl)methanamine
618.41
1.23

662

541

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[3-(methylthio)phenyl]-2- phenyl-1H-imidazol-5- yl}methyl)methanamine
621.41
1.23

663

542

*
1-(1,3-benzodioxol-5-yl)-N-{[4- (1,3-benzodioxol-5-yl)-1-butyl-2- phenyl-1H-imidazol-5-yl]methyl}-N- (1,3-benzodioxol-5- ylmethyl)methanamine
619.42
1.21

664

543

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(dimethoxymethyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
572.41
1.19

665

544

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(difluoromethyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
548.34
1.28

666

545

*
N,N-bis(1,3-benzodioxol-5- ylmethyl)-N-({1-butyl-4- [(methylamino)methyl]-2-phenyl- 1H-imidazol-5-yl}methyl)amine
541.40
1.18

667

546

*
(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)methanol
528.36
1.17

668

547

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
605.36
1.22

669

548

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethoxy)phenyl]-1H- imidazol-5- yl}methyl)methanamine
658.31
1.24

670

549

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
611.34
1.23

671

550

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine
566.31
1.4

672

551

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
639.31
1.36

673

552

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-nitrophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
619.32
1.23

674

553

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,6- difluorobenzyl)-N-(4- methoxybenzyl)methanamine
552.33
1.23

675

554

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- hydroxybenzoic acid
512.34
1.21

676

555

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-methoxybenzoic acid
566.39
1.21

677

556

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-hydroxybenzamide
551.39
1.22

678

557

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- hydroxybenzamide
545.34
1.17

679

558

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](isopentyl)amino]methyl}- 2-methoxybenzamide
539.39
1.16

680

559

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methoxybenzoic acid
560.34
1.17

681

560

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](isopentyl)amino]methyl}- 2-hydroxybenzamide
525.37
1.19

682

561

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- hydroxybenzoic acid
546.33
1.21

683

562

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2-chloro-6- fluorobenzyl)-N-(4- methoxybenzyl)methanamine
568.31
1.24

684

563

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
588.34
1.23

685

564

*
1-[1-butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5-yl]- N,N-bis(3- ethoxybenzyl)methanamine
596.34
1.42

686

565

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N,N-bis(3- ethoxybenzyl)methanamine
567.36
1.43

687

566

*
4-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4- yl)benzonitrile
599.32
1.2

688

567

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[4- (trifluoromethyl)phenyl]-1H- imidazol-5- yl}methyl)methanamine
642.30
1.24

689

568

7-[(butyl{[1-butyl-4-(3- methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]quinazolin- 4-amine

690

569

1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine

691

570

*
methyl 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2- methoxybenzoate
532.31
1.3

692

571

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2- methoxybenzoic acid
518.30
1.26

693

572

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2- methoxybenzamide
517.32
1.25

694

573

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2- hydroxybenzamide
503.30
1.25

695

574

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(1H-indol-5- ylmethyl)methanamine
569.36
1.2

696

575

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(1H-indol-5- ylmethyl)methanamine
525.36
1.21

697

576

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(1H-indol- 5-ylmethyl)butan-1-amine
491.38
1.12

698

577

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-1H-imidazol-5- yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
520.26
1.18

699

578

*
5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4-carboxylic acid
542.27
1.09

700

579

*
methyl 5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4- carboxylate
556.27
1.21

701

580

*
1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N,N-bis(3- ethoxybenzyl)methanamine
498.32
1.23

702

581

*
1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N-[3-(difluoromethoxy)benzyl]- N-[4- (difluoromethoxy)benzyl]methanamine
542.26
1.18

703

582

*
2-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)propan- 2-ol
556.32
1.15

704

583

*
1-(1,3-benzodioxol-5-yl)-N-[(4- bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
598.19
1.32

705

584

*
1-[1-butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis(3-ethoxybenzyl)methanamine
605.39
1.25

706

585

1-[1-butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis(3-ethoxybenzyl)methanamine

707

586

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-4-ethoxy-2-phenyl-1H- imidazol-5- yl)methyl]methanamine
257.18
1.18

708

587

*
1-[1-butyl-2-(3-methoxyphenyl)-4- phenyl-1H-imidazol-5-yl]-N,N- bis(3-ethoxybenzyl)methanamine
604.36
1.26

709

588

*
N-[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(3- ethoxybenzyl)amine
576.24
1.4

710

589

*
N-[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis[4- (difluoromethoxy)benzyl]amine
620.18
1.31

711

590

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(3- ethoxybenzyl)amine
532.29
1.4

712

591

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis[4- (difluoromethoxy)benzyl]amine
576.22
1.33

713

592

*
1-[1-butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
626.32
1.23

714

593

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4- (difluoromethoxy)benzyl]methanamine
626.30
1.21

715

594

*
1-[1-butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis[4- (difluoromethoxy)benzyl]methanamine
648.30
1.2

716

595

*
1-[1-butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
626.33
1.24

717

596

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4- (difluoromethoxy)benzyl]methanamine
626.30
1.21

718

597

*
1-[1-butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis[4- (difluoromethoxy)benzyl]methanamine
648.30
1.21

719

598

*
N-{[1-butyl-4-(3-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
640.34
1.26

720

599

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
640.31
1.23

721

600

*
N-{[1-butyl-4-(3-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine
619.40
1.28

722

601

*
N-{[1-butyl-4-(3-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine
662.31
1.23

723

602

*
1-(1-butyl-2-phenyl-4-thien-3-yl- 1H-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
602.28
1.22

724

603

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
598.19
1.31

725

604

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](4-hydroxy- 3,5- dimethylbenzyl)amino]methyl}benzenesulfonamide
609.35
1.12

726

605

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](4-hydroxy-3- methylbenzyl)amino]methyl}benzenesulfonamide
595.32
1.1

727

606

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)-3-methylbenzyl]amino}methyl)benzenesulfonamide
645.29
1.15

728

607

*
N-benzyl-1-[3,4- bis(difluoromethoxy)phenyl]-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
618.28
1.21

729

608

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]propan-1- amine
504.30
1.18

730

609

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]pentan-1- amine
532.33
1.22

731

610

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]cyclopentan- amine
530.32
1.21

732

611

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]propan-2- amine
504.29
1.18

733

612

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-2,2- dimethylpropan-1-amine
533.35
1.24

734

613

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-3- methylbutan-1-amine
533.35
1.22

735

614

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]cyclohex- anamine
544.33
1.23

736

615

*
N-[(1-butyl-2,4-diphenyl-1H- imidazal-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]ethanamine
490.28
1.16

737

616

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4- (difluoromethoxy)benzyl]pentan-1- amine
524.28
1.32

738

617

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4- (difluoromethoxy)benzyl]methanamine
544.24
1.37

739

618

*
N,1-dibutyl-N-[4- (difluoromethoxy)benzyl]-2-phenyl- 4,5,6,7-tetrahydro-1H- benzimidazol-7-amine
482.33
1.21

740

619

*
N,1-dibutyl-N-(4-methoxy-3,5- dimethylbenzyl)-2-phenyl-4,5,6,7- tetrahydro-1H-benzimidazol-7- amine
474.37
1.26

741

620

*
4-{[butyl(1-butyl-2-phenyl-4,5,6,7- tetrahydro-1H-benzimidazol-7- yl)amino]methyl}-2,6- dimethylphenol
460.34
1.21

742

621

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan-1- amine
510.27
1.28

743

622

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzene- sulfonamide
523.27
1.23

744

623

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- (4-methoxy-3,5- dimethylbenzyl)methanamine
603.39
1.39

745

624

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- [4-(difluoromethoxy)-3,5- dimethylbenzyl]methanamine
639.38
1.37

746

625

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
588.30
1.34

747

626

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- [4-(difluoromethoxy)-3- fluorobenzyl]methanamine
628.29
1.32

748

627

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-(4-methoxy-3,5- dimethylbenzyl)butan-1-amine
502.37
1.27

749

628

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)benzenesulfonamide
623.26
1.24

750

629

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N,N-bis[4- (difluoromethoxy)benzyl]methanamine
610.26
1.33

751

630

*
5-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- (difluoromethoxy)phenol
568.28
1.21

752

631

*
5-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- (difluoromethoxy)phenol
534.30
1.17

753

632

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](4-methoxy- 3,5- dimethylbenzyl)amino]methyl}ben- zenesulfonamide
623.33
1.16

754

633

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2-chloro-4- hydroxybenzyl)amino]methyl}benzenesulfonamide
615.25
1.12

755

634

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](3-fluoro-4- methoxybenzyl)amino]methyl}benzenesulfonamide
613.29
1.12

756

635

*
4-({[4-(aminosulfonyl)benzyl][(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)phenyl acetate
623.29
1.11

757

636

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}phenyl acetate
574.31
1.2

758

637

*
2-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)phenol
590.28
1.21

759

638

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- methylphenyl 3-methylbutanoate
567.40
1.26

760

639

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- methylphenyl 3-methylbutanoate
600.36
1.28

761

640

*
2-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-4- phenyl-1H-imidazol-2-yl)phenol
590.28
1.22

762

641

*
4-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)phenol
590.27
1.2

763

642

*
N-(1,3-benzodioxol-5-ylmethyl)-N- {[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}butan-1-amine
488.25
1.25

764

643

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)- 3-fluorobenzyl]butan-1-amine
528.24
1.34

765

644

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)- 3,5-dimethylbenzyl]butan-1-amine
538.28
1.32

766

645

*
4-[(benzyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzene- sulfonamide
557.22
1.26

767

646

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxybenzyl)-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
575.42
1.25

768

647

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(4-methoxy- 3,5-dimethylbenzyl)methanamine
551.45
1.3

769

648

*
4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- fluorophenol
520.32
1.19

770

649

*
4-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- fluorophenol
486.34
1.15

771

650

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](3-fluoro-4- hydroxybenzyl)amino]methyl}benzenesulfonamide
599.33
1.08

772

651

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}-2- fluorophenol
550.34
1.18

773

652

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(cyclohex-3-en-1- ylmethyl)-N- (cyclohexylmethyl)methanamine
496.39
1.32

774

653

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}cyclohexane-1,2-diol
530.41
1.2

775

654

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(hexahydro- 1,3-benzodioxol-5- ylmethyl)methanamine
542.42
1.26

776

655

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(cyclohex-3-en-1- ylmethyl)-N-[4- (difluoromethoxy)benzyl]methanamine
556.34
1.25

777

656

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)cyclohexane-1,2-diol
590.36
1.15

778

657

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N- (hexahydro-1,3-benzodioxol-5- ylmethyl)methanamine
602.35
1.19

779

658

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
632.31
1.24

780

659

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[(2,2- difluoro-1,3-benzodioxol-5- yl)methyl]methanamine
573.38
1.29

781

660

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(2,2- difluoro-1,3-benzodioxol-5- yl)methyl]-3-methylbutan-1-amine
546.33
1.26

782

661

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]hexan-1- amine
547.40
1.25

783

662

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(2,2- difluoro-1,3-benzodioxol-5- yl)methyl]butan-1-amine
532.32
1.25

784

663

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]heptan-1- amine
560.39
1.26

785

664

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]octan-1- amine
574.41
1.28

786

665

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-3,3- dimethylbutan-1-amine
546.38
1.23

787

666

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-2-cyclohex- 1-en-1-yl-N-[4- (difluoromethoxy)benzyl]ethanamine
570.38
1.26

788

667

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-fluorophenol
526.37
1.24

789

668

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(2,2-difluoro- 1,3-benzodioxol-5- yl)methyl]methanamine
566.32
1.24

790

669

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][(2,2-difluoro- 1,3-benzodioxol-5- yl)methyl]amino}methyl)benzene- sulfonamide
645.31
1.16

791

670

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
596.33
1.25

792

671

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][3-(1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)benzenesulfonamide
681.33
1.14

793

672

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](3- ethoxybenzyl)amino]methyl}ben- zenesulfonamide
609.36
1.16

794

673

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxybenzyl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
632.35
1.23

795

674

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3-ethoxybenzyl)- N-(4- methoxybenzyl)methanamine
560.37
1.25

796

675

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)-3- fluorobenzyl]methanamine
562.27
1.36

797

676

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(4-methoxy-3,5- dimethylbenzyl)methanamine
536.32
1.43

798

677

*
N,N-dibenzyl-1-[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5- yl]methanamine
478.28
1.4

799

678

*
1-(1,3-benzodioxol-5-yl)-N-benzyl- N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}methanamine
522.28
1.39

800

679

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
594.28
1.37

801

680

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(4-hydroxy-3,5- dimethylbenzyl)amino]methyl}ben- zenesulfonamide
601.29
1.23

802

681

*
4-[(benzyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2- fluorophenol
512.28
1.32

803

682

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- [3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
660.28
1.34

804

683

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- (3-fluoro-4- methoxybenzyl)methanamine
592.29
1.34

805

684

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)-2-fluorophenol
578.29
1.29

806

685

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4-(difluoromethoxy)-3- fluorobenzyl]amino}methyl)ben- zenesulfonamide
641.24
1.23

807

686

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(2-chloro-4- hydroxybenzyl)amino]methyl}ben- zenesulfonamide
607.22
1.22

808

687

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzene- sulfonamide
601.25
1.24

809

688

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5- yl)methyl]methanamine
532.23
1.31

810

689

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(3-fluoro-4- methoxybenzyl)methanamine
526.29
1.37

811

690

*
4-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl{-1-butyl-4- phenyl-1H-imidazol-2-yl)phenol
590.32
1.2

812

691

*
4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][3- (difluoromethoxy)benzyl]amino}methyl)benzenesulfonamide
631.32
1.13

813

692

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](3- methoxybenzyl)amino]methyl}ben- zenesulfonamide
595.33
1.13

814

693

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]-N-(4- methoxybenzyl)methanamine
582.34
1.22

815

694

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3- methoxybenzyl)-N-(4- methoxybenzyl)methanamine
546.35
1.22

816

695

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[(2,2-difluoro-1,3-benzodioxol-5- yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
624.25
1.36

817

696

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[(2,2-difluoro-1-3- benzodioxol-5- yl)methyl]amino}methyl)benzene- sulfonamide
637.24
1.27

818

697

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4- bromo-1-butyl-2-phenyl-1H- imidazol-5- yl)methyl]methanamine
576.21
1.31

819

698

*
1-(1,3-benzodioxol-5-yl)-N-(1-3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}methanamine
596.27
1.35

820

699

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- (3-ethoxybenzyl)methanamine
588.30
1.38

821

700

*
N-benzyl-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(3-ethoxybenzyl)methanamine
522.30
1.41

822

701

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzene- sulfonamide
623.30
1.14

823

702

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)ethyl]amino}methyl)benzene sulfonamide
623.30
1.13

824

703

*
4-{[[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)ethyl](cyclohexylmethyl)amino]methyl}benzenesulfonamide
303.21
1.1

825

704

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)pentyl]amino}methyl)benzene- sulfonamide
665.37
1.19

826

705

*
N-(1,3-benzodioxol-5-ylmethyl)-1- (1-butyl-2-phenyl-1H-imidazol-5- yl)-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]pentan-1- amine

827

706

*
N-(1,3-benzodioxol-5-ylmethyl)-1- (1-butyl-2-phenyl-1H-imidazol-5- yl)-N-[4- (difluoromethoxy)benzyl]pentan- 1-amine
576.32
1.22

828

707

*
N-(1,3-benzodioxol-5-ylmethyl)-1- (1-butyl-2-phenyl-1H-imidazol-5- yl)-N-(3-ethoxybenzyl)pentan-1- amine
554.34
1.25

829

708

*
N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2-phenyl-1H- imidazol-5-yl)pentan-1-amine
554.31
1.23

830

709

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)pentyl]amino}methyl)benzene- sulfonamide
665.34
1.18

831

710

*
methyl 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzoate
502.29
1.35

832

711

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzoic acid
488.27
1.28

833

712

*
4-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzamide
487.32
1.25

834

713

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3-(1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)benzenesulfonamide
673.27
1.24

835

714

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(diphenylphosphoryl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
698.34
1.22

836

715

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(2-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
604.34
1.22

837

716

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
619.32
1.35

838

717

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(3-ethoxybenzyl)amino]methyl}benzenesulfonamide
601.25
1.27

839

718

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2- methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzene- sulfonamide
631.22
1.24

840

719

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2- methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-2,6- dimethylphenol
596.29
1.3

841

720

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-(3- ethoxybenzyl)methanamine

842

721

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)- 3-fluorobenzyl]methanamine
637.26
1.34

843

722

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[3- (difluoromethoxy)benzyl]methanamine
619.27
1.34

844

723

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(2,3- difluorobenzyl)methanamine
522.31
1.23

845

724

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(2,3- difluorobenzyl)butan-1-amine
488.32
1.25

846

725

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(2,3- difluorobenzyl)methanamine
529.39
1.28

847

726

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(2,3- difluorobenzyl)methanamine
567.34
1.21

848

727

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3- difluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
591.34
1.23

849

728

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3- difluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
588.31
1.24

850

729

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(3,5- difluorobenzyl)methanamine
522.32
1.24

851

730

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,5- difluorobenzyl)butan-1-amine
489.35
1.23

852

731

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,5- difluorobenzyl)methanamine
528.37
1.29

853

732

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3,5- difluorobenzyl)methanamine
567.34
1.22

854

733

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,5- difluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
590.30
1.24

855

734

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,5- difluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
588.31
1.22

856

735

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3-chloro-4- fluorobenzyl)-N- (cyclohexylmethyl)methanamine
544.35
1.29

857

736

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(3-chloro-4- fluorobenzyl)methanamine
582.29
1.23

858

737

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3-chloro-4- fluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
604.29
1.23

859

738

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(4-chloro-3- fluorobenzyl)methanamine
538.29
1.25

860

739

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4-chloro- 3-fluorobenzyl)butan-1-amine
504.30
1.24

861

740

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4-chloro-3- fluorobenzyl)-N- (cyclohexylmethyl)methanamine
544.35
1.29

862

741

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(4-chloro-3- fluorobenzyl)methanamine
582.29
1.24

863

742

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4-chloro-3- fluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
606.28
1.25

864

743

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(2-chloro- 4-fluorobenzyl)butan-1-amine
504.30
1.25

865

744

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2-chloro-4- fluorobenzyl)-N- (cyclohexylmethyl)methanamine
544.35
1.3

866

745

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-(2-chloro-4- fluorobenzyl)methanamine
582.29
1.24

867

746

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2-chloro-4- fluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
606.28
1.25

868

747

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2-chloro-4- fluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
604.28
1.24

869

748

*
N-benzyl-1-(3-bromo-4- fluorophenyl)-N-[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]methanamine
582.26
1.24

870

749

*
N-(3-bromo-4-fluorobenzyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1-amine
548.26
1.25

871

750

*
1-(3-bromo-4-fluorophenyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N- (cyclohexylmethyl)methanamine
588.30
1.3

872

751

*
1-(1,3-benzodioxol-5-yl)-N-(3- bromo-4-fluorobenzyl)-N-[(1-butyl- 2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
626.25
1.23

873

752

*
1-(3-bromo-4-fluorophenyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
648.25
1.23

874

753

*
3-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)phenol
590.27
1.2

875

754

*
3-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-4- phenyl-1H-imidazol-2-yl)phenol
590.27
1.21

876

755

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2- methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-3- chlorophenol
602.20
1.32

877

756

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H- imidazol-5- yl)methyl]methanamine
580.22
1.2

878

757

*
methyl 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}benzoate
516.28
1.36

879

758

*
methyl 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isobutyl)amino]methyl}benzoate
502.26
1.37

880

759

methyl 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}benzoate
542.30
1.45

881

760

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}benzoic acid
502.26
1.3

882

761

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isobutyl)amino]methyl}benzoic acid
488.25
1.32

883

762

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}benzoic acid
528.28
1.39

884

763

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}benzamide
527.30
1.34

885

764

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isobutyl)amino]methyl}benzamide
487.27
1.28

886

765

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}benzamide
501.29
1.25

887

766

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(pentafluoroethyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
616.34
1.4

888

767

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(pentafluoroethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
688.36
1.38

889

768

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(pentafluoroethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4- (difluoromethoxy)benzyl]methanamine
638.35
1.37

890

769

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(pentafluoroethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine
616.38
1.44

891

770

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(pentafluoroethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [3- (difluoromethoxy)benzyl]methanamine
638.34
1.37

892

771

*
methyl 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3- (difluoromethoxy)benzyl]amino}methyl)benzoate
602.35
1.33

893

772

*
1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)methanamine
520.26
1.21

894

773

*
1-[4-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)phenyl]ethanone
528.29
1.19

895

774

*
1-[4-({butyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)phenyl]ethanone
494.3
1.18

896

775

*
1-[4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)phenyl]ethanone
572.29
1.18

897

776

*
1-[4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)phenyl]ethanone
594.29
1.18

898

777

*
N-[4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)phenyl]acetamide
543.31
1.17

899

778

*
N-[4-({butyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)phenyl]acetamide
509.33
1.13

900

779

*
N-[4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)phenyl]acetamide
587.31
1.17

901

780

*
N-[4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)phenyl]acetamide
609.31
1.18

902

781

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(6- methylpyridin-2- yl)methyl]methanamine
501.30
1.1

903

782

*
N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(6- methylpyridin-2-yl)methyl]butan-1- amine
467.31
1.09

904

783

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(6-methylpyridin-2- yl)methyl]methanamine
545.30
1.09

905

784

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[(6- methylpyridin-2- yl)methyl]methanamine
567.37
1.1

906

785

*
N-[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
598.27
1.36

907

786

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[4-(methylthio)phenyl]-2- phenyl-1H-imidazol-5- yl}methyl)methanamine
620.32
1.24

908

787

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[4-(methylsulfonyl)phenyl]- 2-phenyl-1H-imidazol-5- yl}methyl)methanamine
652.32
1.19

909

788

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- [4- (methylthio)benzyl]methanamine
590.27
1.38

910

789

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (methylthio)benzyl]amino}methyl) benzenesulfonamide
603.27
1.27

911

790

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[4- (methylthio)benzyl]methanamine
598.28
1.4

912

791

1-[1-butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-[4-(difluoromethoxy)benzyl]-N- [4- (methylthio)benzyl]methanamine
621.33
1.37

913

792

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]-N-[4- (methylthio)benzyl]methanamine
599.35
1.23

914

793

1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[4- (methylsulfonyl)benzyl]methanamine
600.27
1.26

915

794

*
methyl 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)benzoate
603.32
1.34

916

795

*
methyl 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzoate
581.32
1.36

917

796

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzoic acid
566.29
1.31

918

797

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)benzoic acid
588.28
1.29

919

798

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4-(difluoromethoxy) benzyl]amino}methyl)benzamide
587.29
1.26

920

799

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzamide
565.29
1.27

921

800

*
methyl 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3-(1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)benzoate
652.37
1.33

922

801

*
methyl 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(3- ethoxybenzyl)amino]methyl}benzoate
580.39
1.39

923

802

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3- (difluoromethoxy)benzyl]amino}methyl)benzoic acid
588.35
1.28

924

803

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3-(1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)benzoic acid
638.36
1.3

925

804

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(3- ethoxybenzyl)amino]methyl}benzic acid
566.38
1.34

926

805

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3- (trifluoromethyl)benzyl]amino}methyl)benzoic acid
590.35
1.32

927

806

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3- (difluoromethoxy)benzyl]amino}methyl)benzamide
587.37
1.26

928

807

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(3- ethoxybenzyl)amino]methyl}benzamide
565.39
1.3

929

808

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3-(1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)benzamide
637.38
1.27

930

809

*
4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[3- (trifluoromethyl)benzyl]amino}methyl)benzamide
589.36
1.29

931

810

*
5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4- carbonitrile
523.33
1.3

932

811

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-pyrazin-2-yl-1H- imidazol-5- yl)methyl]methanamine
576.27
1.15

933

812

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-phenyl-4-(1,3-thiazol-2-yl)- 1H-imidazol-5- yl]methyl}methanamine
581.23
1.15

934

813

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-phenyl-4-(phenylethynyl)- 1H-imidazol-5- yl]methyl}methanamine
598.28
1.28

935

814

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-4-[(1E)-pent-1-enyl]-2- phenyl-1H-imidazol-5- yl}methyl)methanamine
566.31
1.23

936

815

*

566.31
1.24

937

816

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-vinyl-1H-imidazol- 5-yl)methyl]methanamine
524.25
1.19

938

817

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-pyridin-2-yl-1H- imidazol-5- yl)methyl]methanamine
575.28
1.15

939

818

*
1-[4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)phenyl]ethanone
587.27
1.3

940

819

*
1-{4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]phenyl}ethanone
564.24
1.32

941

820

*
4-[((4-acetylbenzyl){[1-butyl-2- phenyl-4-(trifluoromethyl)-1H- imidazol-5- yl]methyl}amino)methyl]benzenesulfonamide
599.23
1.2

942

821

*
N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]ethanamine
580.27
1.37

943

822

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(1-naphthyl)-2-phenyl-1H- imidazol-5- yl]methyl}methanamine
624.31
1.24

944

823

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-pyridin-3-yl-1H- imidazol-5- yl)methyl]methanamine
575.29
1.21

945

824

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-ethoxyphenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
618.30
1.24

946

825

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(5-methylthien-2-yl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
595.29
1.24

947

826

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[2- (trifluoromethyl)phenyl]-1H- imidazol-5- yl}methyl)methanamine
643.32
1.25

948

827

*
5-({(1,3-benzodioxol-5-ylmethyl)[4- (difluoromethoxy)benzyl]amino}methyl)-1-butyl-2-phenyl-1H- imidazole-4-carbonitrile
545.25
1.3

949

828

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-cyano-2- phenyl-1H-imidazol-5- yl)methyl]amino}methyl)benzene- sulfonamide
558.25
1.22

950

829

*
4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-cyano-2- phenyl-1H-imidazol-5- yl)methyl]amino}methyl)benzamide
522.27
1.22

951

830

*
5-{[(1,3-benzodioxol-5-ylmethyl)(3- ethoxybenzyl)amino]methyl}-1- butyl-2-phenyl-1H-imidazole-4- carbonitrile
523.29
1.34

952

831

*
5-({(1,3-benzodioxol-5-ylmethyl)[3- (1,1,2,2- tetrafluoroethoxy)benzyl]amino}methyl)-1-butyl-2-phenyl-1H- imidazole-4-carbonitrile
596.29
1.3

953

832

*
5-({(1,3-benzodioxol-5-ylmethyl)[3- (difluoromethoxy)benzyl]amino}methyl)-1-butyl-2-phenyl-1H- imidazole-4-carbonitrile
546.28
1.29

954

833

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-4-methyl-2-phenyl-1H- imidazol-5- yl)methyl]methanamine
512.27
1.19

955

834

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-4-ethyl-2-phenyl-1H- imidazol-5- yl)methyl]methanamine
526.30
1.2

956

835

*
N-[1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
554.28
1.36

957

836

611.25
1.22

958

837

*
5-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-2- (methylamino)benzenethiol
512.33
1.23

959

838

*
5-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-2- (methylamino)benzenethiol
546.33
1.26

960

839

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(4-ethoxyphenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
618.35
1.23

961

840

*
ethyl (2E)-3-(5-{[bis(1,3- benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)prop-2- enoate
596.31
1.23

962

841

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1- butyl-2-phenyl-4-thien-2-yl-1H- imidazol-5- yl)methyl]methanamine
580.28
1.22

963

842

*
1-[5-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)thien-2- yl]ethanone
622.28
1.25

964

843

*
6-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)-3-methyl- 1,3-benzothiazol-2(3H)-one
539.33
1.18

965

844

*
1-(1-butyl-2-phenyl-4-thien-3-yl- 1H-imidazol-5-yl)-N,N-bis(3- ethoxybenzyl)methanamine

966

845

*
1-(1-butyl-2-phenyl-4-thien-3-yl- 1H-imidazol-5-yl)-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
624.24
1.2

967

846

*
2-(aminocarbonyl)-5-[(butyl{[1- butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}amino)methyl]phenyl acetate
583.35
1.18

968

847

*
4-[(butyl{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]-2- hydroxybenzamide
541.33
1.16

969

848

*
2-(aminocarbonyl)-5-{[{[1-butyl-4- (4-methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}(isopentyl)amino]methyl}phenyl acetate
597.36
1.21

970

849

*
4-{[{[1-butyl-4-(4-methoxyphenyl)- 2-phenyl-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}- 2-hydroxybenzamide
555.35
1.18

971

850

*
2-(aminocarbonyl)-5-{[{[1-butyl-4- (4-methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}phenyl acetate
623.38
1.24

972

851

*
4-{[{[1-butyl-4-(4-methoxyphenyl)- 2-phenyl-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}-2-hydroxybenzamide
581.37
1.23

973

852

*
2-(aminocarbonyl)-5-[((1,3- benzodioxol-5-ylmethyl){[1-butyl-4- (4-methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]phenyl acetate
661.33
1.18

974

853

*
4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]-2- hydroxybenzamide
619.32
1.17

975

854

*
ethyl 5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4- carboxylate
570.27
1.23

976

855

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
554.22
1.32

977

856

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(methoxymethyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
542.28
1.18

978

857

*
N-{[1-butyl-4-(4-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
610.33
1.24

979

858

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
610.30
1.22

980

859

*
N-{[1-butyl-4-(4-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine
588.36
1.28

981

860

*
N-{[1-butyl-4-(4-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine
632.30
1.21

982

861

*
N-{[1-butyl-4-(3-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
611.36
1.24

983

862

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
610.30
1.22

984

863

*
N-{[1-butyl-4-(3-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine
588.36
1.27

985

864

*
N-{[1-butyl-4-(3-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine
632.29
1.22

986

865

*
N-{[1-butyl-4-(4-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine
614.30
1.23

987

866

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine
614.28
1.21

988

867

*
N-{[1-butyl-4-(4-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine
592.34
1.26

989

868

*
N-{[1-butyl-4-(4-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine
636.28
1.2

990

869

*
5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl- N,N-dimethyl-2-phenyl-1H- N,N-dimethyl-2-phenyl-1H- imidazole-4-carboxamide
583.38
1.23

991

870

*
isopropyl 5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl- 2-phenyl-1H-imidazole-4- carboxylate
523.37
1.31

992

871

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(ethoxymethyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine
585.42
1.22

993

872

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3,5-dimethylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
585.42
1.24

994

873

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodiaxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethyl)phenyl]-1H- yl}methyl)methanamine
539.39
1.24

995

874

*
1-(1,3-benzodioxol-5-yl)-N-(1-3- benzodioxol-5-ylmethyl)-N-({1- butyl-2-phenyl-4-[3- (trifluoromethoxy)phenyl]-1H- imidazol-5- yl}methyl)methanamine
605.41
1.23

996

875

*
7-[(butyl{[1-butyl-4-(3- methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]-2,3- dihydroquinazolin-4(1H)-one
583.38
1.23

997

876

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(1-methyl-1H-indol-5- yl)methyl]methanamine
523.37
1.31

998

877

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(cyclohexylmethyl)-N-(1H-indol- 5-ylmethyl)methanamine
585.42
1.22

999

878

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N-[(1-methyl-2,3- dihydro-1H-indol-5- yl)methyl]methanamine
585.42
1.24

1000

879

*
N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(1-methyl-1H- indol-5-yl)methyl]methanamine
539.39
1.24

1001

880

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[(1- methyl-2,3-dihydro-1H-indol-5- yl)methyl]methanamine
605.41
1.23

1002

881

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-(1H- indol-5-ylmethyl)methanamine
561.33
1.29

1003

882

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-(1H-indol-5- ylmethyl)butan-1-amine
483.34
1.15

1004

883

*
N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-[(1-methyl-1H-indol-5- yl)methyl]butan-1-amine
497.35
1.18

1005

884

*
1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]- N-(cyclohexylmethyl)-N-[(1- methyl-1H-indol-5- yl)methyl]methanamine
537.39
1.37

1006

885

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-[(1- methyl-1H-indol-5- yl)methyl]methanamine
605.39
1.23

1007

886

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[(1- methyl-1H-indol-5- yl)methyl]methanamine
575.33
1.34

1008

887

*
1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]-N-(1H- indol-5-ylmethyl)methanamine
591.38
1.2

1009

888

*
1-(1,3-benzodioxol-5-yl)-N-(2,1,3- benzoxadiazol-5-ylmethyl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5- yl]methyl}methanamine

1010

889

*
1-(1,3-benzodioxol-5-yl)-N-(2,1,3- benzoxadiazol-5-ylmethyl)-N-{[1- butyl-4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}methanamine
602.36
1.2

1011

890

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-1H-imidazol-5- yl)methyl]-N-(3- ethoxybenzyl)methanamine
498.33
1.19

1012

891

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-1H-imidazol-5- yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
570.30
1.18

1013

892

*
1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-ethoxy-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
257.21
1.21

1014

893

*
1-(1,3-benzodioxol-5-yl)-N-[(4- bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
576.27
1.35

1015

894

*
1-(1,3-benzodioxol-5-yl)-N-[(4- bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]methanamine
648.25
1.34

1016

895

*
1-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)ethanol

1017

896

*
N-{[1-butyl-4-(3-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine

1018

897

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine

1019

898

*
N-{[1-butyl-4-(3-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine

1020

899

*
N-{[1-butyl-4-(3-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine

1021

900

*
N-{[1-butyl-4-(4-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine

1022

901

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-ethoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine

1023

902

*
N-{[1-butyl-4-(4-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine

1024

903

*
N-{[1-butyl-4-(4-ethoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine

1025

904

*
1-[1-butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine

1026

905

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4- (difluoromethoxy)benzyl]methanamine

1027

906

*
1-[1-butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis(3-ethoxybenzyl)methanamine

1028

907

*
1-[1-butyl-4-(3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]-N,N- bis[4- (difluoromethoxy)benzyl]methanamine

1029

908

*
N-{[1-butyl-4-(3-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine

1030

909

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine

1031

910

*
N-{[1-butyl-4-(3-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine

1032

911

*
N-{[1-butyl-4-(3-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine

1033

912

*
N-{[1-butyl-4-(4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N- [4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)amine

1034

913

*
1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]methanamine

1035

914

*
N-{[1-butyl-4-(4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis(3-ethoxybenzyl)amine

1036

915

*
N-{[1-butyl-4-(4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}- N,N-bis[4- (difluoromethoxy)benzyl]amine

1037

916

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine

1038

917

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine

1039

918

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine

1040

919

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine

1041

920

*
1-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4-yl)ethanone

1042

921

*
5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4- carbaldehyde

1043

922

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1- butyl-2-phenyl-4-(phenylthio)-1H- imidazol-5- yl]methyl}methanamine

1044

923

*
ethyl 5-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]amino}methyl)indoline-1- carboxylate

1045

924

*
ethyl 5-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)indoline-1-carboxylate

1046

925

N-benzyl-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[2-chloro-3- (trifluoromethyl)benzyl]methanamine

[0498]

13

TABLE III

Ca2+

CMP #
STRUCTURE
Mob.
IUPAC NAME
MASS

1047

926

*
7-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}methyl) quinazolin-4-ol
478.037

1048

927

*
1-(1,3-benzodioxol-5-yl)-N-{[2-(1,3- benzodioxol-5-yl)-1-butyl-4-phenyl-1H- imidazol-5-yl]methyl}-N-(1,3- benzodioxol-5-ylmethyl)methanamine
617.698

1049

928

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl- 2-(1-naphthyl)-4-phenyl-1H-imidazol-5- yl]methyl}methanamine
623.749

1050

929

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (2-naphthyl)-4-phenyl-1H-imidazol-5- yl]methyl}methanamine
623.749

1051

930

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{(1-butyl-2- (3-ethoxyphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}methanamine
617.742

1052

931

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (2-fluorophenyl)-4-phenyl-1H- imidazol-5-yl]methyl}methanamine
591.68

1053

932

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (3-methylphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}methanamine
587.716

1054

933

*
1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)-N,N- bis(cyclohexylmethyl)methanamine
497.766

1055

934

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (2-methoxyphenyl)-4-phenyl-1H- imidazol-5-yl]methyl]methanamine
603.715

1056

935

*
1-[1-butyl-2-(2-methoxyphenyl)-4- phenyl-1H-imidazol-5-yl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl)methanamine
617.786

1057

936

*
N-{[-butyl-2-(2-methylphenyl)-4- phenyl-1H-imidazol-5-yl]methyl}-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine
601.787

1058

937

*
5-{[bis(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}-1-butyl-2- phenyl-1H-imidazole-4-carbonitrile
550.656

1059

938

*
N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
529.652

1060

939

*
N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amine
543.636

1061

940

*
4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5- yl)methyl]amino-methyl) benzenesulfonamide
489.081

1062

941

*
4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5- yl)methyl]amino}methyl)benzamide
453.027

1063

942

*
methyl 2-amino-4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)benzoate
524.705

1064

943

*
7-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]amino}methyl)quinazolin-4-ol
519.689

1065

944

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N- (tetrahydro-2H-pyran-4- ylmethyl)amine
510.074

1066

945

*
1-(5-butyl-3-chloro-6-phenylpyridazin- 4-yl)-N-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
558.118

1067

946

*
1-(5-butyl-3-ethoxy-6-phenylpyridazin- 4-yl)-N-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
567.726

1068

947

*
N-(1,3-benzodioxol-5-ylmethyl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-4-isopropylaniline
557.734

1069

948

*
1-[1-butyl-2-(2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine
609.685

1070

949

*
4-({(1,3-benzodioxol-5-ylmethyl)[(1- butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-N,N- dimethylcyclohexanamine
578.796

1071

950

*
1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)-N-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)-N-(tetrahydro-2H-pyran-4- ylmethyl)methanamine
551.727

1072

951

*
1-(5-butyl-3-morpholin-4-yl-6- phenylpyndazin-4-yl)-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
608.779

1073

952

*
N˜1˜-(5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-6- phenylpyridazin-3-yl)-N˜2˜,N˜2˜- dimethylethane-1,2-diamine
609.81

1074

953

*
N-{[1-butyl-2-(2-methylphenyl)-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
593.686

1075

954

*
N-[1-(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)ethyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
560.134

1076

955

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4- chloro-2-(2-methoxyphenyl)-1H- imidazol-5-yl]methyl}methanamine
562.063

1077

956

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-1-(3- ethoxyphenyl)ethanamine
560.134

1078

957

*
1-(5-butyl-6-phenyl-3-pyrrolidin-1- ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N- methylmethanamine
472.629

1079

958

*
1-(5-butyl-6-phenyl-3-piperidin-1- ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N- methylmethanamine
486.656

1080

959

*
methyl 4-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}cyclohexanecarboxylate
566.138

1081

960

*
4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl) cyclohexanecarboxylic acid
552.111

1082

961

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-1-(2,3-dihydro- 1,4-benzadioxin-6-yl)-N-(3- ethoxybenzyl)ethanamine
560.134

1083

962

*
N-[(5-butyl-6-phenylpyrimidin-4- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
523.673

1084

963

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N- (cyclopropylmethyl)-N-(2,3-dihydro- 1,4-benzadioxin-6-ylmethyl)amine
466.022

1085

964

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-ylmethyl)-N-[(6- methoxypyridin-3-yl)methyl]amine
533.069

1086

965

*
5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)(methyl)amino]methyl]-6- phenyl-N,N-dipropylpyridazin-3- amine
502.699

1087

966

*
1-[3-chloro-5-methyl-6-(2- methylphenyl)pyridazin-4-yl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl)methanamine
530.065

1088

967

*
5-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}pyridin-2-ol
519.042

1089

968

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- propoxybenzyl)amine
560.134

1090

969

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- isopropoxybenzyl)amine
560.134

1091

970

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H- indazol-6-ylmethyl)amine
542.08

1092

971

*
methyl 4-({[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl][(2- methyl-1,3-benzothiazol-5- yl)methyl]amino}methyl)benzoate
573.158

1093

972

*
4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
546.064

1094

973

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(3,5- dimethyl-1H-pyrazol-4- yl)methyl]amine
520.074

1095

974

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-(3-ethoxybenzyl)-N-{[5-methyl-6-(2- methylphenyl)-3-pyrrolidin-1- ylpyridazin-4-yl]methyl}methanamine
564.726

1096

975

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-(3-ethoxybenyl)-N-{[5-methyl-6-(2- methylphenyl)-3-pipendin-1- ylpyridazin-4-yl]methyl}methanamine
578.753

1097

976

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(6- methoxypyridin-2-yl)methyl]amine
533.069

1098

977

*
4-({[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl][(2-methyl-1,3- benzothiazol-5- yl)methyl]amino}methyl)benzoic acid
559.131

1099

978

*
3-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]propan-1-ol
470.01

1100

979

*
1-{5-butyl-6-phenyl-3-pyrrolidin-1- ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
592.78

1101

980

*
1-(5-butyl-6-phenyl-3-piperidin-1- ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
606.806

1102

981

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H- indazol-5-ylmethyl)amine
542.08

1103

982

*
1-(5-butyl-3-isopropoxy-6- phenylpyridazin-4-yl)-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
581.753

1104

983

*
1-(5-butyl-3-isobutoxy-6- phenylpyridazin-4-yl)-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
595.779

1105

984

*
4-[(5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl)}-6- phenylpyridazin-3-yl)oxy]-2- methylbutan-2-ol
625.805

1106

985

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3- morpholin-4-ylpropan-1-amine
539.116

1107

986

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(5- methoxypyridin-3-yl)methyl]amine
533.069

1108

987

*
N-[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
480.049

1109

988

*
N-[(5-butyl-6-phenyl-3-piperidin-1- ylpyridazin-4-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
528.737

1110

989

*
N-[(5-butyl-3-isobutoxy-6- phenylpyridazin-4-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
517.71

1111

990

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-2-cyclopropyl-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)ethanamine
480.049

1112

991

*
N-[(4-chloro-2-phenyl-1-propyl-1H- imidazol-5-yl)methyl]-1-(2,3-dihydro- 1,4-benzodioxin-6-yl)-N-(3- ethoxybenzyl)ethanamine
546.107

1113

992

*
N,5-dibutyl-4-{[butyl(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl)-6- phenylpyridazin-3-amine
516.726

1114

993

*
N-{[5-butyl-3-(4-methylpiperazin-1-yl)- 6-phenylpyridazin-4-yl]methyl}-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
543.752

1115

994

*
1-butyl-5-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-2-(2- methoxyphenyl)-1H-imidazole-4- carbonitrile
566.698

1116

995

*
N-{[4-chloro-1-methyl-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl)-1-(2,3-dihydro-1,4- benzodioxin-6-yl)-N-(3- ethoxybenzyl)ethanamine
532.081

1117

996

*
N-{[5-butyl-3-(2-methoxyethoxy)-6- phenylpyridazin-4-yl]methyl)-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine
519.682

1118

997

*
N-(1,3-benzodioxol-5-ylmethyl)-N-[(1- methyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1-amine
453.583

1119

998

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-methyl- 2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine
531.609

1120

999

*
N-(1,3-benzodioxol-5-ylmethyl)-N-[(1- ethyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1-amine
467.61

1121

1000

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-ethyl- 2,4-diphenyl-1H-imadazol-5- yl)methyl]methanamine
545.636

1122

1001

*
N-(1,3-benzodioxol-5-ylmethyl)-N- [(2,4-diphenyl-1-propyl-1H-imidazol- 5-yl)methyl]butan-1-amine
481.637

1123

1002

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(2,4- diphenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine
559.663

1124

1003

*
1-butyl-5-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-2- phenyl-1H-imidazole-4-carbonitrile
536.672

1125

1004

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (3,5-dimethyl-1H-pyrazol-1-yl)-4- phenyl-1H-imidazol-5- yl]methyl}methanamine
591.708

1126

1005

*
1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine
560.134

1127

1006

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{(1-butyl-4- chloro-2-(2-methylphenyl)-1H- imidazol-5-yl]methyl}methanamine
546.064

1128

1007

*
1-butyl-4-chloro-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)-2-phenyl-1H-imidazol- 5-amine
532.081

1129

1008

*
1-(4-chloro-2-phenyl-1-propyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
532.081

1130

1009

*
1-(4-chloro-2-phenyl-1-propyl-1H- imidazol-5-yl)-N,N-bis(2,3-dihydro- 1,4-benzodioxin-6- ylmethy))methanamine
546.064

1131

1010

*
1-(1,3-benzodioxol-5-yl)-N-[(4-chloro- 2-phenyl-1-propyl-1H-imidazol-5- yl)methyl]-N-(3- ethoxybenzyl)methanamine
518.054

1132

1011

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodaoxol-5-ylmethyl)-N-[(4-chloro- 2-phenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine
518.01

1133

1012

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-(3-ethoxybenzyl)-N-[(1-methyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]methanamine
545.68

1134

1013

*
1-(2,3-dihydro-1,4-benzadioxin-6-yl)- N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-[(1-methyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]methanamine
559.663

1135

1014

*
1-(1,3-benzodioxol-5-yl)-N-(3- ethoxybenzyl)-N-[(1-methyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]methanamine
531.653

1136

1015

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-[(2,4-diphenyl-1-propyl-1H- imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
573.733

1137

1016

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-[(2,4-diphenyl-1-propyl- 1H-imidazol-5- yl)methyl]methanamine
587.716

1138

1017

*
1-(1,3-benzodioxol-5-yl)-N-[(2,4- diphenyl-1-propyl-1H-imidazol-5- yl)methyl]-N-(3- ethoxybenzyl)methanamine
559.706

1139

1018

*
1-(1,3-benzodioxol-5-yl)-N-{[1-butyl-4- fluoro-2-(2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine
529.652

1140

1019

*
1-[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine
543.679

1141

1020

*
1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (2-chlorophenyl)-4-phenyl-1H- imidazol-5-yl]methyl}methanamine
608.135

1142

1021

*
N-{(1-butyl-2-(2-chlorophenyl)-4- phenyl-1H-imidazol-5-yl]methyl}-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine
622.205

1143

1022

*
5-{[(1,3-benzodioxol-5-ylmethyl)(3- ethoxybenzyl)amino]methyl}-1-butyl- 2-(2-methylphenyl)-1H-imidazole-4- carbonitrile
536.672

1144

1023

*
1-butyl-5-{[(2,3-dihydro-1,4- benzadioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-2-(2- methylphenyl)-1H-imidazole-4- carbonitrile
550.699

1145

1024

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(2- fluoro-5-methoxybenzyl)amine
550.071

1146

1025

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(4- fluoro-3-methoxybenzyl)amine
550.071

1147

1026

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,6- difluorobenzyl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine
538.035

1148

1027

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- fluorobenzyl)amine
520.045

1149

1028

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3- chlorobenzyl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine
536.5

1150

1029

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- methylbenzyl)amine
516.082

1151

1030

*
1-(3-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}phenyl) ethanone
544.092

1152

1031

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- methoxybenzyl)amine
532.081

1153

1032

*
3-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoic acid
546.064

1154

1033

*
3-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzamide
545.08

1155

1034

*
3-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzonitrile
527.065

1156

1035

*
N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-2- methoxyethanamine
511.662

1157

1036

*
N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-3- methoxypropan-1-amine
525.689

1158

1037

*
N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-2- ethoxyethanamine
525.689

1159

1038

*
4-[[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]butan-1-ol
525.689

1160

1039

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-2- methoxyethanamine
470.01

1161

1040

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3- methoxypropan-1-amine
484.037

1162

1041

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-2- ethoxyethanamine
484.037

1163

1042

*
4-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]butan-1-ol
484.037

1164

1043

*
1-[1-butyl-2-(2-methyl-1,3-thiazol-4- yl)-4-phenyl-1H-imidazol-5-yl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl)methanamine
608.803

1165

1044

*
1-[4-chloro-1-methyl-2-(2- methylphenyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine
518.054

1166

1045

*
1-[4-chloro-1-methyl-2-(2- methylphenyl)-1H-imidazol-5-yl]-N- (3-ethoxybenzyl)-N-(1H-indol-5- ylmethyl)methanamine
499.055

1167

1046

*
1-[1-butyl-4-chloro-2-(4-fluorophenyl)- 1H-imidazol-5-yl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
564.097

1168

1047

*
1-(4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}phenyl)ethanone
544.092

1169

1048

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(4- methylbenzyl)amine
516.082

1170

1049

*
N-[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
590.558

1171

1050

*
N-[(1-butyl-4-methyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine
525.689

1172

1051

*
1-[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N- (3-ethoxybenzyl)-N-(1H-indol-5- ylmethyl)methanamine
524.68

1173

1052

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H- indol-5-ylmethyl)amine
541.092

1174

1053

*
1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-(3-ethoxybenzyl)-N-[(4-methyl-2- phenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine
511.662

1175

1054

*
6-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}-1,2- benzisoxazol-3-amine
558.079

1176

1055

*

593.643

1177

1056

*

560.091

1178

1057

*
2-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]-1- (3-methoxyphenyl)ethanone
560.091

1179

1058

*
N˜2˜-butyl-N˜2˜-{(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5-yl)methyl]- N˜1˜-(2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)glycinamide
525.089

1180

1059

*
2-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzadioxin-6-ylmethyl)amino]-1-(3- methoxyphenyl)ethanol
562.106

1181

1060

*
N-[2-(benzyloxy)ethyl]-N-[(1-butyl-4- chloro-2-phenyl-1H-imidazol-5- yl)methyl]butan-1-amine
454.054

1182

1061

*
N-[2-(benzyloxy)ethyl]-N-[(1-butyl-4- chloro-2-phenyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine
546.107

1183

1062

*
methyl 3-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate
560.091

1184

1063

*
5-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl)-N-(2- methoxyethyl)pyridin-2-amine
576.137

1185

1064

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(6- morpholin-4-ylpyridin-3- yl)methyl]amine
588.148

1186

1065

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(6- chloropyridin-3-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amine
537.488

1187

1066

*
4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
558.075

1188

1067

*
1-(5-butyl-2-methoxy-6- phenylpyrimidin-4-yl)-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
553.699

1189

1068

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-2-(2,3-dihydro- 1,4-benzodioxin-6-yl)-N-(3- ethoxybenzyl)propan-2-amine
574.161

1190

1069

*
4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}-3- chlorobenzoic acid
580.509

1191

1070

*
4-({[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl][1-(2,3-dihydro- 1,4-benzodioxin-6-yl)ethyl]amino}methyl)benzoic acid
560.091

1192

1071

*
4-{[[(5-butyl-3-isopropoxy-6- phenylpyridazin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
581.709

1193

1072

*
4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-3- chlorobenzoic acid
488.456

1194

1073

*
N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine
449.638

1195

1074

*
4-({[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)benzoic acid
554.034

1196

1075

*
5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-6- phenylpyrimidin-2-ol
539.672

1197

1076

*
4-{[[(5-butyl-3-isobutoxy-6- phenypyridazin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
595.736

1198

1077

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H- pyrazol-4-ylmethyl)amine
492.02

1199

1078

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(1- ethyl-1H-pyrazol-4-yl)methyl]amine
520.074

1200

1079

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H- pyrazol-5-ylmethyl)amine
492.02

1201

1080

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(1,4- dimethyl-1H-pyrazol-3-yl)methyl]amine
520.074

1202

1081

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imadazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N- (pyridin-4-ylmethyl)amine
503.043

1203

1082

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[4- (1H-tetraazol-5-yl)benzyl]amine
570.094

1204

1083

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(1- oxidopyridin-4-yl)methyl]amine
519.042

1205

1084

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(5-chloro- 1,3-dimethyl-1H-pyrazol-4-yl)methyl]- N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amine
554.519

1206

1085

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-{[5-chloro-1- methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine
608.489

1207

1086

*
4-{[[(5-butyl-2-methoxy-6- phenylpyrimidin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
553.656

1208

1087

*
4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}-3- fluorobenzoic acid
564.054

1209

1088

*
4-{[[(5-butyl-2-isopropoxy-6- phenylpyrimidin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
581.709

1210

1089

*
4-{[[(5-butyl-2-isobutoxy-6- phenylpyrimidin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
595.736

1211

1090

*
4-({[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)benzoic acid
566.045

1212

1091

*
5-{3-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]propyl}isoxazol-3-ol
537.057

1213

1092

*
5-{5-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]pentyl}isoxazol-3-ol
565.11

1214

1093

*
4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}-3- fluorobenzoic acid
576.065

1215

1094

*
4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}-3- chlorobenzoic acid
592.52

1216

1095

*
4-{[[(1-butyl-4-Chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}-2- fluorobenzoic acid
564.054

1217

1096

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(4- methyl-3,4-dihydro-2H-1,4- benzoxazin-6-yl)methyl]amine
573.133

1218

1097

*
6-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}nicotinic acid
547.052

1219

1098

*
methyl 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
574.117

1220

1099

*
4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
560.091

1221

1100

*
methyl 4-{[[(4-chloro-2-phenyl-1- propyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
546.064

1222

1101

*
methyl 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoate
593.643

1223

1102

*
methyl 4-{[[(1-butyl-4-cyano-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl]benzoate
550.656

1224

1103

*
methyl 4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoate
601.743

1225

1104

*
methyl 4-{[[(1-butyl-4-methyl-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
539.672

1226

1105

*
methyl 4-({(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)[(4-methyl-2- phenyl-1-propyl-1H-imidazol-5- yl)methyl]amino}methyl)benzoate
525.646

1227

1106

*
4-{[[(4-chloro-2-phenyl-1-propyl-1H- imadazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
532.037

1228

1107

*
4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
579.616

1229

1108

*
4-{[[(1-butyl-4-cyano-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
536.629

1230

1109

*
4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
587.716

1231

1110

*
4-{[[(1-butyl-4-methyl-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
525.646

1232

1111

*
4-({(2,3-dihydro-1,4-benzodiaxin-6- ylmethyl)[(4-methyl-2-phenyl-1- propyl-1H-imidazol-5- yl)methyl]amino}methyl)benzoic acid
511.619

1233

1112

*
methyl 4-{[{[1-butyl-4-cyano-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoate
564.682

1234

1113

*
methyl 4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(3-ethoxybenzyl) amino]methyl}benzoate
543.679

1235

1114

*
4-{[{[1-butyl-4-cyano-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoic acid
550.656

1236

1115

*
4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(3-ethoxybenzyl) amino]methyl}benzoic acid
529.652

1237

1116

*
4-{({[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoic acid
543.636

1238

1117

*
methyl 4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoate
557.662

1239

1118

*
N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(1H-indol-5-ylmethyl)- 3-methylbutan-1-amine
477.092

1240

1119

*
N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl)-N-(1H-indol-5- ylmethyl)butan-1-amine
463.065

1241

1120

*
methyl 4-{[[(1-butyl-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
525.646

1242

1121

*
4-{[[(1-butyl-2-phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoic acid
511.619

1243

1122

*
methyl 4-{[[(4-bromo-1-butyl-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
604.542

1244

1123

*
4-{[[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
590.515

1245

1124

*
N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-3- methylbutan-1-amine
496.091

1246

1125

*
methyl 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazoi-5- yl]methyl}(isopentyl)amino]methyl}benzoate
496.091

1247

1126

*
4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}benzoic acid
482.064

1248

1127

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3- methylbutan-1-amine
482.064

1249

1128

*
methyl 2-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
560.091

1250

1129

*
methyl 6-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]hexanoate
540.1

1251

1130

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)prop-2- yn-1-amine
449.979

1252

1131

*
N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)prop-2- en-1-amine
451.995

1253

1132

*
ethyl 2-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxmn-6- ylmethyl)amino]methyl}cyclopropane carboxylate
538.084

1254

1133

*
2-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
546.064

1255

1134

*
6-[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]hexanoic acid
526.073

1256

1135

*
ethyl 4-{3-[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]propyl}benzoate
602.171

1257

1136

*
ethyl 4-(3-{butyl[(4-chloro-2-phenyl- 1-propyl-1H-imidazol-5- yl)methyl]amino}propyl)benzoate
496.091

1258

1137

*
ethyl 4-[3-(butyl{[1-butyl-4-chloro-2- (2-methylphenyl)-1H-imidazol-5- yl]methyl}amino)propyl]benzoate
524.145

1259

1138

*
4-{3-1-(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]propyl}benzoic acid
574.117

1260

1139

*
4-[3-(butyl{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}amino)propyl]benzoic acid
496.091

1261

1140

*
methyl (4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl) acetate
574.117

1262

1141

*
methyl 2-(4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)propanoate
588.144

1263

1142

*
methyl 2-(4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)-2-methylpropanoate
602.171

1264

1143

*
methyl (3-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl) acetate
574.117

1265

1144

*
(4-{[[-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl) amino]methyl}phenyl)acetic acid
560.091

1266

1145

*
2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl) amino]methyl}phenyl)propanoic acid
574.117

1267

1146

*
2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl) amino]methyl}phenyl)-2- methylpropanoic acid
588.144

1268

1147

*
(3-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetic acid
560.091

1269

1148

*
5-(5-{butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}pentyl)isoxazol-3-ol
473.057

[0499]

14

TABLE IV

LCMS

LCMS

Cmp.#
MOLSTRUCTURE
IUPAC Name
(min.)
MW
Mass

1270

1149

methyl 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(neopentyl)amino]methyl}- 2-methoxybenzoate
1.36
526.12
525.28

1271

1150

4-{[{[1 -butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(neopentyl)amino]methyl}-2- methoxybenzoic acid
1.32
512.09
511.26

1272

1151

4-{[{[1 -butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(neopentyl)amino]methyl}-2- methoxybenzamide
1.31
511.11
510.28

1273

1152

4-{[{[1 -butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(neopentyl)amino]methyl}-2- hydroxybenzamide
1.31
497.08
496.26

1274

1153

4-{[{[1 -butyl-4-(4-methoxyphenyl)- 2-phenyl-1H-imidazol-5-yl]methyl}(neopentyl)amino]methyl)-2- hydroxybenzamide
1.19
554.73
554.33

1275

1154

4-[(benzyl{[1-butyl-4-(4-methoxy phenyl)-2-phenyl-1H-imidazol-5- yl]methyl]amino)methyl]-2- hydroxybenzamide
1.18
574.72
574.29

1276

1155

methyl (4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl]phenyl) acetate
1.29
574.12
573.24

1277

1156

methyl 2-(4-{[[(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl)phenyl) propanoate
1.31
588.14
587.26

1278

1157

methyl 2-(4-{[[(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)-2- methylpropanoate
1.33
602.17
601.27

1279

1158

methyl (3-{[[(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl) acetate
1.29
574.12
573.24

1280

1159

(4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl) acetic acid
1.24
560.09
559.22

1281

1160

2-(4-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)propanoic acid
1.26
574.12
573.24

1282

1161

2-(4-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methy](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)-2-methylpropanoic acid
1.28
588.14
587.26

1283

1162

(3-{[[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl) acetic acid
1.25
560.09
559.22

1284

1163

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)butan- 1-amine
1.16
482.06
481.25

1285

1164

4-[(butyl{[1-butyl-4- chloro-2-(2-methyl phenyl)-1H-imidazol-5-yl]methyl}amino)methyl]benzene sulfonamide
1.17
503.11
502.22

1286

1165

4-{[{[1-butyl-4-chloro-2-(2- methyl phenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}benzene sulfonamide
1.2
517.13
516.23

1287

1166

4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl) methyl](2,3-dihydro-1,4-benzodioxin- 6-ylmethyl)amino]methyl}benzenesulfonamide
1.24
581.13
580.19

1288

1167

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol- 5-yl]methyl}-N-[(3- chloro-1H-indol-5-yl)methyl]-3- methylbutan-1-amine
1.18
511.54
510.23

1289

1168

5-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}-1H-indole-3-carbonitrile
1.15
502.10
501.27

1290

1169

4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzenesulfonamide
1.24
595.16
594.21

1291

1170

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(quinoxalin-6- ylmethyl)butan-1-amine
1.25
476.07
475.25

1292

1171

methyl [[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino](phenyl) acetate
1.33
560.09
559.22

1293

1172

N-[(1-butyl-2-phenyl-4-vinyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl) amine
1.2
537.70
537.30

1294

1173

methyl 4-{[[(1-butyl-2-phenyl-4- vinyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
1.2
551.68
551.28

1295

1174

N-[(1-butyl-4-ethyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6- ylethyl)-N-(3-ethoxybenzyl) amine
1.22
539.72
539.31

1296

1175

methyl 4-{[[(1-butyl-4-ethyl-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
1.18
553.70
553.29

1297

1176

(1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-methylpentan-1-amine
1.18
509.69
509.30

1298

1177

(1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-methylpentan-1-amine
1.18
509.69
509.30

1299

1178

N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl) methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-(quinoxalin-6- ylmethyl)amine
1.29
554.09
553.22

1300

1179

4-{[[(1-butyl-2-phenyl-4- vinyl-1H-imidazol-5-yl) methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

537.66

1301

1180

N-{1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl) butan-1-amine
1.16
496.09
495.27

1302

1181

N-{1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-3- methylbutan-1-amine
1.18
510.12
509.28

1303

1182

N-{1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(1H-indol-5-ylmethyl)butan- 1-amine
1.13
477.09
476.27

1304

1183

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-3-methyl-N-[(2-methyl- 1H-indol-5-yl)methyl]butan-1-amine
1.15
491.12
490.29

1305

1184

1-(1-butyl-2-phenyl-1H-imidazol- 5-yl)-N-(cyclohexylmethyl)-N- methylpentan-1-amine
1.11
395.63
395.33

1306

1185

4-{[[(1-butyl-4-ethyl-2- phenyl-1H-imidazol-5-yl) methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl) amino]methyl}benzoicacid
1.16
539.67
539.28

1307

1186

N-{[4-chloro-1-(ethoxymethyl)-2- phenyl-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl) amine

548.08

1308

1187

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl-N-methyl-1,2,3,4- tetrahydronaphthalen-1- amine

422.01

1309

1188

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(1,2,3,4- tetrahydroquinolin-6- ylmethyl) methanamine
1.2
546.80
546.37

1310

1189

1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5- yl]-N-(cyclohexylmethyl)-N- (1,2,3,4-tetrahydroquinolin-6- ylmethyl)methanamine
1.28
538.70
538.33

1311

1190

N-{[4-bromo-1-butyl-2-(2,6- diethylphenyl)-1H-imidazol-5-yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.27
508.54
507.22

1312

1191

methyl 4-{[{[1-butyl-4-(4- methylphenyl)-2-phenyl-1H- imidazol-5-yl] methyl}(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.22
615.77
615.31

1313

1192

methyl 4-{[{[1-butyl-4-(3- fluorophenyl)-2-phenyl-1H- imidazol-5-yl]methyl}2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.2
619.73
619.28

1314

1193

4-{[{[1-butyl-4-(4-methylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl)(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
1.19
601.74
601.29

1315

1194

4-{[{[1-butyl-4-(3-fluorophenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
1.18
605.71
605.27

1316

1195

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (3-methoxybenzyl)butan-1-amine
1.2
454.05
453.25

1317

1196

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)butan-1-amine
1.22
468.08
467.27

1318

1197

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (1H-indol-5-ylmethyl)-3,3- dimethylbutan-1-amine
1.14
491.12
490.29

1319

1198

6-[(butyl{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}amino)methyl]-3,4- dihydroquinolin-2(1H)-one
1.11
493.09
492.27

1320

1199

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (1,2,3,4-tetrahydroquinolin-6- ylmethyl)butan-1-amine
1.13
479.11
478.29

1321

1200

N-{[1-butyl-4-chloro-2-(2,6-diethylphenyl)- 1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.24
464.09
463.28

1322

1201

(1S)-N-{[1-butyl-4-chloro-2-(2,6- diethylphenyl)-1H-imidazol-5-yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.24
464.09
463.28

1323

1202

6-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl}- 3,4-dihydroquinolin-2(1H)- one
1.14
507.12
506.28

1324

1203

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (2,3-dihydro-1-benzofuran-5- ylmethyl)-3-methylbutan- 1-amine
1.16
480.09
479.27

1325

1204

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (4-methoxybenzyl)-3- methylbutan-1-amine
1.17
468.08
467.27

1326

1205

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (3-methoxybenzyl)-3- methylbutan-1-amine
1.21
468.08
467.27

1327

1206

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazoI-5-yl]methyl}-N- (4-ethoxybenzyl)-3- methylbutan-1-amine
1.19
482.11
481.29

1328

1207

N-{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)-3- methylbutan-1-amine
1.23
482.11
481.29

1329

1208

ethyl N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)- beta-alaninate
1.25
526.07
525.24

1330

1209

4-[{[1-butyl-4-chloro-2-(2-methylphenyl)- 1H-imidazol-5-yl]methyl}(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]-2- methylbutan-2-ol
1.11
512.09
511.26

1331

1210

ethyl N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1H-indol-5-ylmethyl)- beta-alaninate
1.15
507.07
506.24

1332

1211

4-[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}(1H-indol-5- ylmethyl)amino]-2- methylbutan-2-ol
1.1
493.09
492.27

1333

1212

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-[(3-chloro-1H-indol- 5-yl)methyl]-3,3- dimethylbutan-1-amine
1.19
525.56
524.25

1334

1213

N-{[1-butyl-2-(2,6-diethylphenyl)-4- (4-methylphenyl)-1H- imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.26
519.77
519.36

1335

1214

N-{[1-butyl-2-(2,6-diethylphenyl)-1H- imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.18
429.65
429.31

1336

1215

N-{[1-butyl-2-(2,6-diethylphenyl)-4- methyl-1H-imidazol-5-yl]methyl}- N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.2
443.68
443.33

1337

1216

methyl 4-{[{[1-butyl-4-(4- fluorophenyl)-2-phenyl-1H-imidazol- 5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.2
619.73
619.28

1338

1217

methyl 4-{[{[1-butyl-4-(3- methylphenyl)-2-phenyl-1H-imidazol- 5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.21
615.77
615.31

1339

1218

methyl 4-{[{[1-butyl-4-(3- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl)(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.21
631.77
631.30

1340

1219

methyl 4-{[{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.2
631.77
631.30

1341

1220

methyl 4-{[{[1-butyl-4-(4- chlorophenyl)-2-phenyl-1H- imidazol-5-yl]methyl}(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.22
636.19
635.26

1342

1221

4-{{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}[(3-chloro- 1H-indol-5-yl)methyl]amino}-2- methylbutan-2-ol
1.13
527.54
526.23

1343

1222

N-{[butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(1H- indol-5-ylmethyl)-2,2- dimethylpropan-1-amine

477.09

1344

1223

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-[(3-chloro-1H-indol-5- yl)methyl]-2,2- dimethylpropan-1-amine
1.37
511.54
510.23

1345

1224

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-2,2- dimethylpropan-1-amine

496.09

1346

1225

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl)-N-(2-fluoro-4- methoxybenzyl)-3- methylbutan-1-amine

486.07

1347

1226

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]methyl}-N-(2-chloro-4- methoxybenzyl)-3- methylbutan-1-amine

502.53

1348

1227

N-{[4-bromo-2-(2,6-diethylphenyl)- 1-(1,3-dioxolan-2-ylmethyl)-1H- imidazol-5-yl]methyl}-N-methyl- 1,2,3,4- tetrahydronaphthalen-1-amine

538.53

1349

1228

N-{[4-bromo-2-(2,6-diethylphenyl)- 1-(ethoxymethyl)-1H-imidazol-5- yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine

510.52

1350

1229

4-{[{[1-butyl-4-(4-fluorophenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

605.71

1351

1230

4-{[{[1-butyl-4-(3-methylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

601.74

1352

1231

4-{[{[1-butyl-4-(3-methoxyphenyl)- 2-phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

617.74

1353

1232

4-{[{[1-butyl-4-(4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

622.16

1354

1233

4-{[{[1-butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid

617.74

1355

1234

N-{[4-bromo-2-(2,6-diethylphenyl)- 1-(2-morpholin-4-ylethyl)-1H- imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.16
565.60
564.25

1356

1235

N-{[4-chloro-1-(2-morpholin-4- ylethyl)-2-phenyl-1H-imidazol-5- yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl) amine
1.2
603.16
602.27

1357

1236

1-[4-chloro-2-phenyl-1-(2-piperidin- 1-ylethyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl) methanamine
1.19
601.19
600.29

1358

1237

methyl 4-[(butyl{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}amino)methyl]benzoate
1.23
537.74
537.34

1359

1238

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(isobutyl) amino]methyl}benzoate
1.24
537.74
537.34

1360

1239

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(2- ethylbutyl)amino]methyl}benzoate
1.27
565.80
565.37

1361

1240

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(isopentyl)amino]methyl}benzoate
1.25
551.77
551.35

1362

1241

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(cyclohexylmethyl)amino]methyl}benzoate
1.28
577.81
577.37

1363

1242

methyl 4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoate
1.25
571.76
571.32

1364

1243

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate
1.23
629.80
629.33

1365

1244

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}(isopentyl) amino]methyl}benzoate
1.24
537.74
537.34

1366

1245

methyl 4-{[{(1-butyl-2-(2- methylphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl) amino]methyl}benzoate
1.22
615.77
615.31

1367

1246

methyl 4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-phenyl-1H-imidazol- 5-yl]methyl}amino) methyl]benzoate
1.22
557.73
557.30

1368

1247

4-[(butyl{[1-butyl-2-(2-methyl- phenyl)-4-(4-methylphenyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoic acid
1.21
523.72
523.32

1369

1248

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(isobutyl) amino]methyl) benzoic acid
1.21
523.72
523.32

1370

1249

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(2-ethylbutyl)amino]metyl}benzoic acid
1.24
551.77
551.35

1371

1250

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(isopentyl) amino]methyl}benzoic acid
1.22
537.74
537.34

1372

1251

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(cyclohexylmethyl) amino]methyl}benzoic acid
1.25
563.78
563.35

1373

1252

4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}amino)methyl]benzoic acid
1.21
557.73
557.30

1374

1253

N-{[4-chloro-2-(2,6- dimethylphenyl)-1-methyl- 1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.09
393.96
393.20

1375

1254

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid
1.2
615.77
615.31

1376

1255

4-{[{[1-butyl-2-(2- methylphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}(isopentyl)amino]methyl}benzoic acid

523.72

1377

1256

4-{[{[1-butyl-2-(2- methylphenyl)-4-phenyl-1H- imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid

601.74

1378

1257

4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}amino) methyl]benzoic acid

543.71

1379

1258

4-[(butyl{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}amino)methyl]benzoic acid
1.19
509.69
509.30

1380

1259

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(propyl)amino]methyl}benzoate

523.72

1381

1260

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl)amino]methyl}benzoate

551.77

1382

1261

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(3,3- dimethylbutyl)amino]methyl}benzoate

565.80

1383

1262

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(pentyl)amino]methyl}benzoate

551.77

1384

1263

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(hexyl)amino]methyl}benzoate

565.80

1385

1264

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(3-methylbut-2-enyl)amino]methyl}benzoate

549.76

1386

1265

methyl 4-[((bicyclo[2.2.1]hept-5-en- 2-ylmethyl){[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoate

587.80

1387

1266

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(tetrahydrofuran-3-ylmethyl) amino]methyl}benzoate

565.75

1388

1267

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(thien-3-ylmethyl)amino]methyl}benzoate

577.79

1389

1268

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(propyl) amino]methyl}benzoic acid
1.19
509.69
509.30

1390

1269

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl) amino]methyl}benzoic acid
1.23
537.74
537.34

1391

1270

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(3,3- dimethylbutyl)amino]methyl}benzoic acid
1.23
551.77
551.35

1392

1271

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(pentyl)amino]methyl}benzoic acid
1.23
537.74
537.34

1393

1272

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(hexyl)amino]methyl}benzoic acid
1.24
551.77
551.35

1394

1273

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(3-methylbut-2-enyl)amino]methyl]benzoic acid
1.22
535.73
535.32

1395

1274

4-[((bicyclo[2.2.1]hept-5-en-2- ylmethyl){[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoic acid
1.24
573.78
573.34

1396

1275

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl)(thien-3- ylmethyl)amino]methyl}benzoic acid
1.19
563.76
563.26

1397

1276

methyl 4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(1H- indol-5-ylmethyl)amino]methyl}benzoate
1.27
610.80
610.33

1398

1277

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(1H- indol-5-ylmethyl)amino]methyl}benzoic acid
1.24
596.77
596.32

1399

1278

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1H-indazol-5- ylmethyl)-3-methylbutan- 1-amine
1.18
478.08
477.27

1400

1279

4-{[{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}(ethyl) amino]methyl}-2- hydroxybenzamide
1.16
512.65
512.28

1401

1280

(1S)-N-{[1-butyl-4-chloro-2-(2,6- dimethylphenyl)-1H- imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1-amine
1.24
436.04
435.24

1402

1281

N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]methyl}-N- (1H-indazol-5-ylmethyl)- 2,2-dimethylpropan-1-amine
1.31
478.08
477.27

1403

1282

1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]-N-(1H-indazol-5-ylmethyl)-N- (3-methoxybenzyl) methanamine
1.33
528.10
527.25

1404

1283

1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5- yl]-N-(1H-indazol-5-ylmethyl)-N- (4-methoxybenzyl) methanamine
1.29
528.10
527.25

1405

1284

4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]methyl}(4- methoxybenzyl)amino]methyl}-2-hydroxybenzamide
1.28
547.10
546.24

1406

1285

4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]methyl}(3- methoxybenzyl)amino]methyl}-2-hydroxybenzamide
1.26
547.10
546.24

1407

1286

4-{[{(1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}(2- methoxyethyl)amino]methyl}-2-hydroxybenzamide
1.11
542.68
542.29

1408

1287

4-{[{[1-butyl-4-(4- methoxyphenyl)-2-pyridin-3-yl-1H- imidazol-5-yl]methyl}(cyclohexylmethyl)amino]methyl}-2-hydroxybenzamide
1.21
581.76
581.34

1409

1288

7-{[{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}(neopentyl)amino]methyl}-2H-1,3- benzoxazine-2,4(3H)-dione
1.23
580.73
580.30

1410

1289

1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)-N-(cyclohexylmethyl)-N- (1H-indazol-5-ylmethyl) methanamine
1.26
531.74
531.34

1411

1290

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(1H- indazol-5-ylmethyl)-2,2- dimethylpropan-1-amine
1.23
505.71
505.32

1412

1291

1-[1-butyl-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]-N- (cyclohexylmethyl)-N- (1H-indazol-5-ylmethyl) methanamine
1.27
561.77
561.35

1413

1292

methyl 4-[((cyclohexylmethyl){[1- [2-(dimethylamino)ethyl]-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}amino)methyl]-2- methoxybenzoate
1.19
624.82
624.37

1414

1293

N-{[4-chloro-2-(2,6-diethylphenyl)- 1-(2-methoxyethyl)-1H- imidazol-5-yl]methyl}-N- propylpropan-1-amine
1.11
406.01
405.25

1415

1294

4-[((cyclahexylmethyl){[1-[2- (dimethylamino)ethyl]-4- (4-methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}amino) methyl]-2-hydroxybenzamide
1.18
595.78
595.35

1416

1295

1-butyl-5-{[(1H-indazol-5- ylmethyl)(neopentyl)amino]methyl}- 2-(2-methylphenyl}-1H- imidazole-4-carbonitrile
1.32
468.65
468.30

1417

1296

1-butyl-5-{[(cyclohexylmethyl)(1H- indazol-5-ylmethyl)amino]methyl}-2-(2-methylphenyl)- 1H-mmidazole-4-carbonitrile
1.35
494.68
494.32

1418

1297

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N-(4-methoxybenzyl)-2,2- dimethylpropan-1-amine
1.32
512.13
511.30

1419

1298

4-{[{[1-butyl-4-cyano-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}cyclohexylmethyl)amino]methyl}-2-hydroxybenzamide
1.33
513.68
513.31

1420

1299

N-{[4-chloro-2-(2,6-diethylphenyl)- 1-(2-methoxyethyl)-1H- imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)-2,2- dimethylpropan-1-amine
1.42
526.16
525.31

1421

1300

N-{[4-chloro-2-(2,6-diethylphenyl)- 1-(2-methoxyethyl)-1H- imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2,2- dimethylpropan-1-amine
1.37
488.16
487.33

1422

1301

N-{[4-chloro-2-(2,6-diethylphenyl)- 1-(2-methoxyethyl)-1H- imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2- methylpropan-2-amine
1.16
474.13
473.32

1423

1302

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- pyridin-4-yl-1H-imidazol-5-yl]methyl}(cyclohexylmethyl) amino]methyl}-2- hydroxybenzamide
1.25
581.76
581.34

1424

1303

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2,2- dimethylpropan-1-amine
1.48
482.11
481.29

1425

1304

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)-2,2- dimethylpropan-1-amine
1.54
496.14
495.30

1426

1305

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2,2- dimethylpropan-1-amine
1.57
458.13
457.32

1427

1306

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2- methylpropan-2-amine
1.19
444.10
443.31

1428

1307

N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-{[1-(2-methoxyethyl)-4- (4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-2,2- dimethylpropan-1-amine
1.25
555.72
555.31

1429

1308

N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-{[1-(2-methoxyethyl)-4- (4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-2-methylpropan-1- amine

541.69

1430

1309

1-cyclopropyl-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-{[1-(2- methoxyethyl)-4-(4- methoxyphenyl)-2-phenyl-1H- imidazol-5-yl]methyl}methanamine

539.67

1431

1310

N-benzyl-N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2-methoxyethyl)- 1H-imidazol-5-yl]methyl}- 2,2-dimethylpropan-1- amine

482.11

1432

1311

N-{[1-butyl-4-chloro-2-(2,6- dimethylphenyl)-1H-imidazol-5- yl]methyl}-N-isopentylheptan-4- amine

460.15

1433

1312

N-{[1-butyl-4-chloro-2-(2,6- dimethylphenyl)-1H-imidazol-5- yl]methyl}-1-[4-(difluoromethoxy) phenyl]-N,4-dimethylpentan-1- amine

532.12

1434

1313

ethyl (4-chloro-5-{[(4-methoxy- benzyl)(neopentyl)amino]methyl)-2-phenyl-1H-imidazol-1- yl)acetate

484.04

1435

1314

ethyl (4-chloro-5-{[(2,3- dihydro-1,4-benzodioxin-6- ylmethyl)(neopentyl)amino]methyl}- 2-phenyl-1H-imidazol-1- yl)acetate

512.05

1436

1315

N-{[4-chloro-2-(2,6-diethylphenyl)-1- (2-methoxyethyl)-1H- imidazol-5-yl]methyl}- N-(1H-indazol-5-ylmethyl)-2- methoxy-ethanamine

510.078

1437

1316

N-{[1-butyl-4-chloro-2-(2,6- dimethylphenyl)-1H-imidazol-5- yl]methyl}-N-(1H- indazol-5-ylmethyl)-2- methoxy-ethanamine

480.053

1438

1317

N-{[4-bromo-2-(2,6- diethylphenyl)-1-ethyl- 1H-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2,2- dimethylpropan-1-amine

526.559

1439

1318

N-{[4-bromo-2-(2,6- diethylphenyl)-1-ethyl- 1H-imidazol-5-yl]methyl}-N- (2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-2,2- dimethylpropan-1-amine

554.569

1440

1319

2-hydroxy-4-{[{[1-(2- methoxyethyl)-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(neopentyl) amino]methyl)benzamide

556.703

Example 44

Preparation of Radiolabeled Probe Compounds of the Invention

[0500] The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I. Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

[0501] Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.

Example 45

Receptor Autoradiography

[0502] Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Examples.

Example 46

Assay for C5a Receptor Mediated Chemotaxis

[0503] This assay is a standard assay of C5a receptor mediated chemotaxis.

[0504] Human promonocytic U937 cells or purified human or non-human neutrophils are treated with dibutyryl cAMP for 48 hours prior to performing the assay. Human neutrophils or those from another mammalian species are used directly after isolation. The cells are pelleted and resuspended in culture media containing 0.1% fetal bovine serum (FBS) and 10 ug/ml calcein AM (a fluorescent dye). This suspension is then incubated at 37° C. for 30 minutes such that the cells take up the fluorescent dye. The suspension is then centrifuged briefly to pellet the cells, which are then resuspended in culture media containing 0.1% FBS at a concentration of approximately 3×106 cells/mL. Aliquots of this cell suspension are transferred to clean test tubes, which contain vehicle (1% DMSO) or varying concentrations of a compound of interest, and incubated at room temperature for at least 30 minutes. The chemotaxis assay is performed in CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, Md.). The bottom wells of the plate are filled with medium containing 0-10 nM of C5a, preferably derived from the same species of mammal as are the neutrophils or other cells (e.g., human C5a for the human U937 cells). The top wells of the plate are filled with cell suspensions (compound or vehicle-treated). The plate is then placed in a tissue culture incubator for 60 minutes. The top surface of the plate is washed with PBS to remove excess cell suspension. The number of cells that have migrated into the bottom well is then determined using a fluorescence reader. Chemotaxis index (the ratio of migrated cells to total number of cells loaded) is then calculated for each compound concentration to determine an IC50 value.

[0505] As a control to ensure that cells retain chemotactic ability in the presence of the compound of interest, the bottom wells of the plate may be filled with varying concentrations chemo-attractants that do not mediate chemotaxis via the C5a receptor (e.g., zymosan-activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4)), rather than C5a, under which conditions the compounds provided herein preferably do not inhibit chemotaxis.

[0506] Preferred compounds exhibit IC50 values of less than 1 μM in the above assay for C5a receptor mediated chemotaxis.

Example 47

Expression of a C5a Receptor

[0507] A human C5a receptor cDNA is obtained by PCR using 1) a forward primer adding a Kozak ribosome binding site and 2) a reverse primer that added no additional sequence, and 3) an aliquot of a Stratagene Human Fetal Brain cDNA library as template. The sequence of the resulting PCR product is as described by Gerard and Gerard, (1991) Nature 349:614-17. The PCR product is subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La Jolla, Calif.) at the Srf I site. It is then excised using the restriction enzymes EcoRI and NotI and subcloned in the appropriate orientation for expression into the baculoviral expression vector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) that has been digested with EcoRI and NotI.

Example 48

Baculoviral Preparations for C5a Expression

[0508] The human C5a (hC5a) receptor baculoviral expression vector is co-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego, Calif.) into Sf9 cells. The Sf9 cell culture supernatant is harvested three days post-transfection. The recombinant virus-containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Lenexa, Kans.) supplemented Grace's salts and with 4.1 mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter “insect medium”) and plaque assayed for recombinant plaques. After four days, recombinant plaques are selected and harvested into 1 ml of insect medium for amplification. Each 1 ml volume of recombinant baculovirus (at passage 0) is used to infect a separate T25 flask containing 2×106 Sf9 cells in 5 m/s of insect medium. After five days of incubation at 27° C., supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum.

[0509] Two of seven recombinant baculoviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect 1×108 cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eight hours post infection, passage 2 medium from each 100 ml prep is harvested and plaque assayed for titer. The cell pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of Sf9 cells. Forty hours post, infection the supernatant medium is harvested to yield passage 3 baculoviral stock.

[0510] The remaining cell pellet is assayed for affinity binding using the “Binding Assays” essentially as described by DeMartino et al. (1994) J. Biol. Chem. 269:14446-50 at page 14447, adapted as follows. Radioligand is 0.005-0.500 nM [125I]C5a (human recombinant; New England Nuclear Corp., Boston, Mass.); the hC5a receptor-expressing baculoviral cells are used instead of 293 cells; the assay buffer contains 50 mM Hepes pH. 7.6, 1 mM CaCl2, 5 mM MgCl2, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100 KIU/ml aprotinin; filtration is carried out using GF/C WHATMAN filters (presoaked in 1.0% polyethyeneimine for 2 hours prior to use); and the filters are washed twice with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin.

[0511] Titer of the passage 3 baculoviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression. A multiplicity of infection of 0.1 and a 72-hour incubation were the best infection parameters found for hC5a receptor expression in up to 1-liter Sf9 cell infection cultures.

Example 49

Baculoviral Infections

[0512] Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad Calif.) are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27° C. Infections are carried out either only with virus directing the expression of the hC5a receptor or with this virus in combination with three G-protein subunit-expression virus stocks: 1) rat Gαi2 G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovine b1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3) human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), all of which may be obtained from BIOSIGNAL Inc. (Montreal, Canada).

[0513] The infections are conveniently carried out at a multiplicity of infection of 0.1:1.0:0.5:0.5. At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining Sf9 cells are harvested via centrifugation (3000 rpm/10 minutes/4° C.).

Example 50

Purified Recombinant Insect Cell Membranes

[0514] Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 ug/ml leupeptin, 2 ug/ml Aprotinin, 200 uM PMSF, and 2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenate is centrifuged (536×g/10 minutes/4° C.) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000×g/30 minutes, 4° C.) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at −80° C. until needed. The protein concentration of the resulting membrane preparation (hereinafter “P2 membranes”) is conveniently measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure, a 1-liter culture of cells typically yields 100-150 mg of total membrane protein.

Example 51

Radioligand Binding Assays

[0515] Purified P2 membranes, prepared by the method given above, are resuspended by Dounce homogenization (tight pestle) in binding buffer (50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, 100 KUI/ml aprotinin).

[0516] For saturation binding analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.005-0.500 nM [125I]C5a (human (recombinant), New England Nuclear Corp., Boston, Mass.). Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, Mo.) and accounts for less than 10% of total binding. For evaluation of guanine nucleotide effects on receptor affinity, GTPγS is added to duplicate tubes at the final concentration of 50 μM.

[0517] For competition analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.030 nM [125I]C5a (human). Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10−10 M to 10−5 M to yield a final volume of 0.250 mL. Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, Mo.) and accounts for less than 10% of total binding. Following a 2-hour incubation at room temperature, the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked (in 1.0% polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters and rinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin. Remaining bound radioactivity is quantified by gamma counting. K, and Hill coefficient (“nH”) are determined by fitting the Hill equation to the measured values with the aid of SIGMAPLOT software (SPSS Inc., Chicago, Ill.).

Example 52

Agonist-Induced GTP Binding

[0518] Agonist-stimulated GTP-gamma 35S binding (“GTP binding”) activity can be used to identify agonist and antagonist compounds and to differentiate neutral antagonist compounds from those that possess inverse agonist activity. This activity can also be; used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a “test compound.” Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of the hC5a receptor and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of Sf9 cells as described in Example 49.

[0519] Agonist-stimulated GTP binding on purified membranes (prepared as described in Example 50) is assessed using hC5a (Sigma Chemical Co., St. Louis, Mo.) as agonist in order to ascertain that the receptor/G-protein-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding.

[0520] P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100 KIU/mL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 30 μg protein/reaction tube. After adding increasing doses of the agonist hC5a at concentrations ranging from 10−12 M to 10−6 M, reactions are initiated by the addition of 100 μM GTP-gamma 35S. In competition experiments, non-radiolabeled test compounds are added to separate assays at concentrations ranging from 10−10 M to 10−5M along with 10 nM hC5a to yield a final volume of 0.25 ML.

[0521] Neutral antagonists are those test compounds that reduce the C5a-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added C5a or other agonist and in the further absence of any test compound).

[0522] In contrast, in the absence of added C5a certain preferred compounds will reduce the GTP binding activity of the receptor-containing membranes below baseline, and are thus characterized as inverse agonists. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the C5a agonist, it is characterized as a neutral antagonist.

[0523] An antagonist test compound that elevates GTP binding activity above baseline in the absence of added hC5a in this GTP binding assay is characterized as having partial agonist activity. Preferred antagonist compounds do not elevate GTP binding activity under such conditions more than 10%, 5% or 2% above baseline.

[0524] Following a 60-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl). The amount of receptor-bound (and thereby membrane-bound) GTP-gamma 35S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 mM GTP-gamma 35S and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments may be conveniently analyzed using SIGMAPLOT software.

Example 53

Calcium Mobilization Assays

[0525] A. Response to C5a

[0526] U937 cells are grown in differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37° C. then reseeded onto 96-well plates suitable for use in a FLIPR™ Plate Reader (Molecular Devices Corp., Sunnyvale Calif.). Cells are grown an additional 24 hours (to 70-90% confluence) before the assay. The cells are then washed once with Krebs Ringer solution. FLUO-3 calcium sensitive dye (Molecular Probes, Inc. Eugene, Oreg.) is added to 10 μg/mL and incubated with the cells at room temperature for 1 to 2 hours. The 96 well plates are then washed to remove excess dye. Fluorescence responses, measured by excitation at 480 nM and emission at 530 nM, are monitored upon the addition of human C5a to the cells to a final concentration of 0.01-30.0 nM, using the FLIPR™ device (Molecular Devices). Differentiated U937 cells typically exhibit signals of 5,000-50,000 Arbitrary Fluorescent Light Units in response to agonist stimulation.

[0527] B. Assays for Determination of ATP Responses

[0528] Differentiated U937 cells (prepared and tested as described above under “A. Response to C5a”) are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01 to 30 μM. This stimulation typically triggers a signal of 1,000 to 12,000 arbitrary fluorescence light units. Certain preferred compounds produce less than a 10%, less than a 5%, or less than a 2% alteration of this calcium mobilization signal when this control assay is carried out in the presence of the compound, as compared to the signal when the assay is performed in the absence of the compound.

[0529] C. Assays for the Identification of Receptor Modulatory Agents: Antagonists and Agonists

[0530] The calcium mobilization assay described above may be readily adapted for identifying test compounds that have agonist or antagonist activity at the human C5a receptor.

[0531] For example, in order to identify antagonist compounds, differentiated U937 cells are washed and incubated with Fluo-3 dye as described above. One hour prior to measuring the fluorescence signal, a subset of the cells is incubated with 1 μM of at least one compound to be tested. The fluorescence response upon the subsequent addition of 0.3 nM (final concentration) human recombinant C5a is monitored using the FLIPR™ plate reader. Antagonist compounds elicit at least a 2-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone. Preferred antagonist compounds elicit at least a 5-fold, preferably at least a 10-fold, and more preferably at least a 20-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone. Agonist compounds elicit an increase in fluorescence without the addition of C5a, which increase will be at least partially blocked by a known C5a receptor antagonist.

Example 53

Assays to Evaluate Agonist Activity of Small Molecule C5a Receptor Antagonists

[0532] Preferred compounds provided herein are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the C5a mediated functional assays discussed herein. Specifically, this undesired agonist activity can be evaluated, for example, in the GTP binding assay of Example 52, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a. Similarly, in a calcium mobilization assay (e.g., that of Example 53), a small molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a. The preferred extent of C5a agonist activity exhibited by compounds provided herein is less than 10%, more preferably less than 5% and most preferably less than 2% of the response elicited by the natural agonist, C5a.

[0533] The foregoing description is illustrative thereof, and it will be understood that variations and modifications can be effected without departing from the scope or spirit of the invention as set forth in the following claims.

	Number	Date	Country
	60369112	Mar 2002	US
	60392145	Jun 2002	US

Aryl imidazoles and related compounds as C5a receptor modulators

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