Patent Application
20110077399
This invention relates to compounds which may be inhibitors of protein tyrosine phosphatases (PTPases), which can be useful for the management, treatment, control, or adjunct treatment of diseases caused by over-activity of PTPases.
The process of protein phosphorylation is now recognized as central to the fundamental processes of cellular signal transduction. Alterations in protein phosphorylation, may therefore constitute either a physiological or pathological change in an in vivo system. Protein de-phosphorylation, mediated by phosphatases, is also central to certain signal transduction processes.
The two major classes of phosphatases are (a) protein serine/threonine phosphatases (PSTPases), which catalyze the dephosphorylation of serine and/or threonine residues on proteins or peptides; and (b) the protein tyrosine phosphatases (PTPases), which catalyze the dephosphorylation of tyrosine residues on proteins and/or peptides. A third class of phosphatases is the dual specificity phosphatases, or DSP's, which possess the ability to act both as PTPases and as PSTPases.
Among the PTPases there exist two important families, the intracellular PTPases, and the transmembrane PTPases. The intracellular PTPases include PTP1B, STEP, PTPD1, PTPD2, PTPMEG1, T-cell PTPase, PTPH1, FAP-1/BAS, PTP1D, and PTP1C. The transmembrane PTPases include LAR, CD45, PTPα, PTPβ, PTPδ, PTPε, PTPξ, PTPκ, PTPμ, PTPσ, HePTP, SAP-1, and PTP-U2. The dual-specificity phosphatases include KAP, cdc25, MAPK phosphatase, PAC-1, and rVH6.
The PTPases, especially PTP1B, are implicated in insulin insensitivity characteristic of type II diabetes (Kennedy, B. P.; Ramachandran, C. Biochem. Pharm. 2000, 60, 877-883). The PTPases, notably CD45 and HePTP, are also implicated in immune system function, and in particular T-cell function. Certain PTPases, notably TC-PTP, DEP-1, SAP-1, and CDC25, are also implicated in certain cancers. Certain PTPases, notably the bone PTPase OST-PTP, are implicated in osteoporosis. PTPases are implicated in mediating the actions of somatostatin on target cells, in particular the secretion of hormone and/or growth factor secretion.
Thus, there is a need for agents which inhibit the action of protein tyrosine phosphatases. Such agents would be useful for the treatment of Type I diabetes, Type II diabetes, immune dysfunction, AIDS, autoimmunity, glucose intolerance, obesity, cancer, psoriasis, allergic diseases, infectious diseases, inflammatory diseases, diseases involving the modulated synthesis of growth hormone or the modulated synthesis of growth factors or cytokines which affect the production of growth hormone, or Alzheimer's disease.
This invention provides azoles which are useful as inhibitors of PTPases. In an embodiment, the present invention provides compounds of Formula (I) as depicted below, methods of their preparation, pharmaceutical compositions comprising the compounds and their use in treating human or animal disorders. The compounds of the invention are useful as inhibitors of protein tyrosine phosphatases and thus are useful for the management, treatment, control and adjunct treatment of diseases mediated by PTPase activity. Such diseases include Type I diabetes, Type II diabetes, immune dysfunction, AIDS, autoimmunity, glucose intolerance, obesity, cancer, psoriasis, allergic diseases, infectious diseases, inflammatory diseases, diseases involving the modulated synthesis of growth hormone or the modulated synthesis of growth factors or cytokines which affect the production of growth hormone, or Alzheimer's disease.
In a first aspect, the present invention provides azole inhibitors of protein tyrosine phosphatases (PTPases) which can be useful for the management and treatment of disease caused by PTPases.
In a second aspect, the present invention provides compounds of Formula (I):
wherein a and b are, independently, equal to 0, 1, or 2, wherein the values of 0, 1, and 2 represent a direct bond, —CH2—, and —CH2CH2—, respectively, and wherein the —CH2— and —CH2CH2— groups are optionally substituted 1 to 2 times with a substituent group, wherein said substituent group(s) comprise: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, and -hydroxyl. In an embodiment, a and b are equal to 0.
W comprises —O—, —S—, or —N(R2)—,
wherein
In further embodiments, W comprises —O— or —N(R2)—, wherein R2 comprises hydrogen, alkyl, or -L3-D-alkylene-aryl, wherein L3 comprises alkylene, and D comprises —CO(NR5)—, wherein R5 comprises hydrogen. In other embodiments, W comprises —N(R2)—, wherein R2 comprises hydrogen.
R1 comprises
In another embodiment, R1 comprises hydrogen or aryl.
L1 comprises:
or a direct bond;
wherein R3 and R4 independently comprise: hydrogen, chloro, fluoro, bromo, alkyl, aryl, -alkylene-aryl, -cycloalkyl, -alkylene-cycloalkyl, -heterocyclyl, -alkylene-heterocyclyl, or -alkynylene. In another embodiment, L1 comprises
In another embodiment, L1 comprises
Ar1 comprises an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused heterocyclylheteroaryl group optionally substituted 1 to 7 times. In an embodiment, Ar1 comprises a mono- or bicyclic aryl group optionally substituted 1 to 7 times. In another embodiment, Ar1 comprises a phenyl or naphthyl group optionally having 1 to 5 substituents, wherein the substituents independently comprise:
bb) -L5-J-aryl;
In another embodiment, Ar1 is a phenyl group optionally substituted 1 to 5 times, wherein the substituents independently comprise:
In another embodiment, Ar1 comprises a phenyl group substituted 1 to 5 times, wherein the substituents comprise: -chloro or -fluoro.
In another embodiment, Ar2 comprises a phenyl group or naphthyl group optionally substituted 1 to 5 times, wherein the substituents independently comprise:
In another embodiment, Ar2 comprises a phenyl group substituted 1 to 5 times, wherein the substituents independently comprise:
L2 comprises: —CH2—, —O—, alkylene, alkenylene, alkynylene, -K-alkylene-, -alkylene-K-, -alkylene-K-alkylene-, -alkenylene-K-alkylene-, -alkylene-K-alkenylene-, -arylene-K-alkylene-, alkylene-K-arylene, -heteroarylene-K-alkylene-, alkylene-K-heteroarylene, -arylene-K-, -K-arylene-, or -heteroarylene-K-, -K-heteroarylene,
wherein K comprises a direct bond, —N(R20)—, —C(O)—, —CON(R20)—, —N(R20)C(O)—, —N(R20)CON(R21)—, —N(R20)C(O)O—, —OC(O)N(R20)—, —N(R20)SO2—, —SO2N(R20)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R20)SO2N(R21)—, —N═N—, or —N(R20)—N(R21)—; —N(R20)—, —C(O)—, —CON(R20)—, —N(R20)C(O)—, —N(R20)CON(R21)—, —N(R20)C(O)O—, —OC(O)N(R20)—, —N(R20)SO2—, —SO2N(R20)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R20)SO2N(R21)—, —N═N—, —N(R20)—N(R21)— or a direct bond, wherein R20 and R21 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
In an embodiment, L2 comprises —O—, —O-alkylene-, -alkylene-O, or a direct bond. In another embodiment, L2 comprises —O-alkylene- or a direct bond.
In another embodiment, T comprises an aryl group substituted by -U-alkylene-R22, wherein U comprises —O— or a direct bond, and R22 comprises —CO2H or an acid isostere.
In another embodiment, the present invention provides compounds of Formula (I) wherein
a and b are equal to zero;
L1 comprises
Ar2 comprises a phenylene group optionally substituted 1 time with a group comprising: -Q-alkyl, wherein Q is —O—;
L2 comprises a direct bond, O-alkylene, or an alkynylene; and
T comprises an aryl group substituted with at least one substituent comprising:
In another embodiment, the present invention provides compounds of Formula (I) wherein
In another embodiment of the compound of Formula (I), wherein a and b are equal to 0, and R1 Ar1, and W are as defined above, the groups T, L2, Ar2, and L1 together comprise: E)-2-(4-methoxyphenyl)vinyl, (E)-2-(3-methoxyphenyl)vinyl, (E)-2-(2-methoxyphenyl)vinyl, (E)-2-(3,4-dimethoxyphenyl)vinyl, (E)-2-(2,3,4-trimethoxyphenyl)vinyl, (E)-2-(4-ethoxyphenyl)vinyl, (E)-2-phenylvinyl, (E)-2-(4-fluorophenyl)vinyl, (E)-2-(4-chlorophenyl)vinyl, (E)-2-(4-bromophenyl)vinyl, (E)-2-(1,1′-biphenyl-4-yl)vinyl, (E)-2-(1-naphthyl)vinyl, (E)-2-(2-naphthyl)vinyl, 9H-fluoren-9-ylidenemethyl, (E)-2-(4′-methoxy-1,1′-biphenyl-4-yl)vinyl, (E)-2-(3′-methoxy-1,1′-biphenyl-4-yl)vinyl, (E)-2-(4-hydroxyphenyl)vinyl, 2-(4-methoxyphenyl)ethyl, (E)-2-(4′-carboxymethyloxy-1,1′-biphenyl-4-yl)vinyl, (E)-2-(4′-(3-methoxycarbonyl-1-propyloxy)-1,1′-biphenyl-4-yl)vinyl, (E)-2-(4′-(3-carboxy-1-propyloxy)-1,1′-biphenyl-4-yl)vinyl, (E)-2-(4′-phenoxy-1,1′-biphenyl-4-yl)vinyl, or (E)-2-(4′-benzyloxy-1,1′-biphenyl-4-yl)vinyl.
In another embodiment of the compound of Formula (I), Ar1 comprises 2,4-dichlorophenyl.
In another embodiment of the compound of Formula (I), W comprises —N(R2)—, wherein R2 comprises -L3-D-alkylene-arylene-G, wherein L3 comprises a direct bond or alkylene, D is a direct bond, or —O—, and G comprises —CN, —SO3H, —P(O)(OH)2, —P(O)(O-alkyl)(OH), —CO2H, —CO2-alkyl, or an acid isostere.
In another aspect, the present invention provides a pharmaceutically acceptable salt, solvate, or prodrug of compounds of Formula (I).
In the compounds of Formula (I), the various functional groups represented should be understood to have a point of attachment at the functional group having the hyphen. In other words, in the case of -alkylene-aryl, it should be understood that the point of attachment is the alkylene group; an example would be benzyl. In the case of a group such as —C(O)—NH— alkylene-aryl, the point of attachment is the carbonyl carbon.
Also included within the scope of the invention are the individual enantiomers of the compounds represented by Formula (I) above as well as any wholly or partially racemic mixtures thereof. The present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more stereocenters are inverted.
Compounds of the present invention which are currently preferred for their biological activity are listed by name below in Table 1.
The ability of compounds Formula (I) to potentially treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of Formula (I) listed in Table I using a standard primary/secondary assay test procedure that measures the inhibition of PTP-1B activity.
The compounds of this invention can be potentially useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention may therefore be particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also potentially useful in modulating glucose levels in disorders such as type I diabetes.
In the structures listed above, it is understood that where a heteroatom such as nitrogen or oxygen has an unfilled valence, a covalent bond exists between a hydrogen and the heteroatom.
In another aspect, the present invention comprises a pharmaceutical composition comprising the compound of Formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents.
As used herein, the term “lower” refers to a group having between one and six carbons.
As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkyl” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
As used herein, the term “alkylene” refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, and the like.
As used herein, the term “alkenyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenyl” group may containing one or more O, S, S(O), or S(O)2 atoms.
As used herein, the term “alkenylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkenylene” as used herein include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.
As used herein, the term “alkynyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynyl” group may containing one or more O, S, S(O), or S(O)2 atoms.
As used herein, the term “alkynylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkynylene” as used herein include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
As used herein, “cycloalkyl” refers to an alicyclic hydrocarbon group optionally possessing one or more degrees of unsaturation, having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. “Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
As used herein, the term “cycloalkylene” refers to an non-aromatic alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “cycloalkylene” as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring optionally possessing one or more degrees of unsaturation, containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.
As used herein, the term “heterocyclylene” refers to a three to twelve-membered heterocyclic ring diradical optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-diyl, and the like.
As used herein, the term “aryl” refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, alkoxycarbonylamino optionally substituted by alkyl, acylamino optionally substituted by alkyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, aryloxycarbonyl, trialkylsilylalkyloxyalkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.
As used herein, the term “arylene” refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, alkoxycarbonylamino optionally substituted by alkyl, acylamino optionally substituted by alkyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, aryloxycarbonyl, trialkylsilylalkyloxyalkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.
As used herein, the term “heteroaryl” refers to a five- to seven-membered aromatic ring, or to a polycyclic heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, alkoxycarbonylamino optionally substituted by alkyl, acylamino optionally substituted by alkyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, aryloxycarbonyl, trialkylsilylalkyloxyalkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of “heteroaryl” used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and indazole, and the like.
As used herein, the term “heteroarylene” refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, alkoxycarbonylamino optionally substituted by alkyl, acylamino optionally substituted by alkyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, aryloxycarbonyl, trialkylsilylalkyloxyalkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
As used herein, the term “fused cycloalkylaryl” refers to one or more cycloalkyl groups fused to an aryl group, the aryl and cycloalkyl groups having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused cycloalkylaryl” used herein include 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,
and the like.
As used herein, the term “fused cycloalkylarylene” refers to a fused cycloalkylaryl, wherein the aryl group is divalent. Examples include
and the like.
As used herein, the term “fused arylcycloalkyl” refers to one or more aryl groups fused to a cycloalkyl group, the cycloalkyl and aryl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused arylcycloalkyl” used herein include 1-indanyl, 2-indanyl, 9-fluorenyl, 1-(1,2,3,4-tetrahydronaphthyl),
and the like.
As used herein, the term “fused arylcycloalkylene” refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include 9,1-fluorenylene,
and the like.
As used herein, the term “fused heterocyclylaryl” refers to one or more heterocyclyl groups fused to an aryl group, the aryl and heterocyclyl groups having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused heterocyclylaryl” used herein include 3,4-methylenedioxy-1-phenyl,
and the like
As used herein, the term “fused heterocyclylarylene” refers to a fused heterocyclylaryl, wherein the aryl group is divalent. Examples include
and the like.
As used herein, the term “fused arylheterocyclyl” refers to one or more aryl groups fused to a heterocyclyl group, the heterocyclyl and aryl groups having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused arylheterocyclyl” used herein include 2-(1,3-benzodioxolyl),
and the like.
As used herein, the term “fused arylheterocyclylene” refers to a fused arylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include
and the like.
As used herein, the term “fused cycloalkylheteroaryl” refers to one or more cycloalkyl groups fused to a heteroaryl group, the heteroaryl and cycloalkyl groups having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused cycloalkylheteroaryl” used herein include 5-aza-6-indanyl,
and the like.
As used herein, the term “fused cycloalkylheteroarylene” refers to a fused cycloalkylheteroaryl, wherein the heteroaryl group is divalent. Examples include
and the like.
As used herein, the term “fused heteroarylcycloalkyl” refers to one or more heteroaryl groups fused to a cycloalkyl group, the cycloalkyl and heteroaryl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused heteroarylcycloalkyl” used herein include 5-aza-1-indanyl,
and the like.
As used herein, the term “fused heteroarylcycloalkylene” refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include
and the like.
As used herein, the term “fused heterocyclylheteroaryl” refers to one or more heterocyclyl groups fused to a heteroaryl group, the heteroaryl and heterocyclyl groups having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused heterocyclylheteroaryl” used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
and the like.
As used herein, the term “fused heterocyclylheteroarylene” refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent. Examples include
and the like.
As used herein, the term “fused heteroarylheterocyclyl” refers to one or more heteroaryl groups fused to a heterocyclyl group, the heterocyclyl and heteroaryl groups having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused heteroarylheterocyclyl” used herein include -5-aza-2,3-dihydrobenzofuran-2-yl,
and the like.
As used herein, the term “fused heteroarylheterocyclylene” refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include
and the like.
As used herein, the term “acid isostere” refers to a substituent group which will ionize at physiological pH to bear a net negative charge. Examples of such “acid isosteres” include but are not limited to heteroaryl groups such as but not limited to isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such acid isosteres include but are not limited to heterocyclyl groups such as but not limited to imidazolidine-2,4-dione-5-yl, imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or 5-hydroxy-4H-pyran-4-on-2-yl.
As used herein, the term “direct bond”, where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a “direct bond”. Where two or more consecutive variables are specified each as a “direct bond”, those substituents flanking (preceding and succeeding) those two or more consecutive specified “direct bonds” are directly joined.
As used herein, the term “alkoxy” refers to the group RaO—, where Ra is alkyl.
As used herein, the term “alkenyloxy” refers to the group RaO—, where Ra is alkenyl.
As used herein, the term “alkynyloxy” refers to the group RaO—, where Ra is alkynyl.
As used herein, the term “alkylsulfanyl” refers to the group RaS—, where Ra is alkyl.
As used herein, the term “alkenylsulfanyl” refers to the group RaS—, where Ra is alkenyl.
As used herein, the term “alkynylsulfanyl” refers to the group RaS—, where Ra is alkynyl.
As used herein, the term “alkylsulfenyl” refers to the group RaS(O)—, where Ra is alkyl.
As used herein, the term “alkenylsulfenyl” refers to the group RaS(O)—, where Ra is alkenyl.
As used herein, the term “alkynylsulfenyl” refers to the group RaS(O)—, where Ra is alkynyl.
As used herein, the term “alkylsulfonyl” refers to the group RaSO2—, where Ra is alkyl.
As used herein, the term “alkenylsulfonyl” refers to the group RaSO2—, where Ra is alkenyl.
As used herein, the term “alkynylsulfonyl” refers to the group RaSO2—, where Ra is alkynyl.
As used herein, the term “acyl” refers to the group RaC(O)—, where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
As used herein, the term “aroyl” refers to the group RaC(O)—, where Ra is aryl.
As used herein, the term “heteroaroyl” refers to the group RaC(O)—, where Ra is heteroaryl.
As used herein, the term “alkoxycarbonyl” refers to the group RaOC(O)—, where Ra is alkyl.
As used herein, the term “acyloxy” refers to the group RaC(O)O—, where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
As used herein, the term “aroyloxy” refers to the group RaC(O)O—, where Ra is aryl.
As used herein, the term “heteroaroyloxy” refers to the group RaC(O)O—, where Ra is heteroaryl.
As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
As used herein, the terms “contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example, —CH2—O—CH2—, —CH2—SO2—CH2—, —CH2—NH—CH3 and so forth.
Whenever the terms “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for “alkyl” and “aryl”. Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. C1-10) shall refer independently to the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term “alkyl” appears as its prefix root.
As used herein, the term “oxo” shall refer to the substituent ═O.
As used herein, the term “halogen” or “halo” shall include iodine, bromine, chlorine and fluorine.
As used herein, the term “mercapto” shall refer to the substituent —SH.
As used herein, the term “carboxy” shall refer to the substituent —COOH.
As used herein, the term “cyano” shall refer to the substituent —CN.
As used herein, the term “aminosulfonyl” shall refer to the substituent —SO2NH2.
As used herein, the term “carbamoyl” shall refer to the substituent —C(O)NH2.
As used herein, the term “sulfanyl” shall refer to the substituent —S—.
As used herein, the term “sulfenyl” shall refer to the substituent —S(O)—.
As used herein, the term “sulfonyl” shall refer to the substituent —S(O)2—.
The compounds can be prepared readily according to the following reaction Schemes (in which variables are as defined before or are defined) using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula (I) along with methods for the preparation of compounds of Formula (I). Unless otherwise specified, structural variables are as defined for Formula (I).
An unsaturated carboxylic acid (Scheme 1) can be reacted with aryl acyl bromides in the presence of base such as DIEA, triethyl amine, or DBU in a polar solvents such as THF, or DMF to afford intermediate keto-ester (2), which can be treated with ammonium acetate in acetic acid at temperatures ranging from 60-120° C., which leads to the corresponding mixture of oxazole (W=O) and imidazole (W=N) (3) (Strzybny, P. P. E; van Es, T.; Backeberg, O. G. J. Org. Chem. 1963, 25, 1151). The ratio of oxazole and imidazole may vary depending on the substitution and reaction conditions and the two compounds were separated through silica gel column. Alternatively other conditions may also be employed for cyclization of keto-esters (2), such as BF3/Et2O, methanolic ammonia, at temperatures ranging from room temperature to 120° C.
In another embodiment, a bromo or iodo aryl compound (4) (Scheme 2) can be subjected to palladium catalyzed coupling (Syn. Commu. 1981, 11, 513-574) with an optionally substituted heteroaryl or aryl boronic acid. Ar3 is a group such as but not limited to a heteroaryl or aryl group. Typical conditions used to carry out the coupling reaction include the use of boronic acid or ester as the coupling partner, a palladium catalyst (2 to 20 mole %) such as Pd(PPh3)4 or [1,1-bis(diphenylphosphino)-ferrocene]dichloro-palladium (II) and base such as potassium carbonate, sodium carbonate, barium hydroxide, potassium phosphate or triethyl amine in a suitable solvent such as aqueous dimethoxyethane, THF, acetone, DMF or toluene at temperatures ranging from 25° C. to 125° C. In this instance, Ar3 is a group such as, but not limited to, an aryl or heteroaryl group.
In another embodiment (Scheme 3), the O-alkyl, or O-aryl group in compound (5) can be dealkylated or dearylated using reagents such as boron tribromide or PhSMe, in a solvent such as dichloromethane or TFA, at temperatures ranging from −20° C. to room temperature to afford hydroxy biphenyls (6). In this instance, Ar4 is a group such as, but not limited to, heteroarylene or arylene, and R30 is a group such as, but not limited to, lower alkyl.
In Scheme 4, the biphenyl alcohols (5) were alkylated with bromo or chloro alkyl carboxylates [(Br or Cl)(CH2)n—CO2—R30] [where n=1 to 6] in the presence of base such as sodium hydride, potassium tert-butoxide, or potassium carbonate using DMF, THF, acetonitrile as the solvent at temperatures ranging from 50° C. to 100° C. Subsequent saponification of esters (6) with bases such as sodium hydroxide, lithium hydroxide in aqueous and organic solvents such as THF, methanol, at temperatures ranging from room temperature to 60° C. produces carboxylic acid (8). In this instance, R30 is a group such as, but not limited to, lower alkyl. In this instance, Ara is a group such as, but not limited to, an arylene or heteroarylene group.
In another embodiment (Scheme 5), the imidazole nitrogen in compound (9) can be alkylated with bromo or chloro alkyl carboxylates [(Br or Cl)(CH2)nCO2R30] in the presence of base such as sodium hydride, potassium tert-butoxide, or potassium carbonate using DMF, THF, or acetonitrile as the solvent at temperatures ranging from 50° C. to 100° C. Subsequent saponification of esters (10) with base such as sodium hydroxide, lithium hydroxide in aqueous and organic solvents such as THF, or methanol at temperatures ranging from room temperature to 60° C. produces carboxylic acid (11). In this instance, R30 is a group such as, but not limited to, lower alkyl.
In Scheme 6 the carboxylic acids (12) can be transformed into their carboxylic acid amide analogs. This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid, reacting with one or more molar equivalents of the desired amine. Methods to activate the carboxylic acid include reacting the acid with one or more molar equivalents of DIC or DIEA, with or without one or more molar equivalents of HOBt or HBTU in a suitable solvent such as dichloromethane or DMF at temperatures ranging from 0° C. to 40° C. to afford amides (13). In this instance, R31 is a group such as, but not limited to, -alkyl or -alkylene-aryl.
In another embodiment (Scheme 7), an imidazole nitrogen in compound (14) was alkylated with alkyl halides [(Br or Cl)(CH2)n—R32] [n=1 to 6] in the presence of base such as sodium hydride, potassium tert-butoxide, or potassium carbonate using DMF, THF, or acetonitrile as the solvent at temperatures ranging from 0° C. to 80° C. afford N-alkylated products (15). In this instance R32 is a group such as, but not limited to, -alkyl, aryl, or -alkenylene-aryl.
The term “amino protecting group” as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenyl benzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonypethoxycarbonyl, 2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the compound of Formula (I) and can be removed at the desired point without disrupting the remainder of the molecule. In an embodiment, amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected amino” or “protected amino group” defines an amino group substituted with an amino-protecting group discussed above.
The term “hydroxyl protecting group” as used herein refers to substituents of the alcohol group commonly employed to block or protect the alcohol functionality while reacting other functional groups on the compound. Examples of such alcohol-protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the trichloroacetyl group, urethane-type blocking groups such as benzyloxycarbonyl, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and thexyldimethylsilyl. The choice of alcohol-protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected hydroxyl” or “protected alcohol” defines a hydroxyl group substituted with a hydroxyl-protecting group as discussed above.
The term “carboxyl protecting group” as used herein refers to substituents of the carboxyl group commonly employed to block or protect the —OH functionality while reacting other functional groups on the compound. Examples of such alcohol-protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the allyl group, the trimethylsilylethoxymethyl group, the 2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and thexyldimethylsilyl. The choice of carboxyl protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected carboxyl” defines a carboxyl group substituted with a carboxyl-protecting group as discussed above.
The general procedures used in the methods of the present invention are described below.
LC-MS data was obtained using gradient elution on a Waters 600 controller equipped with a 2487 dual wavelength detector and a Leap Technologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6 mm column. A three minute gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass spectrometer used was a Micromass ZMD instrument. All data was obtained in the positive mode unless otherwise noted. 1H NMR data was obtained on a Varian 400 MHz spectrometer. Abbreviations used in the Examples are as follows:
APCI=atmospheric pressure chemical ionization
BOC=tert-butoxycarbonyl
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate
d=day
DIAD=diisopropyl azodicarboxylate
DCC=dicyclohexylcarbodiimide
DCM=dichloromethane
DIC=diisopropylcarbodiimide
DIEA=diisopropylethylamine
DMAP=dimethylaminopyridine
DME=1,2 dimethoxyethane
DMPU=1,3-dimethylpropylene urea
DMSO=dimethylsulfoxide
EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
EDTA=ethylenediamine tetraacetic acid
ELISA=enzyme-linked immunosorbent assay
ESI=electrospray ionization
ether=diethyl ether
EtOAc=ethyl acetate
FBS=fetal bovine serum
g=gram
h=hour
HBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
HMPA=hexamethylphosphoric triamide
HOBt=1-hydroxybenzotriazole
Hz=hertz
i.v.=intravenous
kD=kiloDalton
L=liter
LAH=lithium aluminum hydride
LDA=lithium diisopropylamide
LPS=lipopolysaccharide
M=molar
m/z=mass to charge ratio
mbar=millibar
MeOH=methanol
mg=milligram
min=minute
mL=milliliter
mM=millimolar
mmol=millimole
mol=mole
mp=melting point
MS=mass spectrometry
N=normal
NMM=N-methylmorpholine, 4-methylmorpholine
NMR=nuclear magnetic resonance spectroscopy
p.o.=per oral
PBS=phosphate buffered saline solution
PMA=phorbol myristate acetate
ppm=parts per million
psi=pounds per square inch
Rf=relative TLC mobility
rt=room temperature
s.c.=subcutaneous
SPA=scintillation proximity assay
TEA=triethylamine
TFA=trifluoroacetic acid
THF=tetrahydrofuran
THP=tetrahydropyranyl
TLC=thin layer chromatography
TMSBr=bromotrimethylsilane, trimethylsilylbromide
Tr=retention time
To a mixture of a carboxylic acid (1 eq) and an aromatic acyl bromide (2 eq) in anhydrous DMF (0.1-0.5 M) was added DIEA (3 eq). The reaction mixture was stirred at room temperature under nitrogen for 6 to 8 hours. After that, it was poured into water, acidified with 10% citric acid and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over Na2SO4. After evaporation of the solvent, the pale-brown residue was recrystallized from EtOAc-Hexanes, dried and used directly in the next step.
The intermediate obtained above was dissolved in glacial acetic acid (0.1-0.5 M), and ammonium acetate (20 eq) was added. The mixture was then heated at 120° C. under nitrogen for 8 to 10 hours. At completion, it was poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water and brine, and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to afford the desired product.
To a solution of the bromo compound (1 eq) in a 2:1 mixture of toluene and ethanol (0.1-0.5 M) was added the appropriate boronic acid (1.2 eq) and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (0.05 eq), followed by 2 M sodium carbonate solution in water (30 eq). The reaction mixture was stirred at 90° C. under nitrogen for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to afford the desired compound.
To the solution of alkyl phenolic ether (1 eq) in anhydrous DCM (0.1-0.5 M) at −20° C. was added dropwise BBr3 (2 eq, solution in anhydrous DCM). The solution was warmed to room temperature over 30 minutes, and the reaction mixture quenched with ice water. The reaction mixture was then diluted with water/EtOAc and the layers were separated. The aqueous layer was further extracted with EtOAc, and the organic layers combined, washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo, and the residue subjected to silica gel chromatography to yield the final product.
To 1 equivalent of the desired alkene suspension in ethyl acetate (0.1-0.5 M) was added a catalytic amount of platinum(IV) oxide (wet). After degassing and introducing of nitrogen and degassing again, hydrogen was introduced through a hydrogen balloon. The reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then filtered through celite, the celite cake was washed three times with ethyl acetate, and the filtrates combined. The solvent was then removed in vacuo, and the residue was purified by silica gel chromatography to afford the desired compound.
To a solution of imidazole or phenol (1 eq) in anhydrous DMF (0.1-0.5 M) was added an alkyl or aryl halide (2 eq) followed by freshly ground K2CO3 (4 eq). The reaction mixture was heated at 100° C. under nitrogen for 2 hours. The mixture was then diluted with water/EtOAc and the layers separated. The aqueous layer was further extracted with EtOAc, and the organic layers combined and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to yield the final product.
The ester (1 eq) was suspended in a mixture of MeOH:THF:H2O (1:1:1; 0.1-0.2 M). LiOH (10-15 eq) was added and the mixture stirred at 40° C. for 3 hours. The solution was acidified with 10% citric acid solution, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and the solvent removed in vacuo. The residue was purified by silica gel chromatography to yield the final compound.
To a solution of carboxylic acid (1.1 eq) in DMF (0.1-0.5 M), HBTU (1.1 eq) was added followed by DIEA (1.2 eq) and the appropriate protected amine (1 eq.). The reaction mixture was then stirred at room temperature for 4 hours. At completion, the reaction mixture was diluted with water/EtOAc, acidified with 10% citric acid, and the layers were separated. The combined organic layer was washed with water, saturated NaHCO3 and brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford the amide derivative.
To a solution of aryl bromide or aryl iodide (1 eq) in anhydrous DMF (0.1-0.5 M) was added the appropriate terminal acetylene (1.2 eq) followed by tetrakis (triphenylphosphine)palladium(0) (0.05 eq), CuI (0.1 eq), and DIEA (2 eq). The reaction mixture was then heated at 120° C. under nitrogen for 6-8 hours. At completion, the reaction mixture was diluted with water/EtOAc, acidified with 10% citric acid, and the layers separated. The combined organic layers was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford the acetylene derivative.
To a solution of phenol compound (1 eq) in anhydrous DMF (0.1-0.5 M), the appropriate activated aryl fluoride (1.5 eq) was added followed by Cs2CO3 (3 eq). The reaction mixture was then heated at 120° C. under nitrogen for 2 hours. At completion, the reaction mixture was diluted with water/EtOAc and the layers separated. The aqueous layer was reextracted with EtOAc and the organic layers combined, washed with water and brine. The organic phase was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford the diaryl ether derivative.
To a solution of phenol compound (1 eq) in anhydrous NMP (0.1-0.5 M), the appropriate aryl bromide or iodide (1.5 eq) was added followed by CuCl (0.2 eq), 2,2,6,6-tetramethyl-3,5-heptanedione (0.2 eq) and Cs2CO3 (3 eq). The reaction mixture was then heated at 120° C. under nitrogen for 6 to 8 hours. At completion, the reaction mixture was diluted with water/EtOAc and the layers separated. The aqueous layer was reextracted with EtOAc and the organic layers combined, washed with water and brine. The organic phase was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford the diaryl ether derivative.
To a suspension of aryl nitro compound (1 eq) in HOAc (0.1-0.5 M), iron powder (−325 mesh, 4 eq) was added and the mixture was then heated at 120° C. under nitrogen for 3 to 4 hours. At completion, the reaction mixture was diluted with water/EtOAc and the leftover iron powder was filtered and washed with EtOAc. The combined organic layer was washed with water, saturated NaHCO3 and brine. The organic phase was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford the aniline derivative.
To a suspension of aniline compound (1 eq) in anhydrous DCM (0.1-0.5 M) at 0° C. was added DIEA (1.2 eq) followed by the appropriate sulfonyl chloride or sulfonic anhydride (1.1 eq, diluted in anhydrous DCM). The reaction mixture was then warmed up and stirred at room temperature under nitrogen for 3 to 4 hours. At completion, the reaction mixture was diluted with water/EtOAc and the layers separated. The aqueous layer was reextracted with EtOAc and the organic layers combined, washed with 10% citric acid, water and brine. The organic phase was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford the sulfonamide derivative.
To a solution of phenol compound (1 eq) in anhydrous DMF (0.1-0.5 M) was added an appropriate bromoalkylnitrile (2 eq) followed by freshly ground K2CO3 (4 eq). The reaction mixture was heated at 100° C. under nitrogen for 2 hours. The mixture was then diluted with water/EtOAc and the layers separated. The aqueous layer was further extracted with EtOAc, and the organic layers combined and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by silica gel chromatography to yield the nitrile intermediate.
The nitrile intermediate (1 eq) obtained above was dissolved in anhydrous DMF (0.1-0.5 M) and sodium azide (10 eq) and ammonium chloride (10 eq) were added. The reaction mixture was heated at 120° C. under nitrogen for 8 to 10 hours. At completion, the reaction mixture was diluted with water/EtOAc and the layers separated. The aqueous layer was further extracted with EtOAc, and the organic layers combined and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to afford the final product.
1 equivalent of an imidazole was suspended in anhydrous THF (0.1-0.5 M), to which was added 1.4 equivalents of TEA and 1.5 equivalents of di-tert-butyl-dicarbonate. The mixture was stirred for 2 hours and diluted with water and the layers were separated. The aqueous layer was further extracted with EtOAc, the organic layers combined, washed with brine, and the organic layer dried over sodium sulfate. The solvent was removed in vacuo, and the crude product purified by flash chromatography on silica gel to give the final product.
The protected compound was stirred in 4N HCl/dioxane for 1 hour. The solvent removed, and the product triturated several times with ether to afford the desired compound.
To a solution of imidazole or phenol (1 eq) in anhydrous DMF (0.1-0.5M) was added 1-2 eq sodium hydride, either solid or as a suspension in DMF or THF. The mixture was stirred at room temperature for 20 min and a solution of alkyl or aryl halide (1-3 eq) was added in DMF or THF. Stirring continued for 1 hour, then the mixture was diluted with water/EtOAc and neutralized with 10% aqueous citric acid. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography to provide the final product.
To a solution of an aldehyde (1 eq) in ethanol (0.1-0.5 M) was added 1.5 eq of a benzenediamine. The mixture was sealed in a heavy walled glass tube with stir bar and stirred at 100° C. for 2 hours to overnight. The mixture was then evaporated and taken up in water/EtOAc and layers were separated. The aqueous layer was further extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography to give the product.
To a solution of aryl nitro compound (1 eq) in methanol (0.1-0.5 M) was added 0.1 eq of 10% Pd/C catalyst. The flask was flushed with H2 and stirred under H2 pressure (balloon) overnight at room temperature. The mixture was then filtered on a celite pad and evaporated, and the residue was purified by silica gel column chromatography to provide the desired product.
To a solution of O— or N— silyl compound (1 eq) in THF (0.1-0.5 M) was added 5 eq of tetrabutylammonium fluoride as a solution in THF. The mixture was stirred at 65° C. for 1-3 hours, then was evaporated to a small volume and taken up in water/EtOAc. Layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.
To a solution of trimethylsilyl compound (1 eq) in anhydrous methanol (0.1-0.5 M) was added 10 eq anhydrous K2CO3 under nitrogen. The mixture was stirred under nitrogen at room temperature for 3 hours, then diluted with water/EtOAc and layers were separated. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product.
To a solution of amine (1 eq) in 1,2-dichloroethane (0.1-0.5 M) was added an aldehyde (1.2 eq) and a catalytic amount of acetic acid. The mixture was stirred at room temperature for 30 minutes under nitrogen, then sodium triacetoxyborohydride (3 eq) was added and the mixture was allowed to stir for 12-16 hours at room temperature. The mixture was then diluted with water/EtOAc and layers were separated. The aqueous layer was extracted additionally with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product.
To a suspension of double bond containing compound (1 eq) in HOAc (0.1-0.5 M) was added iron powder (−325 mesh, 10-20 eq) and the mixture was stirred and heated at 120° C. for 18-24 hours. The mixture was then diluted with water/EtOAc and filtered to remove excess iron powder, then layers were separated and the aqueous layer was washed again with EtOAc. The combined organic extracts were washed with water, saturated NaHCO3, and brine, then dried over Na2SO4. After evaporation in vacuo, the residue was purified by silica gel column chromatography to provide the desired product.
Trans-4-methoxycinnamic acid (178 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (193 mg, 56% yield).
LCMS: m/z 345 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.82 (s, 3H), 6.88 (d, 1H), 6.95 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
Trans-3-methoxycinnamic acid (178 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(3-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (176 mg, 51% yield).
LCMS: m/z 345 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 6.88 (d, 1H), 7.04 (m, 3H), 7.32 (d, 1H), 7.41 (s, 1H), 7.50 (d, 1H), 7.54 (s, 1H), 7.67 (d, 1H), 7.92 (s, 1H) ppm.
Trans-2-methoxycinnamic acid (178 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(2-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (207 mg, 60% yield).
LCMS: m/z 345 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.82 (s, 3H), 6.88 (d, 1H), 7.04-7.15 (m, 4H), 7.32 (d, 1H), 7.50 (d, 1H), 7.54 (s, 1H), 7.67 (d, 1H), 7.93 (s, 1H) ppm.
Trans-3,4-dimethoxycinnamic acid (208 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(3,4-dimethoxy-phenyl)-(E)-vinyl]-1H-imidazole (176 mg, 47% yield).
LCMS: m/z 375 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.89 (s, 3H), 3.91 (s, 3H), 7.00 (d, 1H), 7.05 (d, 1H), 7.24-7.28 (m, 2H), 7.56 (dd, 1H), 7.66 (d, 1H), 7.69 (d, 1H), 7.75 (d, 1H), 7.89 (s, 1H) ppm.
Trans-2,3,4-trimethoxycinnamic acid (238 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole (170 mg, 42% yield).
LCMS: m/z 405 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.85 (s, 3H), 3.91 (s, 3H), 3.98 (s, 3H), 6.91 (d, 1H), 7.12 (d, 1H), 7.44 (d, 1H), 7.55 (dd, 1H), 7.69 (d, 1H), 7.74 (d, 1H), 7.87 (s, 1H), 7.92 (d, 1H) ppm.
Trans-4-ethoxycinnamic acid (192 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(4-ethoxy-phenyl)-(E)-vinyl]-1H-imidazole (222 mg, 64% yield).
LCMS: m/z 359 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.41 (t, 3H), 4.10 (q, 2H), 6.97 (d, 1H), 7.01 (d, 2H), 7.55 (dd, 1H), 7.63 (d, 2H), 7.68 (d, 1H), 7.69 (d, 1H), 7.74 (d, 1H), 7.88 (s, 1H) ppm.
Trans-cinnamic acid (148 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-styryl-1H-imidazole (202 mg, 64% yield).
LCMS: m/z 315 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.13 (d, 1H), 7.49 (m, 3H), 7.68-7.73 (m, 4H), 7.77 (d, 1H), 8.03 (m, 2H) ppm.
Trans-4-fluorocinnamic acid (166 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(4-fluoro-phenyl)-(E)-vinyl]-1H-imidazole (236 mg, 71% yield).
LCMS: m/z 333 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.12 (d, 1H), 7.51 (d, 2H), 7.68 (d, 2H), 7.70 (m, 2H), 7.72 (d, 1H), 8.03 (m, 1H), 8.04 (s, 1H) ppm.
Trans-4-chlorocinnamic acid (182 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-[2-(4-chloro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (227 mg, 65% yield).
LCMS: m/z 349 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.14 (d, 1H), 7.52 (d, 2H), 7.69 (d, 2H), 7.72-7.73 (m, 2H), 7.74 (d, 1H), 8.03 (m, 1H), 8.05 (s, 1H) ppm.
Trans-4-bromocinnamic acid (2.27 g, 10 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (2.24 g, 57% yield).
LCMS: m/z 394 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.14 (d, 1H), 7.51 (d, 2H), 7.69 (d, 2H), 7.71 (m, 2H), 7.74 (d, 1H), 8.02 (m, 1H), 8.04 (s, 1H) ppm.
Trans-4-phenylcinnamic acid (224 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-(2-biphenyl-4-yl-(E)-vinyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (227 mg, 58% yield).
LCMS: m/z 391 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, 1H), 7.31-7.39 (m, 2H), 7.43-7.48 (m, 3H), 7.61-7.64 (m, 6H), 7.66 (s, 1H), 7.74 (d, 1H), 8.26 (d, 1H) ppm.
Trans-3-(1-naphthyl)acrylic acid (198 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-(2-naphthalen-1-yl-(E)-vinyl)-1H-imidazole (201 mg, 55% yield).
LCMS: m/z 365 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.25 (d, 1H), 7.58-7.69 (m, 4H), 7.75 (d, 1H), 7.78 (d, 1H), 7.97-8.04 (m, 4H), 8.35 (d, 1H), 8.70 (d, 1H) ppm.
Trans-3-(2-naphthyl)acrylic acid (198 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-(2-naphthalen-2-yl-(E)-vinyl)-1H-imidazole (248 mg, 68% yield).
LCMS: m/z 365 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.27 (d, 1H), 7.57-7.69 (m, 4H), 7.75 (d, 1H), 7.76 (d, 1H), 7.96-8.02 (m, 4H), 8.33 (d, 1H), 8.71 (d, 1H) ppm.
5-Phenyl-1,3-oxazole-4-carboxylic acid (189 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-5-phenyl-oxazole (135 mg, 38% yield).
LCMS: m/z 356 (M+H)+.
Trans-4-benzyloxycinnamic acid (254 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-[2-(4-benzyloxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (185 mg, 44% yield).
LCMS: m/z 421 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.16 (s, 2H), 7.48 (d, 2H), 7.51 (s, 5H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
9-Fluorenylideneacetic acid (222 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-1H-imidazole (245 mg, 63% yield).
LCMS: m/z 389 (M+H)+. 1H NMR (CD3OD, 400 MHz): δ 7.25 (m, 1H), 7.37-7.51 (m, 5H), 7.57 (dd, 1H), 7.73 (d, 1H), 7.77-7.82 (m, 3H), 7.93 (d, 1H), 8.08 (s, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-1H-imidazole (39 mg, 0.1 mmol) was treated according to general procedure E using 1-bromobutane to give 1-butyl-4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-1H-imidazole (35 mg, 78% yield).
LCMS: m/z 445 (M+H)+.
Trans-4-methoxycinnamic acid (178 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to afford 4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-oxazole as a less polar by-product (38 mg, 11% yield) along with 4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (193 mg, 56% yield).
LCMS: m/z 346 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 6.89 (d, 1H), 6.95 (d, 2H), 7.34 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.58 (s, 1H), 7.67 (d, 1H), 7.94 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-methoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (30 mg, 72% yield).
LCMS: m/z 421 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.82 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.70 (s, 1H), 7.71 (m, 5H), 7.73 (d, 1H), 7.91 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 3-methoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(3′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (28 mg, 67% yield).
LCMS: m/z 421 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68-7.70 (m, 6H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 2-methoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(2′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (24 mg, 57% yield).
LCMS: m/z 421 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.83 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.55-7.60 (m, 3H), 7.66-7.71 (m, 6H), 7.73 (d, 1H), 7.92 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 3,4-dimethoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(3′,4′-dimethoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (24 mg, 54% yield).
LCMS: m/z 451 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.84 (s, 3H), 3.87 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68-7.71 (m, 5H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 2,4-dimethoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(2′,4′-dimethoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (22 mg, 49% yield).
LCMS: m/z 451 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-n-butoxyphenylboronic acid to give 2-[2-(4′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (24 mg, 52% yield).
LCMS: m/z 463 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.15 (t, 3H), 1.43 (m, 2H), 1.84 (m, 2H), 4.18 (t, 2H), 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.70 (s, 1H), 7.71 (m, 5H), 7.73 (d, 1H), 7.91 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (39 mg, 0.1 mmol) was treated with 4-phenoxyphenyl boronic acid as described in general procedure B to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-phenoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (30 mg, 63% yield).
LCMS: m/z 483 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 7.03 (d, 1H), 7.06 (d, 1H), 7.08 (m, 3H), 7.15 (d, 1H), 7.35 (m, 2H), 7.37 (d, 1H), 7.45 (s, 1H), 7.58 (m, 7H), 7.78 (s, 1H), 8.20 (d, 1H), 9.38 (bs, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (39 mg, 0.1 mmol) was treated with 4-benzyloxy benzene boronic acid as described in general procedure B to give 2-[2-(4′-benzyloxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (39 mg, 78% yield).
LCMS: m/z 497 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.16 (s, 2H), 7.10 (d, 1H), 7.12 (d, 1H), 7.42 (m, 2H), 7.48 (d, 2H), 7.51 (s, 5H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-benzyloxy-3-fluorobenzeneboronic acid to give 2-[2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (36 mg, 71% yield).
LCMS: m/z 515 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.22 (s, 2H), 7.13 (d, 1H), 7.20 (t, 1H), 7.38-7.49 (m, 6H), 7.54 (m, 1H), 7.66 (d, 1H), 7.69-7.72 (m, 5H), 7.74 (s, 1H), 7.75 (d, 1H), 7.86 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid to give 4-(2,4-dichloro-phenyl)-2-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenyl]-(E)-vinyl}-1H-imidazole (27 mg, 61% yield).
LCMS: m/z 449 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 4.28 (s, 4H), 6.91 (d, 1H), 7.12 (d, 1H), 7.15 (m, 2H), 7.51 (m, 1H), 7.62 (d, 1H), 7.64-7.70 (m, 6H), 7.78 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-methoxy-3,5-dimethylbenzeneboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-3′,5′-dimethyl-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (28 mg, 63% yield).
LCMS: m/z 449 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 2.36 (s, 6H), 3.77 (s, 3H), 7.13 (d, 1H), 7.54 (m, 1H), 7.67 (d, 1H), 7.70-7.73 (m, 5H), 7.76 (d, 1H), 7.78 (s, 2H), 7.87 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-ethoxybenzeneboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (29 mg, 68% yield).
LCMS: m/z 435 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.57 (t, 3H), 4.30 (q, 2H), 6.93 (d, 1H), 6.97 (d, 2H), 7.45 (d, 1H), 7.50-7.56 (m, 6H), 7.75 (d, 2H), 8.59 (d, 1H), 8.94 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-trifluoromethoxyphenyl boronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (20 mg, 42% yield).
LCMS: m/z 475 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.71 (m, 6H), 7.73 (d, 1H), 7.91 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 3-trifluoromethoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-2-[2-(3′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (23 mg, 48% yield).
LCMS: m/z 475 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.04 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.74 (m, 7H), 7.92 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using benzo[B]furan-2-boronic acid to give 2-[2-(4-benzofuran-2-yl-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (15 mg, 34% yield).
LCMS: m/z 431 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 5-chloro-2-methoxyphenylboronic acid to give 2-[2-(5′-chloro-2′-methoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (22 mg, 47% yield).
LCMS: m/z 455 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68-7.70 (m, 5H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure B using 4-tert-butylbenzeneboronic acid to give 2-[2-(4′-tert-butyl-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (19 mg, 42% yield).
LCMS: m/z 447 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.22 (s 9H), 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.71 (m, 6H), 7.73 (d, 1H), 7.92 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (79 mg, 0.2 mmol) was treated as described in general procedure B using 4-(2-carboxy(E)-vinyl)benzene boronic acid to give 3-(4′-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yl)-acrylic acid (21 mg, 22% yield).
LCMS: m/z 461 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 6.53 (d, 1H), 7.14 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 1H), 7.68-7.79 (m, 10H), 7.89 (d, 1H), 7.94 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure H using 1-ethynyl-4-methoxybenzene to give 4-(2,4-dichloro-phenyl)-2-{2-[4-(4-methoxy-phenylethynyl)-phenyl]-(E)-vinyl}-1H-imidazole (23 mg, 51% yield).
LCMS: m/z 445 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68-7.70 (m, 6H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure H using 4-pentynoic acid methyl ester followed by ester hydrolysis as described in general procedure F to give 5-(4-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-pent-4-ynoic acid (12 mg, 29% yield).
LCMS: m/z 411 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.53 (m, 2H), 2.64 (m, 2H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68 (m, 2H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was treated as described in general procedure B using 4-carboxybenzeneboronic acid to give 4′-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-carboxylic acid (105 mg, 24% yield).
LCMS: m/z 435 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.71 (m, 6H), 7.73 (d, 1H), 7.92 (s, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-carboxylic acid (44 mg, 0.1 mmol) was treated as described in general procedure G using methyl 4-(aminomethyl)benzoate hydrochloride followed by ester hydrolysis as described in general procedure F to give 4-{[(4′-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-carbonyl)-amino]-methyl}-benzoic acid (25 mg, 44% yield).
LCMS: m/z 568 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.03 (d, 2H), 7.03 (d, 2H), 7.15 (d, 1H), 7.23 (d, 2H), 7.35 (d, 2H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.71 (m, 6H), 7.73 (d, 1H), 7.92 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (44 mg, 0.1 mmol) was treated as described in general procedure B using 4-carboxybenzeneboronic acid to give 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-carboxylic acid (29 mg, 63% yield).
LCMS: m/z 463 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.45 (t, 2H), 4.28 (q, 2H), 7.03 (d, 2H), 7.15 (d, 1H), 7.54 (dd, 1H), 7.62 (d, 2H), 7.68-7.71 (m, 6H), 7.73 (d, 1H), 7.92 (s, 1H) ppm.
2-[2-(4′-Benzyloxy-3′-fluoro-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (52 mg, 0.1 mmol) was treated as described in general procedure E using ethyl bromide to give 2-[2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (39 mg, 71% yield).
LCMS: m/z 543 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.46 (t, 3H), 4.30 (q, 2H), 5.22 (s, 2H), 7.13 (d, 1H), 7.20 (t, 1H), 7.38-7.49 (m, 6H), 7.54 (m, 1H), 7.66 (d, 1H), 7.69-7.72 (m, 5H), 7.74 (s, 1H), 7.75 (d, 1H), 7.86 (s, 1H) ppm.
2-[2-(4′-Benzyloxy-3′-fluoro-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (55 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 4-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3-fluoro-biphenyl-4-yloxymethyl)-benzoic acid (18 mg, 31% yield).
LCMS: m/z 587 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.46 (t, 3H), 4.30 (q, 2H), 5.22 (s, 2H), 7.13 (d, 1H), 7.20 (t, 1H), 7.38-7.49 (m, 5H), 7.54 (m, 1H), 7.66 (d, 1H), 7.69-7.72 (m, 5H), 7.74 (s, 1H), 7.75 (d, 1H), 7.86 (s, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (34 mg, 0.1 mmol) was treated as described in general procedure C to give 4-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenol (20 mg, 61% yield).
LCMS: m/z 331 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 6.88 (d, 1H), 6.95 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (34 mg, 0.1 mmol) was treated as described in general procedure D to give 4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-ethyl]-1H-imidazole (17 mg, 51% yield).
LCMS: m/z 347 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.00 (s, 4H), 3.77 (s, 3H), 6.82 (d, 2H), 7.10 (d, 2H), 7.32 (m, 1H), 7.46 (m, 2H), 7.74 (s, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (34 mg, 0.1 mmol) was treated with ethyl bromide as described in general procedure E to give 4-(2,4-dichloro-phenyl)-1-ethyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (32 mg, 84% yield).
LCMS: m/z 373 (M+H)+.
4-(2,4-Dichloro-phenyl)-1-ethyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (38 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 4-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenoxymethyl)-benzoic acid (17 mg, 34% yield)
LCMS: m/z 493 (M+H)+.
4-(2,4-Dichloro-phenyl)-1-ethyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (38 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 3-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 3-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenoxymethyl)-benzoic acid (15 mg, 30% yield)
LCMS: m/z 493 (M+H)+.
4-(2,4-Dichloro-phenyl)-1-ethyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (38 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenoxy)-butyric acid (15 mg, 33% yield).
LCMS: m/z 445 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.21 (t, 3H), 2.15 (m, 2H), 2.56 (t, 2H), 3.94 (q, 2H), 4.06 (t, 2H), 6.95 (d, 1H), 6.97 (d, 2H), 7.30 (m, 1H), 7.42 (d, 1H), 7.55 (m, 2H), 7.71 (s, 1H), 7.73 (d, 1H), 8.25 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-1-ethyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (38 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with ethyl 6-bromohexanoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 6-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenoxy)-hexanoic acid (18 mg, 38% yield).
LCMS: m/z 473 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (34 mg, 0.1 mmol) was treated with 1-bromobutane as described in general procedure E to give 1-butyl-4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (32 mg, 81% yield)
LCMS: m/z 401 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.01 (t, 3H), 1.46 (m, 2H), 1.90 (m, 2H), 3.87 (s, 3H), 4.31 (t, 2H), 7.04 (d, 2H), 7.16 (d, 1H), 7.71-7.74 (m, 4H), 7.78 (d, 1H), 8.05 (m, 2H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (34 mg, 0.1 mmol) was treated with isobutyl bromide as described in general procedure E to give 4-(2,4-dichloro-phenyl)-1-isobutyl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (29 mg, 72% yield).
LCMS: m/z 401 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.03 (d, 6H), 1.87 (m, 1H), 3.87 (s, 3H), 4.24 (d, 2H), 7.04 (d, 2H), 7.16 (d, 1H), 7.71-7.74 (m, 4H), 7.78 (d, 1H), 8.05 (m, 2H) ppm.
4-{2-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenol (33 mg, 0.1 mmol) was treated with 1-bromobutane as described in general procedure E to give 2-[2-(4-butoxy-phenyl)-(E)-vinyl]-1-butyl-4-(2,4-dichloro-phenyl)-1H-imidazole (34 mg, 76% yield)
LCMS: m/z 443 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.02 (dt, 6H), 1.43 (m, 4H), 1.88 (m, 4H), 4.08 (t, 2H), 4.34 (t, 2H), 7.04 (d, 2H), 7.16 (d, 1H), 7.71-7.74 (m, 4H), 7.78 (d, 1H), 8.05 (m, 2H) ppm.
2-(2-Biphenyl-4-yl-(E)-vinyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (20 mg, 0.05 mmol) was treated with 1-bromobutane as described in general procedure E to give 2-(2-biphenyl-4-yl-(E)-vinyl)-1-butyl-4-(2,4-dichloro-phenyl)-1H-imidazole (16 mg, 73% yield)
LCMS: m/z 447 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.00 (t, 3H), 1.43 (m, 2H), 1.84 (m, 2H), 4.08 (t, 2H), 6.94 (d, 1H), 7.31-7.39 (m, 2H), 7.43-7.48 (m, 3H), 7.61-7.64 (m, 6H), 7.66 (s, 1H), 7.74 (d, 1H), 8.26 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (21 mg, 0.05 mmol) was treated with 1-bromobutane as described in general procedure E to give 1-butyl-4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (18 mg, 76% yield).
LCMS: m/z 477 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.00 (t, 3H), 1.43 (m, 2H), 1.84 (m, 2H), 3.85 (s, 3H), 4.08 (t, 2H), 6.90 (d, 1H), 7.00 (d, 2H), 7.32 (dd, 1H), 7.42 (d, 1H), 7.55-7.61 (m, 6H), 7.63 (s, 1H), 7.74 (d, 1H), 8.26 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole
(21 mg, 0.05 mmol) was treated with isobutyl bromide as described in general procedure E to give 4-(2,4-dichloro-phenyl)-1-isobutyl-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (15 mg, 62% yield).
LCMS: m/z 477 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (21 mg, 0.05 mmol) was treated with 1-bromopropane as described in general procedure E to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-propyl-1H-imidazole (16 mg, 68% yield).
LCMS: m/z 463 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was treated with methyl iodide as described in general procedure E to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (18 mg, 76% yield).
LCMS: m/z 435 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.81 (s, 3H), 3.86 (s, 3H), 6.90 (d, 1H), 7.00 (d, 2H), 7.32 (dd, 1H), 7.42 (d, 1H), 7.55-7.61 (m, 6H), 7.63 (s, 1H), 7.74 (d, 1H), 8.26 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was treated with benzyl bromide as described in general procedure E to give 1-benzyl-4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (32 mg, 63% yield).
LCMS: m/z 511 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.83 (s, 3H), 5.36 (s, 2H), 7.10 (d, 1H), 7.12 (d, 1H), 7.42 (m, 2H), 7.48 (d, 2H), 7.51 (m, 5H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was treated with 2-bromopropane as described in general procedure E to give 4-(2,4-dichloro-phenyl)-1-isopropyl-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (16 mg, 33% yield).
LCMS: m/z 463 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was treated with cyclopropyl bromide as described in general procedure E to give 1-cyclopropyl-4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (14 mg, 30% yield).
LCMS: m/z 461 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure E using ethyl bromide to give 4-(2,4-dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-1-ethyl-1H-imidazole (36 mg, 79% yield).
LCMS: m/z 463 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.46 (t, 3H), 1.57 (t, 3H), 4.09 (q, 2H), 4.30 (q, 2H), 6.94 (d, 1H), 6.97 (d, 2H), 7.45 (d, 1H), 7.50-7.56 (m, 6H), 7.75 (d, 2H), 8.59 (d, 1H), 8.93 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (3.45 g, mmol) was treated with methyl bromoacetate as described in general procedure E followed by ester hydrolysis as described in general procedure F to afford {4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (2.26 g, 56% yield).
LCMS: m/z 403 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.82 (s, 3H), 4.97 (s, 2H), 6.88 (d, 1H), 6.95 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with DL-1-(1-naphthyl)ethylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (42 mg, 78% yield).
LCMS: m/z 556 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.59 (d, 3H), 3.86 (s, 3H), 4.83 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 6H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with (S)-1-(1-naphthyl)ethylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (41 mg, 73% yield).
LCMS: m/z 556 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.61 (d, 3H), 3.83 (s, 3H), 4.78 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 6H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.19 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with n-butylamine following the general procedure G to afford N-butyl-2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetamide (39 mg, 85% yield).
LCMS: m/z 458 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.24 (t, 3H), 1.43 (m, 2H), 1.84 (m, 2H), 3.08 (d, 2H), 3.83 (s, 3H), 4.89 (s, 2H), 6.87 (d, 1H), 6.94 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with isobutylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-isobutyl-acetamide (36 mg, 78% yield).
LCMS: m/z 458 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 0.90 (d, 6H), 1.80 (m, 1H), 3.07 (d, 2H), 3.82 (s, 3H), 4.87 (s, 2H), 6.87 (d, 1H), 6.94 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (20 mg, 0.05 mmol) was coupled with diisopropylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N,N-diisopropyl-acetamide (14 mg, 58% yield).
LCMS: m/z 486 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.32 (d, 6H), 1.38 (d, 6H), 3.61 (m, 1H), 3.82 (s, 3H), 4.13 (m, 1H), 5.12 (s, 2H), 6.81 (d, 1H), 6.94 (d, 2H), 7.45 (d, 1H), 7.50-7.52 (m, 4H), 7.68 (dd, 1H), 7.96 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (20 mg, 0.05 mmol) was coupled with 3-(dimethylamino)-propylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(3-dimethylamino-propyl)-acetamide (19 mg, 78% yield).
LCMS: m/z 487 (M+H)+.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 3-methoxyphenethyl-amine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-[2-(3-methoxy-phenyl)-ethyl]-acetamide (43 mg, 80% yield).
LCMS: m/z 536 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.82 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 5.11 (s, 2H), 6.71-6.80 (m, 3H), 7.01 (d, 1H), 7.04 (d, 2H), 7.15 (m, 1H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.83 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 4-tert-butyl-benzylamine following the general procedure G to afford N-(4-tert-butyl-benzyl)-2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetamide (46 mg, 83% yield).
LCMS: m/z 548 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.22 (s, 9H), 3.85 (s, 3H), 4.43 (d, 2H), 4.82 (s, 2H), 5.82 (m, 1H), 6.69 (d, 1H), 6.93 (d, 2H), 7.08 (d, 2H), 7.17 (d, 2H), 7.33 (dd, 1H), 7.43 (d, 1H), 7.49 (d, 2H), 7.65 (s, 1H), 7.67 (d, 1H), 8.23 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 4-methoxyphenethyl-amine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (47 mg, 87% yield).
LCMS: m/z 536 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.84 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 5.11 (s, 2H), 6.71-6.80 (m, 3H), 7.04 (d, 2H), 7.10 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.81 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 3,4-dimethoxyphenethylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (48 mg, 84% yield).
LCMS: m/z 566 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.84 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 5.11 (s, 2H), 6.71-6.80 (m, 3H), 7.04 (d, 2H), 7.10 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.81 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 4-fluorophenethylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide (48 mg, 91% yield).
LCMS: m/z 524 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.83 (t, 2H), 3.52 (m, 2H), 3.83 (s, 3H), 5.11 (s, 2H), 6.71-6.80 (m, 3H), 7.04 (d, 2H), 7.10 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.81 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 5-aminoisoquinoline following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-isoquinolin-5-yl-acetamide (39 mg, 74% yield).
LCMS: m/z 529 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.83 (s, 3H), 5.12 (s, 2H), 6.73-6.87 (m, 5H), 7.04 (d, 2H), 7.10 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.81 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (41 mg, 0.1 mmol) was coupled with 4-aminopyridine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-pyridin-4-yl-acetamide (33 mg, 68% yield).
LCMS: m/z 479 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.80 (s, 3H), 5.11 (s, 2H), 6.73-6.81 (m, 3H), 7.04 (d, 2H), 7.10 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.83 (s, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-1H-imidazole (389 mg, 1 mmol) was treated with methyl bromoacetate as described in general procedure E followed by ester hydrolysis as described in general procedure F to afford [4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-acetic acid (260 mg, 58% yield).
LCMS: m/z 447 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.02 (s, 2H), 7.25 (m, 1H), 7.37-7.51 (m, 5H), 7.57 (dd, 1H), 7.73 (d, 1H), 7.77-7.82 (m, 3H), 7.93 (d, 1H), 8.08 (s, 1H) ppm.
[4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-acetic acid (45 mg, 0.1 mmol) was coupled with 3-methoxyphenethylamine following the general procedure G to afford 2-[4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-N-[2-(3-methoxy-phenyl)-ethyl]-acetamide (47 mg, 81% yield).
LCMS: m/z 580 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.82 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 5.08 (s, 2H), 6.71-6.80 (m, 3H), 7.01 (d, 1H), 7.25 (m, 1H), 7.37-7.51 (m, 5H), 7.57 (dd, 1H), 7.73 (d, 1H), 7.77-7.82 (m, 3H), 7.93 (d, 1H), 8.08 (s, 1H) ppm.
[4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-acetic acid (45 mg, 0.1 mmol) was coupled with 4-methoxyphenethyl-amine following the general procedure G to afford 2-[4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (51 mg, 88% yield).
LCMS: m/z 580 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.83 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 5.08 (s, 2H), 6.77 (d, 2H), 7.03 (d, 2H), 7.25 (m, 1H), 7.37-7.51 (m, 5H), 7.57 (dd, 1H), 7.73 (d, 1H), 7.77-7.82 (m, 3H), 7.93 (d, 1H), 8.09 (s, 1H) ppm.
[4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-acetic acid (45 mg, 0.1 mmol) was coupled with DL-1-(1-naphthyl)ethylamine following the general procedure G to afford 2-[4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-N-(1-naphthalen-1-yl-ethyl)-acetamide (53 mg, 88% yield).
LCMS: m/z 600 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-fluoren-9-ylidenemethyl-1H-imidazole (39 mg, 0.1 mmol) was treated with methyl 1-bromobutyrate as described in general procedure E followed by ester hydrolysis as described in general procedure F to afford 4-[4-(2,4-dichloro-phenyl)-2-fluoren-9-ylidenemethyl-imidazol-1-yl]-butyric acid (23 mg, 48% yield).
LCMS: m/z 475 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.14 (m, 2H), 2.40 (t, 2H), 4.32 (t, 2H), 7.26 (m, 1H), 7.33 (m, 1H), 7.39 (t, 2H), 7.44 (dd, 1H), 7.53 (s 1H), 7.56 (dd, 1H), 7.75 (t, 2H), 7.97 (s, 1H), 8.02 (d, 1H), 8.12 (d, 1H), 8.83 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (556 mg, 1 mmol) was treated according to the general procedure C to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (412 mg, 76% yield).
LCMS: m/z 542 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.59 (d, 3H), 4.78 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 6H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (54 mg, 0.1 mmol) was treated with methyl bromoacetate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give [4-(2-{4-(2,4-Dichloro-phenyl)-1-[(1-naphthalen-1-yl-ethylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-phenoxy]-acetic acid (21 mg, 35% yield).
LCMS: m/z 600 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.59 (d, 3H), 4.21 (s, 2H), 4.78 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 6H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (54 mg, 0.1 mmol) was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-[4-(2-{4-(2,4-dichloro-phenyl)-1-[(1-naphthalen-1-yl-ethylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-phenoxy]-butyric acid (25 mg, 39% yield).
LCMS: m/z 628 (M+H)+.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (54 mg, 0.1 mmol) was treated with methyl 4-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-[4-(2-{4-(2,4-dichloro-phenyl)-1-[(1-naphthalen-1-yl-ethylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-phenoxymethyl]-benzoic acid (29 mg, 42% yield).
LCMS: m/z 676 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.59 (d, 3H), 4.78 (s, 2H), 5.21 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 10H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (54 mg, 0.1 mmol) was treated with methyl 3-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 3-[4-(2-{4-(2,4-dichloro-phenyl)-1-[(1-naphthalen-1-yl-ethylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-phenoxymethyl]-benzoic acid (26 mg, 38% yield).
LCMS: m/z 676 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.61 (d, 3H), 4.81 (s, 2H), 5.21 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.29-7.52 (m, 10H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.19 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4-hydroxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (54 mg, 0.1 mmol) was treated with ethyl bromide as described in the general procedure E to give 2-{4-(2,4-dichloro-phenyl)-2-[2-(4-ethoxy-phenyl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (47 mg, 82% yield).
LCMS: m/z 570 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.43 (t, 3H), 1.59 (d, 3H), 4.22 (q, 2H), 4.78 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.28-7.50 (m, 6H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H) ppm.
1-Benzyl-4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (51 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4′-{2-[1-benzyl-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (20 mg, 34% yield).
LCMS: m/z 583 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.95 (m, 2H), 2.38 (t, 2H), 4.12 (t, 2H), 5.33 (s, 2H), 7.10 (d, 1H), 7.12 (d, 1H), 7.42 (m, 2H), 7.48 (d, 2H), 7.51 (m, 5H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
1-Butyl-4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (48 mg, 0.1 mmol) was treated as described in general procedure C and the resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4′-{2-[1-butyl-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (22 mg, 39% yield).
LCMS: m/z 549 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (421 mg, 1 mmol) was treated with methyl bromoacetate as described in general procedure E followed by ester hydrolysis as described in general procedure F to afford {4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (268 mg, 56% yield).
LCMS: m/z 479 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.82 (s, 3H), 4.95 (s, 2H), 7.03 (d, 2H), 7.15 (d, 1H), 7.58-7.61 (m, 3H), 7.68-7.70 (m, 6H), 7.73 (d, 1H), 7.90 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (24 mg, 0.05 mmol) was coupled with DL-1-(1-naphthyl)ethylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (21 mg, 67% yield).
LCMS: m/z 632 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.61 (d, 3H), 3.83 (s, 3H), 4.78 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.29-7.52 (m, 10H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.19 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (64 mg, 0.1 mmol) was treated as described in the general procedure C to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (52 mg, 83% yield).
LCMS: m/z 618 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.63 (d, 3H), 4.80 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.29-7.52 (m, 10H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.17 (d, 1H) ppm.
2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (62 mg, 0.1 mmol) was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to afford 4-[4′-(2-{4-(2,4-dichloro-phenyl)-1-[(1-naphthalen-1-yl-ethylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid (38 mg, 53% yield).
LCMS: m/z 704 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.63 (d, 3H), 1.97 (m, 2H), 2.41 (t, 2H), 4.12 (t, 2H), 4.80 (s, 2H), 5.77 (m, 1H), 5.98 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.29-7.52 (m, 10H), 7.56 (s, 1H), 7.60 (d, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (d, 1H), 8.03 (d, 1H), 8.17 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (24 mg, 0.05 mmol) was coupled with 4-(2-aminoethyl)-morpholine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide (23 mg, 76% yield).
LCMS: m/z 591 (M+H)+.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (24 mg, 0.05 mmol) was coupled with 3,3-dimethylbutylamine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(3,3-dimethyl-butyl)-acetamide (23 mg, 82% yield).
LCMS: m/z 562 (M+H)+.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (24 mg, 0.05 mmol) was coupled with 4-methoxyphenethyl-amine following the general procedure G to afford 2-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (25 mg, 83% yield).
LCMS: m/z 612 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.84 (t, 2H), 3.53 (m, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 5.02 (s, 2H), 6.71-6.80 (m, 3H), 7.04 (d, 2H), 7.10 (d, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.57 (dd, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.81 (s, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (48 mg, 0.1 mmol) was coupled with methylamine as described in the general procedure G and then demethylated as described in the general procedure C. The resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to afford 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methylcarbamoylmethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (13 mg, 23% yield).
LCMS: m/z 564 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.95 (m, 2H), 2.38 (t, 2H), 2.88 (d, 3H), 4.12 (t, 2H), 4.88 (s, 2H), 7.10 (d, 1H), 7.12 (d, 1H), 7.42 (m, 2H), 7.48 (d, 2H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (48 mg, 0.1 mmol) was coupled with ethylamine as described in the general procedure G and then demethylated as described in the general procedure C. The resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to afford 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethylcarbamoylmethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (15 mg, 26% yield).
LCMS: m/z 578 (M+H)+.
{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (48 mg, 0.1 mmol) was coupled with n-butylamine as described in the general procedure G and then demethylated as described in the general procedure C. The resulting phenol was treated with methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to afford 4-(4′-{2-[1-butylcarbamoylmethyl-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (19 mg, 31% yield).
LCMS: m/z 606 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was demethylated as described in the general procedure C and the resulting intermediate was treated with 2 equivalents of methyl 4-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to afford 4-[2-{2-[4′-(3-carboxy-propoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-butyric acid (16 mg, 27% yield).
LCMS: m/z 579 (M+H)+.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (42 mg, 0.1 mmol) was treated with methyl 1-bromobutyrate as described in general procedure E followed by ester hydrolysis as described in general procedure F to provide 4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-butyric acid (27 mg, 53% yield).
LCMS: m/z 507 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-butyric acid (26 mg, 0.05 mmol) was coupled with DL-1-(1-naphthyl)ethylamine following the general procedure G to afford 4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(1-naphthalen-1-yl-ethyl)-butyramide (15 mg, 45% yield).
LCMS: m/z 660 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-butyric acid (26 mg, 0.05 mmol) was coupled with 3,3-dimethylbutylamine following the general procedure G to afford 4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(3,3-dimethyl-butyl)-butyramide (22 mg, 75% yield).
LCMS: m/z 590 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was treated as described in general procedure E using ethyl bromide to give 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (367 mg, 87% yield).
LCMS: m/z 422 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 4.14 (q, 2H), 7.14 (d, 1H), 7.51 (d, 2H), 7.70 (d, 2H), 7.72 (m, 2H), 7.75 (d, 1H), 8.02 (m, 1H), 8.05 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (300 mg, 0.71 mmol) was treated as described in general procedure B using 4-methoxyphenylboronic acid to give 4-(2,4-dichloro-phenyl)-1-ethyl-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (210 mg, 66% yield).
LCMS: m/z 449 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 3.86 (s, 3H), 4.14 (q, 2H), 6.94 (d, 1H), 6.99 (d, 2H), 7.32 (m, 1H), 7.42 (d, 1H), 7.55-7.63 (m, 6H), 7.67 (s, 1H), 7.73 (d, 1H), 8.25 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-1-ethyl-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (200 mg, 0.44 mmol) was treated as described in general procedure C to give 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (153 mg, 79% yield).
LCMS: m/z 435 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.42 (t, 3H), 4.10 (q, 2H), 6.86 (d, 2H), 7.46 (d, 1H), 7.58 (d, 2H), 7.66 (dd, 1H), 7.70 (d, 2H), 7.82 (d, 2H), 7.85-7.92 (m, 3H), 8.19 (s, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl bromoacetate according to the general procedure E followed by ester hydrolysis according to the general procedure F to give (4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-acetic acid (23 mg, 47% yield).
LCMS: m/z 493 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.50 (t, 3H), 4.35 (q, 2H), 4.79 (s, 2H), 6.94 (d, 1H), 6.99 (d, 2H), 7.32 (m, 1H), 7.42 (d, 1H), 7.55-7.63 (m, 6H), 7.67 (s, 1H), 7.73 (d, 1H), 8.25 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with (DL-)-methyl 2-bromobutyrate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 2-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (17 mg, 32% yield).
LCMS: m/z 521 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (87 mg, 0.2 mmol) was treated with methyl 4-bromobutyrate following the general procedure E to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (86 mg, 81% yield).
LCMS: m/z 535 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.21 (t, 3H), 2.15 (m, 2H), 2.56 (t, 2H), 3.71 (s, 3H), 3.94 (q, 2H), 4.06 (t, 2H), 6.95 (d, 1H), 6.97 (d, 2H), 7.30 (m, 1H), 7.42 (d, 1H), 7.55-7.61 (m, 6H), 7.71 (s, 1H), 7.73 (d, 1H), 8.25 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (54 mg, 0.1 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (45 mg, 86% yield).
LCMS: m/z 521 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 1.96 (m, 2H), 2.41 (t, 2H), 4.04 (t, 2H), 4.27 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.50 (dd, 1H), 7.57 (d, 1H), 7.64-7.67 (m, 5H), 7.79 (d, 2H), 7.96 (s, 1H), 8.25 (d, 1H) ppm.
(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-phenyl-acetic acid
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl α-bromophenylacetate according to the general procedure E followed by ester hydrolysis according to the general procedure F to give (4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-phenyl-acetic acid (21 mg, 37% yield).
LCMS: m/z 569 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.50 (t, 3H), 4.35 (q, 2H), 5.79 (s, 1H), 6.94 (d, 1H), 6.99 (d, 2H), 7.32 (m, 1H), 7.42 (d, 1H), 7.49 (m, 5H), 7.55-7.63 (m, 6H), 7.67 (s, 1H), 7.73 (d, 1H), 8.25 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with 4-bromobutyronitrile as described in the general procedure E followed by tetrazole formation as described in the general procedure M to give 5-[3-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-propyl]-1H-tetrazole (22 mg, 41% total yield).
LCMS: m/z 545 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.22 (t, 3H), 2.08 (m, 2H), 2.55 (t, 2H), 3.95 (q, 2H), 4.09 (t, 2H), 6.94 (d, 1H), 6.97 (d, 2H), 7.12 (s, 1H), 7.41 (d, 1H), 7.47-7.57 (m, 6H), 7.62 (s, 1H), 7.78 (d, 1H), 8.14 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with α-bromo-p-tolunitrile as described in the general procedure E followed by tetrazole formation as described in the general procedure M to give 5-[4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxymethyl)-phenyl]-1H-tetrazole (22 mg, 37% total yield).
LCMS: m/z 593 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with 4-iodobenzonitrile as described in the general procedure J followed by tetrazole formation as described in the general procedure M to give 5-[4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-phenyl]-1H-tetrazole (13 mg, 22% total yield).
LCMS: m/z 579 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.37 (t, 3H), 4.30 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (d, 1H), 7.74 (d, 2H), 7.79-7.86 (m, 6H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
Trans-5-bromo-2-methoxycinnamic acid (257 mg, 1 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-[2-(5-bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (195 mg, 46% yield).
LCMS: m/z 424 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.98 (s, 3H), 6.99 (d, 1H), 7.26 (d, 1H), 7.49-7.56 (m, 2H), 7.61-7.66 (m, 2H), 7.75 (d, 1H), 7.79 (s, 1H), 7.95 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (43 mg, 0.1 mmol) was treated as described in general procedure H using 1-ethynyl-4-methoxybenzene to give 4-(2,4-dichloro-phenyl)-2-{2-[2-methoxy-5-(4-methoxy-phenylethynyl)-phenyl]-(E)-vinyl}-1H-imidazole (19 mg, 39% yield).
LCMS: m/z 475 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 3.88 (s, 3H), 6.94 (dd, 1H), 6.99 (d, 1H), 7.07 (m, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 7.26 (m, 2H), 7.35 (dd, 1H), 7.44-7.48 (m, 2H), 7.63 (s, 1H), 7.72 (d, 1H), 7.83 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (43 mg, 0.1 mmol) was treated as described in general procedure H using 4-(methoxy-carbonyl-methoxy)-phenylacetylene to give [4-(3-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-acetic acid methyl ester (26 mg, 49% yield).
LCMS: m/z 533 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.78 (s, 3H), 3.98 (s, 3H), 4.50 (s, 2H), 6.94 (dd, 1H), 6.99 (d, 1H), 7.07 (m, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 7.26 (m, 2H), 7.35 (dd, 1H), 7.44-7.48 (m, 2H), 7.63 (s, 1H), 7.72 (d, 1H), 7.83 (d, 1H) ppm.
[4-(3-{2-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-acetic acid methyl ester (20 mg, 0.037 mmol) was treated as described in general procedure F to give [4-(3-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenyl-ethynyl)-phenoxy]-acetic acid (17 mg, 88% yield).
LCMS: m/z 519 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.97 (s, 3H), 4.51 (s, 2H), 6.94 (dd, 1H), 6.99 (d, 1H), 7.07 (m, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 7.26 (m, 2H), 7.35 (dd, 1H), 7.44-7.49 (m, 2H), 7.64 (s, 1H), 7.74 (d, 1H), 7.85 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (43 mg, 0.1 mmol) was treated with 3-(methoxy-carbonyl-methoxy)-phenyl acetylene as described in general procedure H followed by ester hydrolysis as described in general procedure F to give [3-(3-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-acetic acid (15 mg, 29% yield).
LCMS: m/z 519 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.81 (s, 3H), 4.59 (s, 2H), 6.94 (dd, 1H), 6.99 (d, 1H), 7.07 (m, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 7.26 (m, 2H), 7.35 (dd, 1H), 7.44-7.48 (m, 2H), 7.63 (s, 1H), 7.72 (d, 1H), 7.83 (d, 1H) ppm.
[4-(3-{2-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-acetic acid methyl ester (25 mg, 0.05 mmol) was treated with methyl iodide as described in general procedure E followed by ester hydrolysis as described in general procedure F to give [4-(3-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-acetic acid (18 mg, 68% yield).
LCMS: m/z 533 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.84 (s, 3H), 3.87 (s, 3H), 4.69 (s, 2H), 6.94 (dd, 1H), 6.99 (d, 1H), 7.07 (m, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 7.26 (m, 2H), 7.35 (dd, 1H), 7.44-7.49 (m, 2H), 7.64 (s, 1H), 7.74 (d, 1H), 7.85 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (43 mg, 0.1 mmol) was treated as described in general procedure H using 4-(4-methoxy-carbonyl-propyloxy)-phenyl acetylene followed by ester hydrolysis as described in general procedure F to give 4-[4-(3-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-phenylethynyl)-phenoxy]-butyric acid (16 mg, 29% yield).
LCMS: m/z 547 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.18 (m, 2H), 2.53 (t, 2H), 3.80 (s, 3H), 4.10 (t, 2H), 6.95 (d, 1H), 6.97 (d, 2H), 7.13 (s, 1H), 7.42 (d, 1H), 7.47-7.59 (m, 5H), 7.64 (s, 1H), 7.78 (d, 1H), 8.19 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure H using 3-(4-methoxy-carbonyl-propyloxy)-phenyl acetylene followed by ester hydrolysis as described in general procedure F to give 4-[3-(4-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenylethynyl)-phenoxy]-butyric acid (14 mg, 27% yield).
LCMS: m/z 517 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.12 (m, 2H), 2.53 (t, 2H), 4.08 (t, 2H), 6.93 (m, 1H), 7.06-7.13 (m, 3H), 7.27 (m, 1H), 7.36 (dd, 1H), 7.38 (d, 1H), 7.49 (d, 1H), 7.52-7.58 (m, 4H), 7.65 (s, 1H), 7.85 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (40 mg, 0.1 mmol) was treated as described in general procedure H using 4-(4-methoxy-carbonyl-propyloxy)-phenylacetylene followed by ester hydrolysis as described in general procedure F to give 4-[4-(4-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenylethynyl)-phenoxy]-butyric acid (15 mg, 29% yield).
LCMS: m/z 517 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 2.18 (m, 2H), 2.53 (t, 2H), 4.10 (t, 2H), 6.95 (d, 1H), 6.97 (d, 2H), 7.13 (s, 1H), 7.42 (d, 1H), 7.47-7.59 (m, 6H), 7.64 (s, 1H), 7.78 (d, 1H), 8.19 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was demethylated as described in general procedure C and the resulting phenol intermediate was treated with methyl 4-bromobutyrate as described in the general procedure E to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (32 mg, 61% total yield).
LCMS: m/z 521 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.15 (m, 2H), 2.56 (t, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 4.09 (t, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.55-7.67 (m, 8H), 8.01 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (26 mg, 0.05 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (21 mg, 84% yield).
LCMS: m/z 507 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.14 (m, 2H), 2.55 (t, 2H), 3.87 (s, 3H), 4.09 (t, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.35 (dd, 1H), 7.47 (d, 1H), 7.56-7.66 (m, 8H), 7.99 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was demethylated as described in general procedure C and the resulting phenol intermediate was treated with 4-bromobutyronitrile as described in the general procedure E followed by tetrazole formation as described in the general procedure L to give 5-[3-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-propyl]-1H-tetrazole (11 mg, 21% total yield).
LCMS: m/z 531 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.15 (m, 2H), 2.56 (t, 2H), 3.86 (s, 3H), 4.09 (t, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.55-7.67 (m, 8H), 8.01 (d, 1H) ppm.
(4′-{2-[4-(2,4-Dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-acetic acid
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was demethylated as described in general procedure C and the resulting phenol intermediate was treated with methyl bromoacetate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give (4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-acetic acid (32 mg, 61% total yield).
LCMS: m/z 479 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.87 (s, 3H), 4.81 (s, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.35 (dd, 1H), 7.47 (d, 1H), 7.56-7.66 (m, 8H), 7.99 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was treated as described in general procedure C to give the phenolic intermediate. The intermediate was treated with methyl 5-bromovalerate following the general procedure E to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-pentanoic acid methyl ester (31 mg, 58% total yield).
LCMS: m/z 535 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.69 (m, 2H), 1.77 (m, 2H), 2.31 (t, 2H), 3.74 (s, 3H), 3.86 (s, 3H), 4.02 (t, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.55-7.67 (m, 8H), 8.01 (d, 1H) ppm.
5-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-pentanoic acid methyl ester (27 mg, 0.05 mmol) was treated as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-pentanoic acid (21 mg, 82% yield).
LCMS: m/z 521 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.67 (m, 2H), 1.74 (m, 2H), 2.30 (t, 2H), 3.85 (s, 3H), 4.02 (t, 2H), 7.02 (d, 2H), 7.31 (d, 1H), 7.49 (dd, 1H), 7.57 (d, 1H), 7.63-7.67 (m, 5H), 7.78 (d, 2H), 7.96 (s, 1H), 8.25 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was demethylated as described in general procedure C and the resulting phenol intermediate was treated with methyl 4-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxymethyl)-benzoic acid (25 mg, 44% total yield).
LCMS: m/z 555 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.87 (s, 3H), 5.25 (s, 2H), 7.00 (d, 2H), 7.06 (d, 1H), 7.27 (d, 2H), 7.35 (dd, 1H), 7.47 (d, 1H), 7.56-7.66 (m, 8H), 7.74 (d, 2H), 7.99 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1-methyl-1H-imidazole (44 mg, 0.1 mmol) was demethylated as described in general procedure C and the resulting phenol intermediate was treated with methyl methyl 4-fluoro-2-bromobenzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 2-bromo-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (24 mg, 39% total yield).
LCMS: m/z 620 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 3.87 (s, 3H), 7.00 (d, 2H), 7.06 (d, 1H), 7.27 (d, 2H), 7.35 (dd, 1H), 7.47 (d, 1H), 7.56-7.66 (m, 7H), 7.74 (d, 2H), 8.02 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (79 mg, 0.2 mmol) was treated with 1-iodo-2,2,2-trifluoroethane as described in general procedure E followed by Suzuki coupling with 4-methoxybenzeneboronic acid as described in general procedure B. The resulting intermediate was demethylated as described in general procedure C, treated with methyl 4-bromobutyrate as described in general procedure E followed by ester hydrolysis as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (19 mg, 16% yield).
LCMS: m/z 575 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.96 (m, 2H), 2.41 (t, 2H), 4.04 (t, 2H), 4.72 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.50 (dd, 1H), 7.57 (d, 1H), 7.64-7.67 (m, 5H), 7.79 (d, 2H), 7.96 (s, 1H), 8.27 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (43 mg, 0.1 mmol) was treated with 4-aminobenzeneboronic acid as described in general procedure B. The resulting intermediate was treated with methyl 4-bromobutyrate as described in general procedure E followed by ester hydrolysis as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ylamino)-butyric acid (19 mg, 36% total yield).
LCMS: m/z 520 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 1.96 (m, 2H), 2.41 (t, 2H), 4.04 (m, 2H), 4.36 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.50 (dd, 1H), 7.57 (d, 1H), 7.64-7.67 (m, 5H), 7.79 (d, 2H), 7.96 (s, 1H), 8.27 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (43 mg, 0.1 mmol) was treated with 4-aminobenzeneboronic acid as described in general procedure B. The resulting intermediate was heated in anhydrous DMF (0.1-0.5 M) with 2 equivalents of succinic anhydride and 2 equivalents of DIEA at 100° C. for 2 hours. At completion, the reaction mixture was worked up with EtOAc and water. The combined organic layer was washed, condensed and purified by silica gel chromatography to afford N-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yl)-succinamic acid (18 mg, 33% total yield).
LCMS: m/z 534 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 2.45-2.58 (m, 4H), 4.36 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.50 (dd, 1H), 7.57 (d, 1H), 7.64-7.67 (m, 5H), 7.79 (d, 2H), 7.96 (s, 1H), 8.27 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl 4-(bromomethyl)benzoate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxymethyl)-benzoic acid (31 mg, 54% total yield).
LCMS: m/z 569 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.30 (q, 2H), 5.25 (s, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (d, 1H), 7.74 (d, 2H), 7.79-7.86 (m, 6H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl 4-(bromomethyl)phenylacetate as described in the general procedure E followed by ester hydrolysis as described in the general procedure F to give [4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxymethyl)-phenyl]-acetic acid (22 mg, 37% total yield).
LCMS: m/z 583 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 3.21 (s, 2H), 4.32 (q, 2H), 5.25 (s, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (d, 1H), 7.74 (d, 2H), 7.79-7.86 (m, 6H), 7.99 (s, 1H), 8.19 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure J using methyl 4-iodobenzoate to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (26 mg, 46% yield).
LCMS: m/z 569 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 3.81 (s, 3H), 4.31 (q, 2H), 7.07 (dd, 1H), 7.25 (d, 2H), 7.33 (d, 1H), 7.38 (d, 1H), 7.52 (dd, 1H), 7.63 (d, 1H), 7.68 (d, 1H), 7.74 (d, 2H), 7.80-7.87 (m, 6H), 8.00 (s, 1H), 8.19 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (18 mg, 0.03 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (14 mg, 81% yield).
LCMS: m/z 555 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.30 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (d, 1H), 7.74 (d, 2H), 7.79-7.86 (m, 6H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure J using methyl 3-iodobenzoate followed by ester hydrolysis as described in general procedure F to give 3-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (21 mg, 38% yield).
LCMS: m/z 555 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 4.31 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 7.74 (d, 2H), 7.81-7.89 (m, 6H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure J using methyl 2-fluoro-4-bromobenzoate followed by ester hydrolysis as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-fluoro-benzoic acid (20 mg, 34% yield).
LCMS: m/z 573 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.32 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 7.74 (d, 2H), 7.81-7.89 (m, 5H), 8.01 (s, 1H), 8.19 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure J using methyl 4-bromo-2-methyl-benzoate followed by ester hydrolysis as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methyl-benzoic acid (17 mg, 30% yield).
LCMS: m/z 569 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 2.39 (s, 3H), 4.31 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 7.74 (d, 2H), 7.80-7.87 (m, 5H), 7.99 (s, 1H), 8.14 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with 5-bromofuroic acid methyl ester as described in general procedure J to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-furan-2-carboxylic acid methyl ester (21 mg, 38% yield).
LCMS: m/z 559 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 3.79 (s, 3H), 4.27 (q, 2H), 6.86 (d, 1H), 7.12 (d, 2H), 7.33 (d, 1H), 7.48 (dd, 1H), 7.57 (d, 1H), 7.63 (d, 1H), 7.68 (d, 2H), 7.74 (m, 3H), 7.82 (d, 2H), 7.95 (s, 1H), 8.24 (d, 1H) ppm.
5-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-furan-2-carboxylic acid methyl ester (18 mg, 0.03 mmol) was treated as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-furan-2-carboxylic acid (14 mg, 80% yield).
LCMS: m/z 545 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.35 (t, 3H), 4.26 (q, 2H), 6.85 (d, 1H), 7.12 (d, 2H), 7.32 (d, 1H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.62 (d, 1H), 7.68 (d, 2H), 7.73 (m, 3H), 7.81 (d, 2H), 7.95 (s, 1H), 8.23 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure J using ethyl 5-bromonicotinate followed by ester hydrolysis as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-nicotinic acid (13 mg, 23% yield).
LCMS: m/z 556 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl 5-bromothiophene-2-carboxylate as described in general procedure J followed by ester hydrolysis as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-thiophene-2-carboxylic acid (14 mg, 25% yield).
LCMS: m/z 561 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with ethyl 2-bromothiazole-4-carboxylate as described in general procedure J followed by ester hydrolysis as described in general procedure F to give 2-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-thiazole-4-carboxylic acid (12 mg, 21% yield).
LCMS: m/z 562 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.42 (t, 3H), 4.10 (q, 2H), 6.86 (d, 2H), 7.46 (d, 1H), 7.58 (d, 2H), 7.66 (dd, 1H), 7.70 (d, 2H), 7.82 (d, 2H), 7.85-7.92 (m, 3H), 8.00 (s, 1H), 8.19 (s, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated with methyl 6-bromo-2-naphthoate as described in general procedure J followed by ester hydrolysis as described in general procedure F to give 6-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-naphthalene-2-carboxylic acid (21 mg, 35% yield).
LCMS: m/z 605 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 4.31 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 7.74 (d, 2H), 7.73-7.89 (m, 8H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (127 mg, 0.3 mmol) was treated with 4-formylphenylboronic acid as described in general procedure B. The resulting intermediate was heated in anhydrous EtOH (0.1-0.5 M) with 1.5 equivalents of methyl 3,4-diaminobenzoate at 100° C. for 5 to 6 hours. At completion, the reaction mixture was worked up with EtOAc and water. The combined organic layer was washed, condensed and purified by silica gel chromatography to afford the ester intermediate which was then hydrolyzed as described in general procedure F to afford 2-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yl)-1H-benzoimidazole-5-carboxylic acid (40 mg, 23% total yield).
LCMS: m/z 579 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.40 (t, 3H), 4.36 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.42-7.51 (m, 3H), 7.57 (d, 1H), 7.64-7.67 (m, 6H), 7.79 (d, 2H), 7.96 (s, 1H), 8.27 (d, 1H) ppm.
2-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yl)-1H-benzoimidazole-5-carboxylic acid (29 mg, 0.05 mmol) was treated with 2 equivalents of ethyl bromide as described in general procedure E followed by ester hydrolysis as described in general procedure F to afford 2-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yl)-3-ethyl-3H-benzoimidazole-5-carboxylic acid (14 mg, 44% yield).
LCMS: m/z 607 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.43 (m, 6H), 4.35 (m, 4H), 7.04 (d, 2H), 7.32 (d, 1H), 7.42-7.51 (m, 3H), 7.57 (d, 1H), 7.64-7.67 (m, 6H), 7.79 (d, 2H), 7.96 (s, 1H), 8.25 (d, 1H) ppm.
Trans-4-formylcinnamic acid (88 mg, 0.5 mmol) was treated with 2,4-dichlorophenacyl bromide as described in general procedure A followed by reaction with ethyl bromide as described in general procedure E. The resulting intermediate was heated in anhydrous EtOH (0.1-0.5 M) with 1.5 equivalents of methyl-3,4-diaminobenzoate at 100° C. for 5 to 6 hours. At completion, the reaction mixture was worked up with EtOAc and water. The combined organic layer was washed, condensed and purified by silica gel chromatography to afford the ester intermediate which was then hydrolyzed as described in general procedure F to afford 2-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-1H-benzoimidazole-5-carboxylic acid (48 mg, 19% total yield).
LCMS: m/z 503 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.38 (t, 3H), 4.34 (q, 2H), 7.04 (d, 2H), 7.32 (d, 1H), 7.42-7.47 (m, 2H), 7.57 (d, 1H), 7.64-7.68 (m, 3H), 7.79 (d, 2H), 7.96 (s, 1H), 8.27 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure I using methyl 2-bromo-4-fluorobenzoate to give 2-bromo-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (44 mg, 68% yield).
LCMS: m/z 648 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 3.82 (s, 3H), 4.29 (q, 2H), 7.07 (dd, 1H), 7.25 (d, 2H), 7.33 (d, 1H), 7.38 (d, 1H), 7.52 (dd, 1H), 7.63 (d, 1H), 7.68 (d, 1H), 7.74 (d, 2H), 7.80-7.87 (m, 5H), 8.00 (s, 1H), 8.17 (d, 1H) ppm.
2-Bromo-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (33 mg, 0.05 mmol) was treated as described in general procedure F to give 2-bromo-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (24 mg, 75% yield).
LCMS: m/z 634 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.30 (q, 2H), 7.06 (dd, 1H), 7.24 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.52 (dd, 1H), 7.62 (d, 1H), 7.67 (d, 1H), 7.74 (d, 2H), 7.80-7.86 (m, 5H), 7.99 (s, 1H), 8.17 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (44 mg, 0.1 mmol) was treated as described in general procedure I using methyl 4-fluoro-2-(trifluoromethyl)benzoate to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-trifluoromethyl-benzoic acid methyl ester (46 mg, 73% yield).
LCMS: m/z 637 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 3.83 (s, 3H), 4.31 (q, 2H), 7.27 (d, 2H), 7.31 (dd, 1H), 7.35 (d, 1H), 7.45 (d, 1H), 7.49 (dd, 1H), 7.58 (d, 1H), 7.63 (d, 1H), 7.73 (d, 2H), 7.81-7.84 (m, 4H), 7.91 (d, 1H), 7.96 (s, 1H), 8.26 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-trifluoromethyl-benzoic acid methyl ester (32 mg, 0.05 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-trifluoromethyl-benzoic acid (26 mg, 85% yield).
LCMS: m/z 623 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.36 (t, 3H), 4.29 (q, 2H), 7.26 (d, 2H), 7.30 (dd, 1H), 7.34 (d, 1H), 7.45 (d, 1H), 7.49 (dd, 1H), 7.57 (d, 1H), 7.62 (d, 1H), 7.73 (d, 2H), 7.82-7.85 (m, 4H), 7.90 (d, 1H), 7.95 (s, 1H), 8.24 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (87 mg, 0.2 mmol) was treated as described in general procedure I using methyl 4-fluoro-2-nitrobenzoate to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-nitro-benzoic acid methyl ester (96 mg, 78% yield).
LCMS: m/z 614 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 3.84 (s, 3H), 4.28 (q, 2H), 7.20 (d, 1H), 7.30 (d, 2H), 7.35 (d, 1H), 7.48 (dd, 1H), 7.58 (d, 1H), 7.63 (d, 1H), 7.73 (d, 2H), 7.82-7.84 (m, 4H), 7.97 (s, 1H), 8.17 (dd, 1H), 8.24 (d, 1H), 8.53 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-nitro-benzoic acid methyl ester (31 mg, 0.05 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-nitro-benzoic acid (24 mg, 81% yield).
LCMS: m/z 600 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.27 (q, 2H), 7.19 (d, 1H), 7.30 (d, 2H), 7.34 (d, 1H), 7.48 (dd, 1H), 7.57 (d, 1H), 7.62 (d, 1H), 7.73 (d, 2H), 7.82-7.84 (m, 4H), 7.95 (s, 1H), 8.16 (dd, 1H), 8.24 (d, 1H), 8.51 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-nitro-benzoic acid methyl ester (61 mg, 0.1 mmol) was treated as described in general procedure K to afford 2-amino-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (44 mg, 76% yield).
LCMS: m/z 584 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.43 (t, 3H), 3.81 (s, 3H), 4.45 (q, 2H), 6.92 (d, 1H), 7.19 (d, 2H), 7.47 (dd, 1H), 7.51 (d, 1H), 7.67 (dd, 1H), 7.77-7.83 (m, 8H), 8.01 (d, 1H), 8.10-8.24 (m, 2H) ppm.
2-Amino-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (12 mg, 0.02 mmol) was treated as described in general procedure F to afford 2-amino-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (8 mg, 72% yield).
LCMS: m/z 570 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.41 (t, 3H), 4.41 (q, 2H), 6.91 (d, 1H), 7.18 (d, 2H), 7.46 (dd, 1H), 7.51 (d, 1H), 7.65 (dd, 1H), 7.76-7.83 (m, 8H), 8.01 (d, 1H), 8.10-8.22 (m, 2H) ppm.
2-Amino-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid methyl ester (29 mg, 0.05 mmol) was treated as described in general procedure L using methanesulfonyl chloride to afford 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methanesulfonylamino-benzoic acid methyl ester (22 mg, 67% yield).
LCMS: m/z 662 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 3.07 (s, 3H), 3.77 (s, 3H), 4.32 (q, 2H), 6.98 (d, 1H), 7.27 (d, 2H), 7.37 (d, 1H), 7.51 (dd, 1H), 7.60 (d, 1H), 7.65 (d, 1H), 7.73 (d, 2H), 7.77 (dd, 1H), 7.80-7.85 (m, 4H), 7.98 (s, 1H), 8.01 (d, 1H), 8.26 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methanesulfonylamino-benzoic acid methyl ester (20 mg, 0.03 mmol) was treated as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methanesulfonylamino-benzoic acid (14 mg, 73% yield).
LCMS: m/z 648 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 3.07 (s, 3H), 4.29 (q, 2H), 6.97 (d, 1H), 7.24 (d, 2H), 7.35 (d, 1H), 7.50 (dd, 1H), 7.59 (d, 1H), 7.64 (d, 1H), 7.73 (d, 2H), 7.77 (dd, 1H), 7.80-7.86 (m, 4H), 7.97 (s, 1H), 8.01 (d, 1H), 8.25 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was treated as described in general procedure I using methyl 4-fluoro-3-nitrobenzoate to give the nitro compound intermediate, which was then reduced as described in general procedure K to give the ester (327 mg, 56% yield). The resulted ester (29 mg, 0.05 mmol) was treated as described in general procedure F to afford 3-amino-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-benzoic acid (22 mg, 77% yield).
LCMS: m/z 570 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.41 (t, 3H), 4.42 (q, 2H), 6.91 (d, 1H), 7.18 (d, 2H), 7.46 (dd, 1H), 7.51 (d, 1H), 7.65 (dd, 1H), 7.76-7.83 (m, 8H), 8.01 (d, 1H), 8.10-8.22 (m, 2H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was treated as described in general procedure I using methyl 4-fluoro-3-nitrobenzoate to give the nitro compound intermediate, which was then reduced as described in general procedure K to give the ester (327 mg, 56% total yield). The resulted ester (59 mg, 0.1 mmol) was treated as described in general procedure L using methanesulfonyl chloride to give methanesulfonamide, which was then hydrolyzed as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-3-methanesulfonylamino-benzoic acid (26 mg, 41% yield).
LCMS: m/z 648 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 3.07 (s, 3H), 4.29 (q, 2H), 6.97 (d, 1H), 7.23 (d, 2H), 7.35 (d, 1H), 7.50 (dd, 1H), 7.59 (d, 1H), 7.64 (d, 1H), 7.73 (d, 2H), 7.77 (dd, 1H), 7.79-7.85 (m, 4H), 7.97 (s, 1H), 8.01 (d, 1H), 8.24 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was treated as described in general procedure I using methyl 4-fluoro-3-nitrobenzoate to give the nitro compound intermediate, which was then reduced as described in general procedure K to give the ester (327 mg, 56% yield). The resulted ester (59 mg, 0.1 mmol) was treated as described in general procedure L using trifluoromethanesulfonic acid anhydride to give trifluoromethanesulfonamide, which was then hydrolyzed as described in general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-3-trifluoromethanesulfonyl-amino-benzoic acid (26 mg, 37% yield).
LCMS: m/z 702 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 4.29 (q, 2H), 6.98 (d, 1H), 7.12 (d, 2H), 7.36 (d, 1H), 7.41 (dd, 1H), 7.60 (d, 1H), 7.64 (d, 1H), 7.74 (d, 2H), 7.77 (dd, 1H), 7.79-7.85 (m, 4H), 7.98 (s, 1H), 8.01 (d, 1H), 8.22 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was treated as described in general procedure I using methyl 2-amino-5-bromobenzoate to give the ester (245 mg, 42% yield). The ester (59 mg, 0.1 mmol) was treated as described in general procedure L using methanesulfonyl chloride to give the methanesulfonamide, which was then hydrolyzed as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methanesulfonylamino-benzoic acid (25 mg, 39% yield).
LCMS: m/z 648 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 3.17 (s, 3H), 4.28 (q, 2H), 7.14 (d, 2H), 7.34 (d, 1H), 7.44 (dd, 1H), 7.50 (dd, 1H), 7.58 (d, 1H), 7.60-7.66 (m, 3H), 7.71 (d, 2H), 7.77 (d, 2H), 7.83 (d, 2H), 7.97 (s, 1H), 8.24 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was treated as described in general procedure I using methyl 2-amino-5-bromobenzoate to give the ester (245 mg, 42% yield). The ester (59 mg, 0.1 mmol) was treated as described in general procedure L using trifluoromethanesulfonic anhydride to give trifluoromethanesulfonamide, which was then hydrolyzed as described in general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-trifluoromethanesulfonylamino-benzoic acid (31 mg, 44% total yield).
LCMS: m/z 702 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.38 (t, 3H), 4.29 (q, 2H), 7.08 (d, 2H), 7.25 (dd, 1H), 7.36 (d, 1H), 7.51 (m, 2H), 7.60 (d, 1H), 7.62 (d, 1H), 7.66 (d, 1H), 7.71 (d, 2H), 7.74 (d, 2H), 7.83 (d, 2H), 7.98 (s, 1H), 8.22 (d, 1H) ppm.
To a solution of 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (52 mg, 0.1 mmol) in anhydrous DMF (5 mL) is added chloromethyl pivalate (30 mg, 0.2 mmol) followed by freshly ground K2CO3 (56 mg, 0.4 mmol). The reaction mixture is heated at 65° C. under nitrogen for 2 to 4 hours. At completion, the mixture is then diluted with water/EtOAc and the layers separated. The aqueous layer is further extracted with EtOAc, and the organic layers combined and dried over Na2SO4. The solvent is removed in vacuo and the residue is purified by silica gel chromatography to afford (56 mg, 88% yield) 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid 2,2-dimethyl-propionyloxymethyl ester.
LCMS: m/z 635 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.11 (s, 9H), 1.42 (t, 3H), 1.99 (m, 2H), 2.54 (t, 2H), 4.03 (t, 2H), 4.41 (q, 2H), 5.70 (s, 2H), 7.01 (d, 2H), 7.46 (d, 1H), 7.65 (dd, 1H), 7.68 (d, 2H), 7.74 (d, 2H), 7.84 (d, 2H), 7.85 (s, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.19 (s, 1H) ppm.
4-(4-Chloro-phenyl)-2-[2-(4-ethoxy-phenyl)-(E)-vinyl-1H-imidazole (258 mg, 79%) was synthesized using trans-4-ethoxycinnamic acid (192 mg, 1 mmol) and 4-chlorophenacyl bromide (233 mg 1 mmol) according to general procedure A.
LCMS: m/z 325 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.43 (t, 2H), 1.62 (d, 1H), 4.08 (q, 2H), 6.88 (d, 1H), 6.95 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 2H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
4-(2,4-Difluoro-phenyl)-2-[2-(4-ethoxy-phenyl)-(E)-vinyl]-1H-imidazole (249 mg, 76%) was prepared using trans-4-ethoxycinnamic acid (192 mg, 1 mmol) and 4-fluorophenacyl bromide (217 mg 1 mmol) according to general procedure A.
LCMS: m/z 327 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.43 (t, 2H), 1.62 (d, 1H), 4.08 (q, 2H), 6.88 (d, 1H), 6.95 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.52 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H), 7.93 (s, 1H) ppm.
2-[2-(4-Ethoxy-phenyl)-(E)-vinyl]-4(4-methoxy-phenyl)-1H-imidazole (221 mg, 69%) was prepared according to general procedure A using trans-4-ethoxycinnamic acid (198 mg, 1 mmol) and 4-methoxyphenacyl bromide (229 mg, 1 mmol).
LCMS: m/z 321 (M+H)+.
2-[2-(4-Ethoxy-phenyl)-(E)-vinyl]-4-(2,3,4-trichloro-phenyl)-1H-imidazole (279 mg, 70%) was prepared according to general procedure A using trans-4-ethoxycinnamic acid (198 mg, 1 mmol) and 2,3,4-trichlorophenacyl bromide (302 mg. 1 mmol).
LCMS: m/z 393 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.43 (t, 2H), 1.62 (d, 1H), 4.08 (q, 2H), 6.38 (d, 1H), 6.81 (d, 1H), 6.90 (d, 1H), 7.28 (d, 2H), 7.38 (d, 1H), 7.48 (d, 2H), 7.74 (d, 1H), 9.1 (d, 1H) ppm.
4-[2-(4-Naphthalen-1-yl-1H-imidazole-2-yl)-(E)-vinyl]-phenol (241 mg, 78%) was prepared according to general procedure A using trans-4-hydroxycinnamic acid (164 mg, 1 mmol) and 1-naphthaleneacylbromide (249 mg, 1 mmol).
LCMS: m/z 313 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 6.69 (s, 1H), 6.95 (d, 2H), 7.42 (d, 1H), 7.55 (d, 2H), 7.63 (d, 2H), 7.65 (d, 2H), 7.89-7.77 (m, 4H) ppm.
4-{2-[4-(4-Chloro-phenyl)-5-phenyl-1H-imidazole-2-yl]-(E)-vinyl}-phenol (285 mg, 76%) was prepared according to general procedure A using trans-4-hydroxycinnamic acid (164 mg, 1 mmol) and 2-bromo-1-(4-chlorophenyl)-2-phenylethan 1-one (309 mg, 1 mmol).
LCMS: m/z 373 (M+H)+.
4-Biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (281 mg, 80%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-4-phenylacetophenone (275 mg, 1 mmol).
LCMS: m/z 353 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.78 (s, 3H), 6.95-6.93 (m, 2H), 7.36-7.33 (m, 2H), 7.48-7.44 (m, 2H), 7.55-7.53 (m, 2H), 7.71-7.64 (m, 6H), 7.90-7.88 (m, 2H) ppm.
(4-{2-[2-(4-Methoxy-phenyl)-(E)-vinyl]-1H-imidazole-4-yl}-phenyl-diazene (291 mg, 77%) was prepared according to general procedure A using trans 4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-4-phenylazoacetophenone (303 mg, 1 mmol).
LCMS: m/z 381 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.77 (s, 3H), 6.80 (d, 2H), 6.85 (d, 2H), 7.27 (s, 1H), 7.36 (d, 1H), 7.53 (m, 4H), 7.83 (d, 2H), 7.91 (d, 2H), 7.93 (d, 2H) ppm.
4-Biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (352 mg, 1 mmol) was treated with methyl bromoacetate (153 mg, 1 mmol) according to general procedure E to give {4-biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazole-1-yl}-acetic acid methyl ester (375 mg, 88%).
LCMS: m/z 425 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.78 (s, 3H), 3.96 (s, 3H), 5.17 (s, 2H), 6.95-6.93 (m, 2H), 7.36-7.33 (m, 2H), 7.48-7.44 (m, 2H), 7.55-7.53 (m, 2H), 7.71-7.64 (m, 6H), 7.90-7.88 (m, 2H) ppm.
{4-Biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazole-1yl)-acetic acid methyl ester (212 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give {4-biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazole-1yl}-acetic acid (212 mg, 80%).
LCMS: m/z 411 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.78 (s, 3H), 5.17 (s, 2H), 6.95-6.93 (m, 2H), 7.36-7.33 (m, 2H), 7.48-7.44 (m, 2H), 7.55-7.53 (m, 2H), 7.71-7.64 (m, 6H), 7.90-7.88 (m, 2H) ppm.
4-(4-Chloro-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-5-p-tolyl-1H-imidazole (299 mg, 75%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-1-(4-chlorophenyl)-2-(4-methyl phenyl)-ethan-1-one (323 mg, 1 mmol).
LCMS: m/z 401 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 2.40 (s, 3H), 3.85 (s, 3H), 6.89 (d, 1H), 6.95 (d, 2H), 7.22 (d, 2H), 7.37 (d, 1H), 7.52-7.50 (m, 4H), 7.64-7.53 (m, 4H) ppm.
{4-Biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazole-1yl)-acetic acid (410 mg, 1 mmol) was coupled with DL-1-(1-naphthyl)-ethyl amine (171 mg, 1 mmol) following general procedure G to give 2-{4-biphenyl-4-yl-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-imidazole-1yl}-N-(1-naphthalen-1-yl-ethyl)-acetamide (497 mg, 88%).
LCMS: m/z 564 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.59 (d, 3H), 3.85 (s, 3H), 4.73 (d, 2H), 5.91 (d, 1H), 5.97 (m, 1H), 6.59 (d, 1H), 6.89 (d, 2H), 7.14 (s, 1H), 7.22-7.41 (m, 2H), 7.50-7.42 (m, 7H), 7.60-7.42 (m, 4H), 7.64-7.62 (m, 3H), 7.71 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H) ppm.
4-(4-Bromo-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (281 mg, 79%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2,4-dibromo acetophenone (278 mg, 1 mmol).
LCMS: m/z 356 (M+H)+.
Diethyl-(4-{2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazol-4yl}-phenyl)-amine (247 mg, 72%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-1-(4-diethylamino-phenyl)-ethan-1-one (270 mg, 1 mmol).
LCMS: m/z 348 (M+H)+.
2-[2-(4-Methoxy-phenyl)-(E)-vinyl]-4-pentafluorophenyl-1H-imidazole (271 mg, 74%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and bromoacetyl pentafluorobenzene (288 mg, 1 mmol).
LCMS: 367 (M+H)+. 1H NMR (CDCl3, 400 MHz): δ 3.86 (s, 3H), 6.38 (d, 1H), 6.58 (d, 2H), 7.33 (d, 1H), 7.51 (d, 2H), 7.93 (s, 1H) ppm.
4-(3′,5′-Dichloro-biphenyl-4-yl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (313 mg, 74%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-4-(3,5-dichloro-phenyl)acetophenone (344 mg, 1 mmol).
LCMS: 421 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 3.78 (s, 3H), 6.94-6.96 (m, 2H), 7.31-7.34 (m, 2H), 7.44-7.48 (m, 2H), 7.55 (d, 2H), 7.61-7.71 (m, 4H), 7.90 (s, 1H), 12.40 (s, 1H) ppm.
2-[2-(4-Methoxy-phenyl)-(E)-vinyl]-4-(4-pentyl-phenyl)-1H-imidazole (240 mg, 70%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-1-(4-pentyl phenyl)-ethan-1-one (269 mg, 1 mmol).
LCMS: m/z 347 (M+H)+.
4-{2-[2-(4-Methoxy-phenyl)-(E)-vinyl]-1H-imidazol-4-yl}-benzoic acid phenyl ester (259 mg, 65%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-(4-phenyl benzoate) acetophenone (319 mg, 1 mmol).
LCMS: m/z 397 (M+H)+.
4-(3′,5′-Dichloro-biphenyl-4-yl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (421 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) according to general procedure E to give 4-(3′,5′-dichloro-biphenyl-4-yl)-1-ethyl-2-[-2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (401 mg, 89%).
LCMS: m/z 449 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.21 (t, 3H), 3.78 (s, 3H), 3.93 (q, 2H), 6.94-6.96 (m, 2H), 7.31-7.34 (m, 2H), 7.44-7.48 (m, 2H), 7.55 (d, 2H), 7.61-7.71 (m, 4H), 7.90 (s, 1H), 12.40 (s, 1H) ppm.
4-(4-tert-Butyl-phenyl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (218 mg, 66%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 4-(tert-butyl)-phenacyl bromide (255 mg, 1 mmol).
LCMS: m/z 333 (M+H)+.
2-[2-(4-Methoxy-phenyl)-(E)-vinyl]-4-(3-trifluoromethyl-phenyl)-1H-imidazole (229 mg, 67%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-1-(3-trifluoromethyl)-phenyl-1-ethanone (267 mg, 1 mmol).
LCMS: m/z 345 (M+H)+.
4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-2-[2-(4-methoxy-phenyl)-(E)-vinyl]-1H-imidazole (219 mg, 65%) was prepared according to general procedure A using trans-4-methoxycinnamic acid (178 mg, 1 mmol) and 2-bromo-1-(2-3-dihydro-1-4-benzodioxepin-6-yl)-ethan-1-one (257 mg, 1 mmol).
LCMS: m/z 335 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-methoxy-phenyl)-1H-imidazole (249 mg, 65%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 2-bromo-4-methoxyacetophenone (229 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(4-methoxy-phenyl)-1H-imidazole (355 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 384 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-cyano-phenyl)-1H-imidazole (319 mg, 84%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 4-cyanophenacyl bromide (224 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(4-cyano-phenyl)-1H-imidazole (350 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 379 (M+H)+.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-methoxy-phenyl)-1H-imidazole (383 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[1-ethyl-4-(4-methoxy-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (396 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[1-ethyl-4-(4-methoxy-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (351 mg, 70%).
LCMS: m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.51 (t, 3H), 2.16 (m, 2H), 2.57 (m, 2H), 3.70 (s, 3H), 3.83 (s, 3H), 4.09 (q, 2H), 4.13 (t, 2H), 6.92 (d, 2H), 6.94-6.97 (m, 1H), 7.53-7.61 (m, 8H), 7.75 (d, 2H), 7.77 (d, 2H) ppm.
4-(4′-{2-[1-Ethyl-4-(4-methoxy-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (248 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[1-ethyl-4-(4-methoxy-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (192 mg, 80%).
LCMS: m/z 483 (M+H)+; 1H NMR (DMSO, 400 MHz): 1.15 (t, 3H), 1.36 (m, 2H), 1.97 (m, 2H), 2.42 (t, 2H), 3.77 (s, 3H), 4.0 (q, 2H), 4.2 (t, 2H), 6.93 (d, 2H), 7.01 (d, 2H), 7.28 (d, 1H), 7.47 (d, 1H), 7.62-7.66 (m, 4H), 7.75-7.77 (m, 4H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazole (314 mg, 75%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 2-bromo-1-(3-trifluoromethyl)-phenyl-1-ethanone (267 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(3-trifluoromethyl-phenyl)-1H-imidazole (393 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 422 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 4.12 (q, 2H), 6.91 (d, 2H), 7.31 (d, 1H), 7.41 (d, 2H), 7.43-7.49 (m, 2H), 7.68 (d, 2H), 7.99 (d, 2H), 8.08 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazole (421 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[1-ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (434 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-[2-[1-ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (432 mg, 80%).
LCMS: m/z 535 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.55 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.70 (s, 3H), 4.07 (q, 2H), 4.16 (t, 2H), 6.91 (s, 1H), 6.98 (d, 2H), 7.30 (s, 1H), 7.48 (d, 2H), 7.54-7.56 (m, 4H), 7.61 (d, 1H), 7.78 (s, 1H), 8.01 (d, 2H), 8.09 (s, 1H) ppm.
4-(4′-[2-[1-Ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (267 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-[2-[1-ethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (216 mg, 83%).
LCMS: m/z 521 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.15 (t, 3H), 1.36 (m, 2H), 1.97 (m, 2H), 2.42 (t, 2H), 4.0 (q, 2H), 4.2 (t, 2H), 6.93 (d, 2H), 7.01 (d, 2H), 7.28 (d, 1H), 7.47 (d, 1H), 7.62-7.66 (m, 4H), 7.75-7.77 (m, 4H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(4-tert-butyl-phenyl)-1-ethyl-1H-imidazole (316 mg, 77%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 4-(tert-butyl)-phenacyl bromide (255 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(4-tert-butyl-phenyl)-1H-imidazole (381 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 410 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 9H), 1.57 (t, 3H), 4.16 (q, 2H), 6.98 (d, 2H), 7.33 (s, 1H), 7.47-7.50 (m, 4H), 7.55 (d, 1H), 7.57 (d, 1H), 7.73 (d, 1H), 7.82 (d, 1H) ppm.
Step 1: 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(4-tert-butyl-phenyl)-1-ethyl-1H-imidazole (409 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(4-tert-Butyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (422 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-tert-butyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (411 mg, 78%).
LCMS: m/z 523 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 9H), 1.57 (t, 3H), 2.23 (m, 2H), 2.65 (t, 2H), 3.78 (s, 3H), 4.14 (q, 2H), 4.18 (t, 2H), 6.99 (s, 1H), 7.05 (d, 2H) 7.33 (s, 1H), 7.48 (d, 2H), 7.61-7.67 (m, 4H), 7.69 (d, 2H), 7.78 (s, 1H), 7.83 (d, 2H) ppm.
Step 2: 4-(4′-{2-[4-tert-Butyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (261 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-tert-butyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (218 mg, 85%).
LCMS: m/z 509 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 0.89 (s, 9H), 1.30 (t, 3H), 1.50 (m, 2H), 2.17 (t, 2H), 4.06 (q, 2H), 4.10 (t, 2H), 6.82 (d, 2H), 6.93 (d, 2H) 7.14 (s, 1H), 7.39-7.41 (m, 4H), 7.43 (d, 1H), 7.54 (d, 2H), 7.71 (d, 2H), 7.75 (s, 1H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazole (372 mg, 88%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 2-bromo-1-(4-trifluoromethyl)-phenyl-1-ethanone (267 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]l-4-(4-trifluoromethyl-phenyl)-1H-imidazole (393 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: 422 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 4.11 (q, 2H), 6.91 (d, 1H), 7.31 (d, 1H), 7.41 (d, 2H), 7.43 (d, 2H), 7.51 (d, 1H), 7.61-7.68 (m, 2H), 7.68 (s, 1H), 7.93 (d, 1H) ppm.
Step 1: 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazole (421 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[1-ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (434 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(−4′-{2-[1-ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (409 mg, 77%).
LCMS: m/z 535 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.51 (t, 3H), 2.17 (m, 2H), 2.59 (m, 2H), 3.71 (s, 3H), 4.06 (q, 2H), 4.15 (t, 2H), 6.92 (s, 1H), 6.99 (d, 2H), 7.32 (s, 1H), 7.54-7.59 (m, 4H), 7.61-7.64 (m, 2H), 7.74 (d, 1H), 7.78 (s, 2H), 7.95 (d, 2H) ppm.
Step 2: 4-(−4′-{2-[1-Ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (267 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(−4′-{2-[1-ethyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (209 mg, 80%).
LCMS: m/z 521 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 1.98 (m, 2H), 2.40 (t, 2H), 4.02 (q, 2H), 4.25 (t, 2H), 7.02 (d, 2H), 7.04 (s, 1H), 7.34 (d, 1H), 7.59 (d, 1H), 7.65-7.72 (m, 4H), 7.74-7.80 (m, 4H), 7.97 (s, 1H), 8.03 (d, 1H) ppm.
Step 1: 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-cyano-phenyl)-1H-imidazole (378 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[1-ethyl-4-(4-cyanophenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (391 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(−4′-{2-[1-ethyl-4-(4-cyanophenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (352 mg, 71%).
LCMS: m/z 492 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.51 (t, 3H), 2.16 (m, 2H), 2.57 (m, 2H), 3.83 (s, 3H), 4.09 (q, 2H), 4.13 (t, 2H), 6.92 (d, 2H), 6.94-6.97 (m, 1H), 7.53-7.61 (m, 8H), 7.75 (d, 2H), 7.77 (d, 2H) ppm
Step 2: 4-(−4′-{2-[1-Ethyl-4-(4-cyano-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (246 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(−4′-{2-[1-ethyl-4-(4-cyano-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (197 mg, 82%).
LCMS: m/z 478 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.15 (t, 3H), 1.36 (m, 2H), 1.97 (m, 2H), 2.42 (t, 2H), 4.0 (q, 2H), 4.2 (t, 2H), 6.93 (d, 2H), 7.01 (d, 2H), 7.28 (d, 1H), 7.47 (d, 1H), 7.62-7.66 (m, 4H), 7.75-7.77 (m, 4H) ppm.
2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-chloro-phenyl)-1H-imidazole (292 mg, 75%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 4-chlorophenacyl bromide (233 mg, 1 mmol) and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(4-chloro-phenyl)-1H-imidazole (359 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 388 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.47 (t, 3H), 4.12 (q, 2H), 6.90 (d, 2H), 7.33 (s, 1H), 7.35-7.40 (m, 2H), 7.41-7.42 (m, 2H), 7.48 (d, 1H), 7.50 (d, 1H), 7.76 (d, 2H) ppm
Step 1: 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-4-(4-chloro-phenyl)-1H-imidazole (387 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[1-ethyl-4-(4-chloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (401 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(−4′-{2-[1-ethyl-4-(4-chloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (381 mg, 76%).
LCMS: m/z 501 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.51 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.70 (s, 3H), 4.06 (q, 2H), 4.16 (t, 2H), 6.96-6.98 (m, 2H), 7.17-7.19 (m, 2H), 7.33-7.39 (m, 2H), 7.40-7.42 (m, 2H), 7.54-7.60 (m, 4H), 7.68 (s, 1H), (d, 2H) ppm.
Step 2: 4-(−4′-{2-[1-Ethyl-4-(4-chloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (251 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(−4′-{2-[1-ethyl-4-(4-chloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (196 mg, 80%).
LCMS: m/z 487 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.15 (t, 3H), 1.39 (m, 2H), 1.98 (m, 2H), 2.42 (t, 2H), 4.05 (q, 2H), 4.30 (t, 2H), 7.02 (d, 2H), 7.18 (s, 1H), 7.42 (d, 1H), 7.46 (d, 1H), 7.57-7.70 (m, 4H), 7.79-7.97 (m, 4H) ppm.
4-{2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazol-4-yl}-benzoic acid methyl ester (306 mg, 75%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and 4-(−2-bromoacetyl)benzoic acid methyl ester (257 mg, 1 mmol) and obtained 4-{2-[2-(4-bromo-phenyl)-(E)-vinyl]-1H-imidazol-4-yl}-benzoic acid methyl ester (383 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 412 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 3.92 (s, 3H), 4.12 (q, 2H), 6.87 (s, 1H), 6.91 (s, 1H), 7.34 (d, 2H), 7.41-7.43 (m, 2H), 7.49-7.51 (m, 2H), 7.64 (d, 1H), 7.88 (d, 1H), 8.06 (d, 1H) ppm.
Step 1: 4-{2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazol-4-yl}-benzoic acid methyl ester (411 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4-{1-ethyl-2-[2-(4-hydroxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazol-4-yl}-benzoic acid methyl ester (424 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(1-ethyl-2-{2-[4′-(3-methoxycarbonyl-propoxy)-biphenyl-4-yl}-1H-imidazol-4-yl)-benzoic acid methyl ester (404 mg, 77%).
LCMS: m/z 525 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.50 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.70 (s, 3H), 3.92 (s, 3H), 4.06 (q, 2H), 4.15 (t, 2H), 6.92 (s, 1H), 6.96-6.98 (m, 2H), 7.34 (s, 1H), 7.35-7.61 (m, 4H), 7.63 (s, 1H), 7.74 (s, 1H), 7.78 (s, 1H), 7.92 (d, 2H), 8.07 (d, 2H) ppm.
Step 2: 4-(1-Ethyl-2-{2-[4′-(3-Methoxycarbonyl-propoxy)-biphenyl-4-yl}-1H-imidazol-4-yl)-benzoic acid methyl ester (262 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(1-ethyl-2-{2-[4′-(3-methoxycarbonyl-propoxy)-biphenyl-4-yl}-1H-imidazol-4-yl)-benzoic acid (189 mg, 64%).
LCMS: m/z 497 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.36 (t, 3H), 1.96 (m, 2H), 2.37 (m, 2H), 4.03 (q, 2H), 4.23 (t, 2H), 7.02 (d, 2H), 7.27 (s, 1H), 7.31 (s, 1H), 7.52 (d, 1H), 7.56 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 7.90 7.95 (m, 4H) ppm.
Step 1: 4-{2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazol-4-yl}-benzoic acid (397 mg, 1 mmol) was coupled with methylamine according to general procedure G to give 4-{2-[2-(4-bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazol-4-yl}-N-methyl-benzamide.
4-{2-[2-(4-Bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazol-4-yl}-N-methyl-benzamide (410 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4-{1-ethyl-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazol-4-yl}-N-methyl-benzamide (423 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[1-ethyl-4-(4-methylcarbamoyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (406 mg, 78%).
LCMS: m/z 524 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.40 (t, 3H), 2.01 (m, 2H), 2.79 (d, 2H), 3.33 (s, 3H), 3.61 (s, 3H), 4.05 (q, 2H), 4.25 (t, 2H), 7.03 (d, 2H), 7.32 (d, 1H), 7.57 (d, 1H), 7.67 (d, 2H), 7.77 (d, 2H), 7.80-7.89 (m, 6H), 8.41 (d, 2H) ppm.
Step 2: 4-(4′-{2-[1-Ethyl-4-(4-methylcarbamoyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (262 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[1-ethyl-4-(4-methylcarbamoyl-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (199 mg, 78%).
LCMS: m/z 510 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.40 (t, 3H), 1.96 (m, 2H), 2.35 (m, 2H), 2.79 (s, 3H), 4.05 (q, 2H), 4.23 (t, 2H), 7.04 (d, 2H), 7.28 (s, 1H), 7.32 (s, 1H), 7.53 (s, 1H), 7.56 (s, 1H), 7.64 (d, 2H), 7.77 (d, 2H), 7.83-7.89 (m, 4H), 8.41 (d, 2H) ppm.
Step 1: 4-Biphenyl-4-yl-2-[2-(4-bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazole (429 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-[2-(4-biphenyl-4-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-ol (442 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-{4′-[2-(4-biphenyl-4-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid methyl ester (399 mg, 74%).
LCMS: m/z 543 (M+H)+; 1H NMR (CDCl3, 400 MHz): 1.54 (t, 3H), 2.17 (m, 2H), 2.59 (m, 2H), 3.71 (s, 3H), 4.05 (q, 2H), 4.15 (t, 2H), 6.94 (s, 1H), 6.96-6.99 (m, 2H), 7.29 (s, 1H), 7.34-7.43 (m, 2H), 7.45-7.47 (m, 2H), 7.55-7.58 (m, 4H), 7.62-7.67 (m, 5H), 7.79 (s, 1H), 7.93 (d, 2H) ppm.
Step 2: 4-{4′-[2-(4-Biphenyl-4-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid methyl ester (271 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-{4′-[2-(4-biphenyl-4-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid (201 mg, 76%).
LCMS: m/z 529 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): 1.41 (t, 3H), 1.97 (m, 2H), 2.42 (t, 2H), 4.04 (q, 2H), 4.23 (t, 2H), 7.03 (d, 2H), 7.28 (s, 1H), 7.32-7.37 (m, 2H), 7.37-7.44 (m, 2H), 7.46-7.48 (m, 4H), 7.53 (s, 1H), 7.57 (s, 1H), 7.78-7.82 (m, 5H), 7.92 (d, 2H) ppm.
4-Biphenyl-3-yl-2-[2-(4-bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazole (314 mg, 73%) was prepared according to general procedure A using trans-4-bromocinnamic acid (227 mg, 1 mmol) and α-bromo-3-phenyl-acetophenone (275 mg, 1 mmol) and obtained 4-biphenyl-3-yl-2-[2-(4-bromo-phenyl)-(E)-vinyl]-1H-imidazole (401 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 430 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.54 (t, 3H), 4.17 (q, 2H), 6.90 (s, 1H), 7.34 (d, 2H), 7.43 (d, 2H), 7.44-7.51 (m, 4H), 7.61-7.65 (m, 4H), 7.91 (d, 2H), 8.01 (s, 1H) ppm.
Step 1: 4-Biphenyl-3-yl-2-[2-(4-bromo-phenyl)-(E)-vinyl]-1-ethyl-1H-imidazole (429 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-[2-(4-biphenyl-3-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-ol (442 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-{-4′-[2-(4-biphenyl-3-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid methyl ester (418 mg, 77%).
LCMS: m/z 543 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 2.14 (m, 2H), 2.56 (m, 2H), 3.70 (s, 3H), 4.07 (q, 2H), 4.13 (t, 2H), 6.93 (s, 1H), 6.95-6.97 (m, 2H), 7.29 (s, 1H), 7.35-7.37 (m, 2H), 7.44-7.46 (m, 2H), 7.47-7.57 (m, 4H), 7.61-7.70 (m, 5H), 7.74-7.8 (m, 2H), 8.07 (s, 1H) ppm
Step 2: 4-{-4′-[2-(4-Biphenyl-3-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid methyl ester (271 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-{-4′-[2-(4-biphenyl-3-yl-1-ethyl-1H-imidazol-2-yl)-(E)-vinyl]-biphenyl-4-yloxy}-butyric acid (201 mg, 76%).
LCMS: m/z 529 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.41 (t, 3H), 1.97 (m, 2H), 2.42 (t, 2H), 4.04 (q, 2H), 4.23 (t, 2H), 7.03 (d, 2H), 7.28 (s, 1H), 7.32-7.37 (m, 2H), 7.37-7.44 (m, 2H), 7.46-7.48 (m, 4H), 7.53 (s, 1H), 7.78-7.82 (m, 5H), 7.92 (d, 2H), 8.02 (s, 1H) ppm.
Trans-4-bromocinnamic acid (227 mg, 1 mmol) was reacted with 2-chloro phenacylbromide (233 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2-chloro-phenyl)-1H-imidazole (359 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure. The resulted 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2-chloro-phenyl)-1-ethyl-1H-imidazole (387 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2-chloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (401 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2-chloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (399 mg, 79%).
LCMS: m/z 501 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.70 (s, 3H), 4.06 (q, 2H), 4.14 (t, 2H), 6.92 (s, 1H), 6.96-6.98 (m, 2H), 7.17-7.19 (m, 2H), 7.33-7.40 (m, 2H), 7.42 (d, 2H), 7.54-7.59 (m, 2H), 7.60-7.67 (m, 2H), 7.72 (s, 1H), 7.76 (s, 1H) ppm
4-(4′-{2-[4-(2-Chloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (250 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-(2-chloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (196 mg, 80%).
LCMS: m/z 487 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 1.98 (m, 2H), 2.42 (t, 2H), 4.05 (q, 2H), 4.30 (t, 2H), 7.04 (d, 2H), 7.23-7.29 (m, 2H), 7.33 (s, 1H), 7.38-7.40 (m, 2H), 7.42 (d, 1H), 7.47 (s, 1H), 7.49 (s, 1H), 7.54-7.67 (m, 2H), 7.80 (d, 1H), 7.91 (s, 1H), 8.21 (d, 1H) ppm.
Trans-4-bromocinnamic acid (227 mg, 1 mmol) was reacted with 2-methoxy phenacylbromide (229 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2-methoxy-phenyl)-1H-imidazole (355 mg, 1 mmol) was treated with bromoethane (109 mg, 1 mmol) following general procedure E. The resulted 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2-methoxy-phenyl)-1-ethyl-1H-imidazole (383 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2-methoxy-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (396 mg, 1 mmol) was alkylated with methyl 4-bromobutyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2-methoxy-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (375 mg, 75%).
LCMS: m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.70 (s, 3H), 3.96 (s, 3H), 4.07 (q, 2H), 4.13 (t, 2H), 6.93 (s, 1H), 6.95-6.96 (m, 2H), 6.97-7.07 (m, 2H), 7.23-7.25 (m, 2H), 7.53-7.55 (m, 2H), 7.57-7.60 (m 2H), 7.72 (s, 1H), 7.76 (s, 1H), 8.35 (d, 2H) ppm.
4-(4′-{2-[4-(2-Methoxy-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (248 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-(2-methoxy-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (189 mg, 78%).
LCMS: m/z 483 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 2.16 (m, 2H), 2.58 (m, 2H), 3.95 (s, 3H), 4.03 (q, 2H), 4.13 (t, 2H), 6.84 (d, 2H), 6.91 (s, 1H), 6.95 (d, 1H), 6.97-7.09 (m, 2H), 7.23-7.25 (m, 2H), 7.44-7.46 (m, 2H), 7.52-7.57 (m 2H), 7.74 (s, 1H), 7.78 (s, 1H), 8.24 (d, 1H) ppm.
Step 1: 2-[2-(4-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (321 mg, 73%) was prepared according to general procedure A using trans-4-bromo-2-fluorocinnamic acid (245 mg, 1 mmol) and α-bromo-2,4-dichloroacetophenone (267 mg, 1 mmol) and obtained 2-[2-(4-bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (412 mg, 1 mmol) which was then treated with bromoethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 440 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 4.08 (q, 2H), 4.14 (t, 2H), 7.07 (d, 1H), 7.25-7.28 (m, 2H), 7.29-7.39 (m, 2H), 7.42 (s, 1H), 8.24 (d, 1H) ppm.
Step 2: 2-[2-(4-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-4-ol (453 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-4-yloxy)-butyric acid methyl ester (453 mg, 81%).
LCMS: m/z 553 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 2.17 (m, 2H), 2.58 (m, 2H), 3.71 (s, 3H), 4.07 (q, 2H), 4.15 (t, 2H), 6.96 (d, 2H), 7.08 (s, 1H), 7.12 (s, 1H), 7.28-7.37 (m, 2H), 7.43 (s, 1H), 7.53-7.61 (m, 4H), 7.69 (s, 1H), 8.29 (d, 1H) ppm.
Step 3: 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-4-yloxy)-butyric acid methyl ester (276 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-4-yloxy)-butyric acid (212 mg, 79%).
LCMS: m/z 539 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 1.97 (m, 2H), 2.42 (t, 2H), 4.04 (q, 2H), 4.30 (t, 2H), 7.05 (d, 2H), 7.38 (s, 1H), 7.42 (s, 1H), 7.50 (d, 1H), 7.53 (s, 1H), 7.58 (d, 2H), 7.67-7.73 (m, 2H), 8.01-8.05 (m, 2H), 8.21 (d, 1H) ppm.
2-[2-(4-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 3-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-3-ol (453 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-3-yloxy)-butyric acid methyl ester (409 mg, 74%).
LCMS: m/z 553 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 2.16 (m, 2H), 2.56 (m, 2H), 3.69 (s, 3H), 4.05 (q, 2H), 4.15 (t, 2H), 6.88 (d, 2H), 6.90-7.08 (m, 2H), 7.11 (d, 1H), 7.12 (s, 1H), 7.17-7.32 (m, 2H), 7.57-7.68 (m, 2H), 7.79 (s, 1H), 8.27 (d, 1H), 8.27 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-3-yloxy)-butyric acid methyl ester (276 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give-4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-3-yloxy)-butyric acid (210 mg, 78%).
LCMS: m/z 539 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 1.97 (m, 2H), 2.41 (t, 2H), 4.06 (q, 2H), 4.29 (t, 2H), 6.98 (d, 2H), 7.29-7.37 (m, 2H), 7.39-7.48 (m, 2H), 7.50-7.64 (m, 2H), 7.70 (s, 1H), 7.99 (s, 1H), 8.06-8.08 (m, 2H), 8.25 (d, 1H) ppm.
Step 1: 2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (312 mg, 74%) was prepared according to general procedure A using trans 3-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was treated with bromo ethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 422 (M+H)+.
Step 2: 2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (422 mg, 1 mmol) was coupled with 3-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-ol (435 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-yloxy)-butyric acid methyl ester (429 mg, 80%).
LCMS: m/z 535 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 2.15 (m, 2H), 2.58 (m, 2H), 3.69 (s, 3H), 4.07 (q, 2H), 4.15 (t, 2H), 6.88 (d, 2H), 6.95 (s, 1H), 6.98 (s, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.30-7.33 (m, 2H), 7.35-7.46 (m, 2H), 7.50-7.53 (m, 2H), 7.74 (d, 1H), 8.26 (d, 1H) ppm.
Step 1: 2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (318 mg, 70%) was prepared according to general procedure A using trans-5-bromo-2-methoxycinnamic acid (257 mg, 1 mmol) and 2-bromo-2,4-dichloro-acetophenone (267 mg, 1 mmol) and obtained 2-[2-(5-bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (424 mg, 1 mmol) was treated with bromo ethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 452 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 3.88 (s, 3H), 4.14 (q, 2H), 4.14 (t, 2H), 6.80 (d, 1H), 7.29-7.32 (m, 2H), 7.41 (s, 1H), 7.66 (d, 1H), 7.90 (d, 1H), 8.27 (d, 1H) ppm.
Step 2: 2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (452 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-biphenyl-4-ol (465 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-biphenyl-4-yloxy)-butyric acid methyl ester (417 mg, 74%).
LCMS: m/z 565 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 2.15 (m, 2H), 2.57 (m, 2H), 3.71 (s, 3H), 3.95 (s, 3H), 4.05 (q, 2H), 4.14 (t, 2H), 6.96-6.99 (m, 2H), 7.12 (d, 2H), 7.31 (d, 2H), 7.32-7.42 (m, 2H), 7.44-7.52 (m, 2H), 7.67 (s, 1H), 7.90 (d, 1H), 8.3 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-biphenyl-4-yloxy)-butyric acid methyl ester (283 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-biphenyl-4-yloxy)-butyric acid title compound (219 mg, 79%).
LCMS: m/z 551 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.35 (t, 3H), 1.97 (m, 2H), 2.41 (t, 2H), 3.91 (s, 3H), 4.03 (q, 2H), 4.27 (t, 2H), 7.01 (d, 2H), 7.11 (d, 2H), 7.33 (s, 1H), 7.37 (s, 1H), 7.48 (d, 1H), 7.50 (d, 1H), 7.64 (d, 1H), 7.85 (d, 1H), 7.94 (s, 1H), 8.02 (d, 1H), 8.24 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (452 mg, 1 mmol) was coupled with 3-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4-methoxy-biphenyl-3-ol (465 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-methoxy-biphenyl-3-yloxy)-butyric acid methyl ester (413 mg, 73%).
LCMS: 565 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 2.15 (m, 2H), 2.59 (m, 2H), 3.69 (s, 3H), 3.96 (s, 3H), 4.08 (q, 2H), 4.15 (t, 2H), 6.86 (d, 2H), 7.00 (d, 1H), 7.09 (s, 1H), 7.11-7.17 (m, 2H), 7.19 (d, 1H), 7.31-7.42 (m, 2H), 7.48 (d, 1H), 7.76 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-methoxy-biphenyl-3-yloxy)-butyric acid methyl ester (283 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-methoxy-biphenyl-3-yloxy)-butyric acid (212 mg, 77%).
LCMS: m/z 551 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.36 (t, 3H), 1.98 (m, 2H), 2.41 (t, 2H), 3.92 (s, 3H), 4.06 (q, 2H), 4.27 (t, 2H), 6.92 (d, 2H), 7.12 (d, 2H), 7.23 (s, 1H), 7.27 (s, 1H), 7.29 (d, 1H), 7.47 (d, 1H), 7.49-7.63 (m, 2H), 7.84 (s, 1H), 8.06 (d, 1H), 8.24 (d, 1H) ppm.
2-[2-(5-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (369 mg, 84%) was prepared according to general procedure A using trans-5-bromo-2-fluorocinnamic acid (245 mg, 1 mmol) and 2-bromo-2,4-dichloroacetophenone (267 mg, 1 mmol) and obtained 2-[2-(5-bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (412 mg, 1 mmol) was treated with bromo ethane (109 mg, 1 mmol) following general procedure E.
LCMS: m/z 440 (M+H)+.
2-[2-(5-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-4′-fluoro-biphenyl-4-ol (453 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-fluoro-biphenyl-4-yloxy)-butyric acid methyl ester (415 mg, 75%).
LCMS: m/z 553 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 2.17 (m, 2H), 2.58 (m, 2H), 3.71 (s, 3H), 4.07 (q, 2H), 4.15 (t, 2H), 6.96 (d, 2H), 7.08-7.12 (m, 2H), 7.16 (s, 1H), 7.18 (d, 1H), 7.21 (d, 2H), 7.36 (d, 2H), 7.53 (d, 1H), 7.89 (s, 1H), 8.29 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-fluoro-biphenyl-4-yloxy)-butyric acid methyl ester (276 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-fluoro-biphenyl-4-yloxy)-butyric acid (214 mg, 805).
LCMS: m/z 539 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 1.98 (m, 2H), 2.42 (t, 2H), 4.04 (q, 2H), 4.28 (t, 2H), 7.05 (d, 2H), 7.31-7.46 (m, 2H), 7.47 (d, 2H), 7.50 (s, 1H), 7.64-7.69 (m 2H), 7.73 (d, 1H), 7.98 (s, 1H), 8.18 (d, 1H), 8.25 (d, 1H) ppm.
2-[2-(4-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-4-ol (453 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro biphenyl-4-yloxymethyl)-benzoic acid methyl ester (423 mg, 70%).
LCMS: 601 (M+H)+. 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 3.92 (s, 3H), 4.15 (q, 2H), 5.18 (d, 2H), 7.03-7.07 (m, 2H), 7.11 (s, 1H), 7.27 (d, 2H), 7.30-7.36 (m, 2H), 7.42 (d, 2H), 7.51-7.60 (m, 4H), 7.68 (s, 1H), 7.78 (d, 1H), 8.08 (d, 1H), 8.28 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (301 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro biphenyl-4-yloxymethyl)-benzoic acid (227 mg, 78%).
LCMS: m/z 587 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 4.29 (q, 2H), 5.28 (d, 2H), 7.11 (d, 2H), 7.37 (s, 1H), 7.49 (d, 2H), 7.51-7.58 (m, 2H), 7.60 (d, 1H), 7.65-7.74 (m, 4H), 7.96-8.0 (m 4H), 8.22 (d, 1H) ppm.
2-[2-(4-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 3-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and obtained 4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-3′-fluoro-biphenyl-3-ol (453 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro biphenyl-3-yloxymethyl)-benzoic acid methyl ester (449 mg, 75%).
LCMS: m/z 601 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 3.92 (s, 3H), 4.14 (q, 2H), 5.19 (d, 2H), 7.03-7.07 (m, 2H), 7.11 (s, 1H), 7.20 (d, 2H), 7.30-7.49 (m, 4H), 7.52-7.63 (m, 4H), 7.68 (s, 1H), 7.80 (d, 1H), 8.08 (d, 1H), 8.27 (d, 1H) ppm.
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro-biphenyl-3-yloxymethyl)-benzoic acid methyl ester (301 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-3′-fluoro biphenyl-3-yloxymethyl)-benzoic acid (226 mg, 77%).
LCMS: m/z 587 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.28 (q, 2H), 5.29 (d, 2H), 7.05 (d, 2H), 7.35 (d, 2H), 7.37-7.46 (m 4H), 7.48 (d, 1H), 7.58-7.68 (m, 4H), 7.95 (d, 2H), 8.21 (d, 1H), 8.23 (d, 1H) ppm.
2-[2-(5-Bromo-2-fluoro-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (440 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-fluoro-biphenyl-4-ol (453 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-fluoro biphenyl-4-yloxymethyl)-benzoic acid methyl ester (429 mg, 72%).
LCMS: m/z 601 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 3.91 (s, 3H), 4.13 (q, 2H), 5.18 (d, 2H), 7.06 (d, 2H), 7.10-7.16 (m, 2H), 7.31 (d, 1H), 7.42 (d, 2H), 7.44-7.54 (m, 4H), 7.68 (s, 1H), 8.02-8.08 (m, 4H), 8.28 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-fluorobiphenyl-4-yloxymethyl)-benzoic acid methyl ester (301 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-fluorobiphenyl-4-yloxymethyl)-benzoic acid (226 mg, 77%).
LCMS: m/z 587 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.29 (q, 2H), 5.28 (d, 2H), 7.15 (d, 2H), 7.31-7.41 (m, 2H), 7.31-7.46 (m, 4H), 7.58 (d, 1H), 7.63-7.72 (m, 4H), 7.90 (d, 1H), 7.98 (d, 1H), 8.18 (d, 1H), 8.24 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (452 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-methoxy-biphenyl-4-ol (465 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (467 mg, 76%).
LCMS: m/z 613 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.10 (q, 2H), 5.18 (d, 2H), 6.89 (d, 2H), 6.92-6.96 (m, 2H), 6.98-7.05 (m, 2H), 7.34 (d, 1H), 7.35-7.45 (m, 4H), 7.48 (d, 1H), 7.89-8.01 (m, 4H), 8.23 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (301 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid (229 mg, 78%).
LCMS: m/z 599 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 3.92 (s, 3H), 4.26 (q, 2H), 5.26 (d, 2H), 7.10 (d, 2H), 7.21-7.31 (m, 2H), 7.32-7.36 (m, 2H), 7.38 (d, 1H), 7.42-7.57 (m, 4H), 7.69 (d, 1H), 7.78-8.26 (m, 4H), 8.18 (d, 1H) ppm.
2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (452 mg, 1 mmol) was coupled with 3-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-4′-methoxy-biphenyl-3-ol (465 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-3-yloxymethyl)-benzoic acid methyl ester (479 mg, 78%).
LCMS: m/z 613 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.52 (t, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.13 (q, 2H), 5.20 (d, 2H), 6.92 (d, 2H), 6.94 (d, 1H), 6.97 (d, 1H), 7.01-7.11 (m, 2H), 7.20-7.21 (m, 2H), 7.30-7.38 (m, 2H), 7.41 (d, 1H), 7.46 (d, 1H), 7.47-7.49 (m, 2H), 7.74 (d, 1H), 8.06 (d, 1H), 8.29 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-3-yloxymethyl)-benzoic acid methyl ester (301 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-4′-methoxy-biphenyl-3-yloxymethyl)-benzoic acid (227 mg, 77%).
LCMS: m/z 599 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 3.90 (s, 3H), 4.24 (q, 2H), 5.28 (d, 2H), 7.09 (d, 2H), 7.11-7.21 (m, 2H), 7.28-7.36 (m, 2H), 7.38 (d, 1H), 7.41-7.56 (m, 4H), 7.71 (d, 1H), 7.76-8.02 (m. 4H), 8.16 (d, 1H) ppm.
2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (422 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (435 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (419 mg, 72%).
LCMS: m/z 583 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 3.92 (s, 3H), 4.14 (q, 2H), 5.19 (d, 2H), 6.97 (d, 2H), 7.07 (d, 1H), 7.30 (d, 1H), 7.41-7.54 (m, 8H), 7.56-7.67 (m, 4H), 8.08 (d, 1H), 8.26 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (292 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-4-yloxymethyl)-benzoic acid (219 mg, 77%).
LCMS: m/z 569 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (t, 3H), 4.29 (q, 2H), 5.28 (d, 2H), 7.12 (d, 2H), 7.41-7.57 (m, 4H), 7.59-7.72 (m, 8H), 7.89 (d, 1H), 7.91 (d, 1H), 7.99 (d, 1H), 8.2 (d, 1H) ppm.
2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (422 mg, 1 mmol) was coupled with 3-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and obtained 3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-ol (435 mg, 1 mmol) was alkylated with methyl 4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-3-yloxymethyl)-benzoic acid methyl ester (449 mg, 77%).
LCMS: m/z 583 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.50 (t, 3H), 3.92 (s, 3H), 4.13 (q, 2H), 5.21 (d, 2H), 6.97 (d, 2H), 6.99 (d, 1H), 7.23 (d, 1H), 7.31-7.51 (m, 8H), 7.54-7.67 (m, 4H), 8.04 (d, 1H), 8.27 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-3-yloxymethyl)-benzoic acid methyl ester (292 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl-}-biphenyl-3-yloxymethyl)-benzoic acid (225 mg, 79%).
LCMS: m/z 569 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (t, 3H), 4.29 (q, 2H), 5.31 (d, 2H), 7.06 (d, 2H), 7.34-7.42 (m, 4H), 7.44-7.60 (m, 6H), 7.62-7.74 (m, 2H), 7.76 (d, 1H), 7.96-7.99 (m 2H), 8.23 (d, 1H) ppm.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(3-methoxycarbonyl-propoxy)-biphenyl-3-yl]-(E)-vinyl}-imidazol-1-yl)-butyric acid methyl ester (421 mg, 69%) was prepared according to general procedure A using trans-3-bromocinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloroacetophenone (267 mg, 1 mmol) and obtained 2-[2-(3-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was coupled with 4-hydroxyphenylboronic acid (137 mg, 1 mmol) following general procedure B and resulting 3′-{2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (407 mg, 1 mmol) was di-alkylated with methyl 4-bromobutyrate (362 mg, 2 mmol) following general procedure E.
LCMS: m/z 607 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 2.18 (m, 2H), 2.42 (t, 3H), 2.56 (t, 3H), 3.66 (s, 3H), 3.70 (s, 3H), 4.06 (q, 2H), 4.20 (q, 2H), 6.96 (d, 2H), 7.07 (d, 2H), 7.31 (d, 1H), 7.33-7.42 (m, 2H), 7.44-7.52 (m, 2H), 7.56 (d, 2H), 7.64 (s, 1H), 7.77 (d, 1H), 8.27 (d, 1H) ppm.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(3-methoxycarbonyl-propoxy)-biphenyl-3-yl]-(E)-vinyl}-imidazol-1-yl)-butyric acid methyl ester (304 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-[2-{2-[4′-(3-carboxy-propoxy)-biphenyl-3-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-butyric acid (212 mg, 73%).
LCMS: m/z 579 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.96 (m, 2H), 2.28 (t, 3H), 2.42 (t, 3H), 4.03 (q, 2H), 4.25 (q, 2H), 7.03 (d, 2H), 7.40-7.55 (m 4H), 7.61-7.65 (m, 4H), 7.67-7.69 (m, 2H), 7.94 (d, 1H), 8.26 (d, 1H) ppm.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-methoxycarbonylmethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (379 mg, 65%) was prepared according to general procedure A using trans 3-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was alkylated with methyl bromo acetate (153 mg, 1 mmol) following general procedure E. The obtained 2-[2-(3-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazol-1-yl]-acetic acid methyl ester (466 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and resulting 4{-(2,4-dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-3-yl]-imidazol-1-yl}acetic acid methyl ester (479 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E.
LCMS: m/z 579 (M+H)+.
4-(3′-{2-[4-(2,4-Dichloro-phenyl)-1-methoxycarbonylmethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (290 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(3′-{2-[4-(2,4-dichloro-phenyl)-1-methoxycarbonylmethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (382 mg, 69%).
LCMS: m/z 551 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.98 (m, 2H), 2.42 (t, 2H), 4.03 (t, 2H), 5.17 (d, 2H), 7.03 (d, 1H), 7.30 (s, 1H), 7.34 (s, 1H), 7.38-7.49 (m, 2H), 7.50-7.54 (m, 2H), 7.55-7.71 (m, 4H), 7.94 (d, 1H), 7.97 (d, 1H), 8.30 (d, 1H) ppm.
Trans-3-(6-methoxynaphthalene-2-yl)acrylic acid (228 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloroacetophenone (267 mg, 1 mmol) according to general procedure A and obtained 4-(2,4-dichloro-phenyl)-2[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-1H-imidazol (198 mg, 0.5 mmol) was treated with bromo ethane (55 mg, 1 mmol) following general procedure E. The resulted 4-(2,4-dichloro-phenyl)-1-ethyl-2[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-1H-imidazole (211 mg, 0.5 mmol) was de-alkylated as described in general procedure C and obtained 6-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole-2-yl]-(E)-vinyl}-naphthalen-2-ol (205 mg, 0.5 mmol) was alkylated with methyl 4-bromobutyrate (91 mg, 0.5 mmol) following general procedure E. The resulted 4-(6-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-naphthalen-2-yloxy)-butyric acid methyl ester (255 mg, 0.5 mmol) was hydrolyzed according to general procedure F to give 4-(6-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-naphthalen-2-yloxy)-butyric acid (327 mg, 66%).
LCMS: m/z 495 (M+H)+.
2-[2-(6-Benzyloxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole (141 mg, 57%) was prepared according to general procedure A using trans-3-(6-methoxy naphthalene-2-yl)acrylic acid (Rwerechem-BKHW-0217) (228 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 4-(2,4-dichloro-phenyl)-2[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-1H-imidazol (197 mg, 0.5 mmol) was treated with bromo ethane (99 mg, 0.5 mmol) following general procedure E. The resulted 4-(2,4-dichloro-phenyl)-1-ethyl-2-[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-1H-imidazole (212 mg, 0.5 mmol) was de-alkylated as described in general procedure C and obtained 6-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-naphthalen-2-ol (204 mg, 0.5 mmol) was alkylated with benzyl bromide (86 mg, 0.5 mmol) following general procedure E.
LCMS: m/z 499 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H), 4.29 (q, 2H), 5.23 (s, 2H), 7.33 (d, 1H), 7.37-7.45 (m, 5H), 7.51-7.53 (m, 2H), 7.63 (d, 1H), 7.65 (d, 1H), 7.83-7.96 (m, 4H), 7.97 (d, 1H), 8.06 (s, 1H), 8.27 (d, 1H) ppm.
2-[2-(6-Benzyloxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-acetic acid methyl ester (139 mg, 51%) was prepared according to general procedure A using trans-3-(6-methoxy naphthalene-2-yl)acrylic acid (Rwerechem-BKHW-0217) (228 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 4-(2,4-dichloro-phenyl)-2[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-1H-imidazol (197 mg, 0.5 mmol) was alkylated with methyl bromo acetate (77 mg, 0.5 mmol) following general procedure E. The resulted 4-(2,4-dichloro-phenyl)-2-[2-(6-methoxy-naphthalen-2-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid methyl ester (233 mg, 0.5 mmol) was de-alkylated as described in general procedure C and obtained 4-(2,4-dichloro-phenyl)-2-[2-(6-hydroxy-naphthalen-2-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid methyl ester (227 mg, 0.5 mmol) was alkylated with benzyl bromide (171 mg, 1 mmol) following general procedure E.
LCMS: m/z 543 (M+H)+.
2-[2-(6-Benzyloxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-acetic acid methyl ester (135 mg, 0.25 mmol) was hydrolyzed according to general procedure F to give 2-[2-(6-Benzyloxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-acetic acid methyl ester (75 mg, 57%).
LCMS: m/z 529 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 5.17 (s, 2H), 5.23 (s, 2H), 7.15 (d, 1H), 7.19-7.28 (m, 2H), 7.32-7.37 (m, 2H), 7.40-7.48 (m, 2H), 7.51-7.55 (m, 2H), 7.68 (d, 1H), 7.80-7.95 (m, 3H), 7.98 (s, 1H), 8.04 (s, 1H), 8.20 (d, 1H), 8.31 (d, 1H) ppm
Trans-3-(6-methoxy naphthalene-2-yl)acrylic acid methyl ester (242 mg, 1 mmol) was de-alkylated as described in general procedure C and obtained 3-(6-hydroxy-naphthalen-2-yl)-acrylic acid methyl ester (228 mg, 1 mmol) was alkylated with benzyl bromide (171 mg, 1 mmol) following general procedure E. The resulted 3-(6-benzyloxy-naphthalen-2-yl)-acrylic acid methyl ester (159 mg, 0.5 mmol) was hydrolyzed according to general procedure F and obtained 3-(6-benzyloxy-naphthalen-2-yl)-acrylic acid (152 mg, 0.5 mmol) was treated with 2-bromo-2,4-dichloroacetophenone (134 mg, 0.5 mmol) following general procedure A to give 2-[2-(6-benzyloxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (119 mg, 50%).
LCMS: m/z 471 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 5.23 (s, 2H), 7.15 (d, 1H), 7.16 (d, 1H), 7.19-7.27 (m, 2H), 7.35-7.37 (m, 2H), 7.40-7.49 (m, 2H), 7.50-7.56 (m, 2H), 7.64 (d, 1H), 7.80 (d, 2H), 7.83 (d, 1H), 8.22 (d, 1H), 11.99 (s, 1H), 12.6 (s, 1H) ppm.
Trans-3-(6-methoxynaphthalene-2-yl)acrylic acid methyl ester (242 mg, 1 mmol) was de-alkylated as described in general procedure C and obtained 3-(6-hydroxy-naphthalen-2-yl)-acrylic acid methyl ester (228 mg, 1 mmol) was alkylated with bromo butane (137 mg, 1 mmol) following general procedure E. The resulted 3-(6-butoxy-naphthalen-2-yl)-acrylic acid methyl ester (142 mg, 0.5 mmol) was hydrolyzed according to general procedure F and obtained 3-(6-butoxy-naphthalen-2-yl)-acrylic acid (135 mg, 0.5 mmol) was treated with 2-bromo-2,4-dichloroacetophenone (134 mg, 0.5 mmol) following general procedure A to give 2-[2-(6-butoxy-naphthalen-2-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (109 mg, 50%).
LCMS: m/z 437 (M+H)+.
Trans-3-bromocinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloroacetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(3-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and resulted 3′-(2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (407 mg, 1 mmol) was protected with di-tert-butyl-dicarbonate according to general procedure N. The obtained 4-(2,4-dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-3-yl)-(E)-vinyl]-imidazole-1-carboxylic acid tert-butyl ester (507 mg, 1 mmol) was alkylated with 4-bromomethyl butyrate (181 mg, 1 mmol) following general procedure E and resulted 4-(2,4-dichloro-phenyl)-2-[2-(4′-(3-methoxy-carbonyl-propoxy)-biphenyl-3-yl)-(E)-vinyl]-imidazole-1-carboxylic acid tert-butyl ester ester (303 mg, 0.5 mmol) was hydrolyzed & de-protected according to general procedure F & O to give 4-(3-{2-[-4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (121 mg, 50%).
LCMS: m/z 493 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.49 (m, 2H), 1.98 (m, 2H), 2.21 (t, 2H), 4.22 (t, 2H), 6.88 (d, 2H), 7.38-7.40 (m, 2H), 7.46-7.48 (m, 2H), 7.49-7.57 (m, 2H), 7.61 (d, 1H), 7.87 (d, 2H), 8.24 (d, 1H) ppm.
Trans-bromocinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(3-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (137 mg, 1 mmol) following general procedure B and resulted 3′-(2-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (407 mg, 1 mmol) was protected with di-tert-butyl-dicarbonate according to general procedure N. The obtained 4-(2,4-dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-3-yl)-(E)-vinyl]-imidazole-1-carboxylic acid tert-butyl ester (507 mg, 1 mmol) was alkylated with methyl omethyl)benzoate (229 mg, 1 mmol) following general procedure E and resulted 4-(2,4-dichloro-phenyl)-2-[2-(4′-(4-methoxy-carbonyl-benzyloxy)-biphenyl-3-yl)-(E)-vinyl]-imidazole-1-carboxylic acid tert-butyl ester ester (327 mg, 0.5 mmol) was hydrolyzed & de-protected according to general procedure F & O to give 4-(3-{2-[-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxymethyl)-benzoic acid (129 mg, 48%).
LCMS: m/z 541 (M+H)+.
4-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenol (300 mg, 0.84 mmol) was treated with ethyl 4-iodobenzoate using general procedure J, followed by ester hydrolysis according to general procedure F to give 4-(4-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-phenoxy)-benzoic acid (5.7 mg, 1.4% yield).
LCMS: m/z 479 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.34 (t, 3H), 4.24 (q, 2H), 7.06 (d, 2H), 7.13 (d, 2H), 7.25 (d, 1H), 7.47 (dd, 1H), 7.54 (d, 1H), 7.62 (d, 1H), 7.81 (d, 2H), 7.94 (m, 3H), 8.22 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (100 mg, 0.23 mmol) was treated with ethyl 7-bromoheptanoate using general procedure E, followed by ester hydrolysis according to general procedure F to give 7-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-heptanoic acid (2 mg, 1.5% yield).
LCMS: m/z 563 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.35 (t, 3H), 1.42-1.56 (m, 4H), 1.70 (m, 4H), 2.20 (t, 2H), 4.00 (t, 2H) 4.25 (q, 2H), 7.01 (d, 2H), 7.30 (d, 1H), 7.48 (dd, 1H), 7.55 (d, 1H), 7.62-7.67 (m, 5H), 7.77 (d, 2H), 7.94 (s, 1H), 8.24 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4′-methoxy-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (350 mg, 0.83 mmol) was treated with 1-bromo-3-methyl-butane using general procedure E, followed by ether cleavage according to general procedure C. Treatment with methyl 4-bromobutyrate, followed by ester hydrolysis according to general procedures E and F respectively gave 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-(3-methyl-butyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (2 mg, 0.4% yield).
LCMS: m/z 563 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (100 mg, 0.23 mmol) was treated with methyl 5-bromopentanoate using general procedure E, followed by ester hydrolysis according to general procedure F to give 5-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-pentanoic acid (5 mg, 4% yield).
LCMS: m/z 535 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (100 mg, 0.23 mmol) was treated with ethyl 6-bromohexanoate using general procedure E, followed by ester hydrolysis according to general procedure F to give 6-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-hexanoic acid (2 mg, 1.6% yield).
LCMS: m/z 549 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (57 mg, 0.13 mmol) was treated with 3-bromopropionic acid using general procedure P to give 3-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-propionic acid (8.2 mg, 12% yield).
LCMS: m/z 507 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.55 (t, 3H), 2.76 (t, 2H), 4.22 (q, 2H), 4.30 (t, 3H), 6.98-7.09 (m, 3H), 7.35 (m, 1H), 7.47 (d, 1H), 7.54-7.69 (m, 8H), 8.00 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-propenyl}-biphenyl-4-ol (100 mg, 0.22 mmol) was treated with methyl 4-bromobutyrate using general procedure E, followed by ester hydrolysis according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-propenyl}-biphenyl-4-yloxy)-butyric acid (14 mg, 12% yield).
LCMS: m/z 535 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.53 (t, 3H), 2.14 (m, 2H), 2.42 (s, 3H), 2.55 (t, 2H), 4.09 (t, 2H), 4.18 (q, 2H), 6.79 (br s, 1H), 7.01 (m, 2H), 7.33 (dd, 1H), 7.45 (d, 1H) 7.50 (d, 2H), 7.58 (d, 2H), 7.63 (d, 2H), 7.66 (s, 1H), 7.97 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(Z)-2-fluoro-vinyl}-biphenyl-4-ol (20 mg, 0.044 mmol) was treated with methyl 4-bromobutyrate using general procedure E, followed by ester hydrolysis according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(Z)-2-fluoro-vinyl}-biphenyl-4-yloxy)-butyric acid (6 mg, 25% yield).
LCMS: m/z 539 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.53 (t, 3H), 2.16 (m, 2H), 2.62 (t, 2H), 4.06 (t, 2H), 4.26 (q, 2H), 6.81 (d, 1H), 6.95 (d, 2H), 7.32 (dd, 1H), 7.44 (d, 1H), 7.51-7.59 (m, 4H), 7.68 (m, 3H), 8.14 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-2-fluoro-vinyl}-biphenyl-4-ol (43 mg, 0.095 mmol) was treated with methyl 4-bromobutyrate using general procedure E, followed by ester hydrolysis according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-2-fluoro-vinyl}-biphenyl-4-yloxy)-butyric acid (15 mg, 29% yield).
LCMS: m/z 539 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.34 (t, 3H), 2.13 (m, 2H), 2.60 (t, 2H), 3.89 (q, 2H), 4.04 (t, 2H), 6.81 (d, 1H), 6.92 (d, 2H), 7.15 (d, 2H), 7.29 (dd, 1H), 7.40-7.49 (m, 5H), 7.75 (s, 1H), 8.14 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (90 mg, 0.21 mmol) was treated with 4-bromo-2-methylbutyric acid methyl ester using general procedure E, followed by ester hydrolysis according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-2-methyl-butyric acid (25 mg, 22% yield).
LCMS: m/z 535 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.23 (d, 3H), 1.48 (t, 3H), 1.87 (m, 1H), 2.17 (m, 1H), 2.70 (m, 1H), 4.04 (t, 2H), 4.15 (q, 2H), 6.92-6.98 (m, 3H), 7.30 (dd, 1H), 7.41 (d, 1H), 7.50-7.63 (m, 8H), 7.98 (d, 1H) ppm.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-ol (90 mg, 0.21 mmol) was treated with 4-bromopentanoic acid methyl ester using general procedure E, followed by ester hydrolysis according to general procedure F to give 4-(4′-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-pentanoic acid (22 mg, 20% yield).
LCMS: m/z 535 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.35 d, 3H), 1.52 (t, 3H), 1.96-2.09 (m, 2H), 2.55 (t, 2H), 4.13 (q, 2H), 4.51 (m, 1H), 6.90-6.97 (m, 3H), 7.32 (dd, 1H), 7.43 (d, 1H), 7.48-7.60 (m, 6H), 7.64 (s, 1H), 7.73 (d, 1H), 8.20 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazole-2-carbaldehyde (20 mg, 0.074 mmol) was treated with methyl 3,4-diaminobenzoate using general procedure Q followed by ester hydrolysis according to general procedure F. The resulting acid was coupled with methyl 4-aminobutyrate using general procedure G, then ester hydrolysis according to general procedure F gave 4-({2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3H-benzoimidazole-5-carbonyl}-amino)-butyric acid (1.6 mg, 4.5% yield).
LCMS: m/z 486 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.55 (t, 3H), 1.95 (m, 2H), 2.40 (t, 2H), 4.27 (m, 2H), 4.82 (q, 2H), 7.42 (dd, 1H), 7.54 (d, 1H), 7.60-7.65 (m, 2H), 7.72 (m, 1H), 8.04 (s, 1H), 8.27 (d, 1H) ppm.
6-[4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-naphthalen-2-ol (40 mg, 0.1 mmol) was treated with 6-bromohexanoic acid ethyl ester using general procedure E, followed by ester hydrolysis according to general procedure F to give 6-{6-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-naphthalen-2-yloxy}-hexanoic acid (10 mg, 20% yield).
LCMS: m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.47 (m, 5H), 1.68 (m, 2H), 1.81 (m, 2H), 2.35 (t, 2H), 3.97 (t, 2H), 4.15 (q, 2H), 7.12 (d, 1H), 7.19 (dd, 1H), 7.31 (dd, 1H), 7.44 (d, 1H), 7.69 (dd, 1H), 7.76-7.84 (m, 3H), 8.04 (s, 1H), 8.21 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-1-ethyl-1H-imidazole-2-carbaldehyde (50 mg, 0.186 mmol) was treated with methyl 3,4-diaminoanwasole using general procedure Q followed by benzimidazole alkylation with iodoethane according to general procedure E. The resulting compound was demethylated using general procedure C. The phenol was then treated with 6-bromohexanoic acid ethyl ester using general procedure E, followed by ester hydrolysis according to general procedure F to give 6-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3-ethyl-3H-benzoimidazol-5-yloxy}-hexanoic acid (4 mg, 4.3% yield).
LCMS: m/z 515 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.47-1.57 (m, 6H), 1.62 (m, 2H), 1.77 (m, 2H), 1.87 (m, 2H), 2.43 (t, 2H), 4.07 (t, 2H), 4.74 (m, 4H), 6.87-6.96 (m, 2H), 7.32 (dd, 1H), 7.46 (d, 1H), 7.68 (d, 1H), 7.86 (s, 1H), 8.21 (d, 1H) ppm.
3,4-dinitrophenol and ethyl 6-bromohexanoate were reacted using general procedure E, followed by nitro reduction using general procedure R. The resulting diamine and 4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazole-2-carbaldehyde (25 mg, 0.093 mmol) reacted using general procedure Q, followed by ester hydrolysis according to general procedure F to give 6-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3H-benzoimidazol-5-yloxy}-hexanoic acid (3 mg, 6.5% yield).
LCMS: m/z 487 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.55-1.63 (m, 5H), 1.75 (m, 2H), 1.87 (m, 2H), 2.37 (t, 2H), 4.07 (t, 2H), 4.77 (m, 2H), 6.95 (br s, 1H), 7.06 (br s, 1H), 7.38 (dd, 1H), 7.50 (d, 1H), 7.66 (br s, 1H), 7.86 (s, 1H), 8.12 (d, 1H) ppm.
6-Bromo-2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (28.3 mg, 0.05 mmol) was treated with (3-ethynyl-phenoxy)-acetic acid methyl ester using general procedure H, followed by silyl group deprotection (with concurrent ester hydrolysis) according to general procedure S to give (3-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3H-benzoimidazol-5-ylethynyl}-phenoxy)-acetic acid (1 mg, 4% yield).
LCMS: m/z 531 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 1.48 (t, 3H), 4.39 (s, 2H), 4.77 (q, 2H), 6.88 (m, 1H), 7.01-7.06 (m, 2H), 7.19 (t, 1H), 7.32-7.39 (m, 2H), 7.46 (d, 1H), 7.96 (s, 1H), 8.19 (d, 1H) ppm.
6-Bromo-2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (28.3 mg, 0.05 mmol) was treated with (3-ethynyl-phenoxy)-butyric acid methyl ester using general procedure H, followed by silyl group deprotection (with concurrent ester hydrolysis) according to general procedure S to give 4-(3-{2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3H-benzoimidazol-5-ylethynyl}-phenoxy)-butyric acid (2 mg, 8% yield).
LCMS: m/z 559 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 1.60 (t, 3H), 2.18 (m, 2H), 2.60 (t, 2H), 4.09 (t, 2H), 4.90 (q, 2H), 6.87 (d, 1H), 7.13 (d, 2H), 7.35 (d, 1H), 7.43-7.50 (m, 2H), 7.66 (s, 1H), 7.70-7.77 (m, 2H), 7.86 (d, 1H) 7.96 (s, 1H) ppm.
6-Bromo-2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (36 mg, 0.06 mmol) was treated with (3-ethynyl-phenoxy)-acetic acid methyl ester using general procedure H, followed by ester hydrolysis according to general procedure F to give {3-[2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5-ylethynyl]-phenoxy}-acetic acid (2 mg, 5% yield).
LCMS: m/z 661 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 0.13 (s, 9H), 1.10 (m, 2H), 1.68 (t, 3H), 3.73 (m, 2H), 4.81-4.95 (m, 4H), 6.51 (d, 2H), 7.10 (m, 1H), 7.26 (s, 1H), 7.38 (d, 1H), 7.42-7.49 (m, 2H), 7.61 (d, 1H), 7.63-7.72 (m, 2H), 7.90 (d, 1H), 8.07 (s, 1H), 8.31 (d, 1H) ppm.
6-Bromo-2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (59 mg, 0.1 mmol) was treated with trimethylsilylacetylene using general procedure H, followed by selective TMS group removal using general procedure T. The resulting acetylene was treated with ethyl 3-iodobenzoate using general procedure H, followed by ester hydrolysis according to general procedure F to give 3-[2-[4-(2,4-dichloro-phenyl)-1-ethyl-1H-imidazol-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5-ylethynyl]-benzoic acid (0.3 mg, 0.5% yield).
LCMS: m/z 631 (M+H)+.
4-[(2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetylamino)-methyl]-benzoic acid methyl ester (179 mg, 55%) was prepared according to General Procedure A using trans 4-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was alkylated with methyl bromo acetate (153 mg, 1 mmol) following general procedure E. The obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazol-1-yl]-acetic acid methyl ester (466 mg, 1 mmol) was coupled with 4-ethoxy phenyl boronic acid (165 mg, 1 mmol) following General Procedure B and resulting 4{-(2,4-dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-3-yl]-imidazol-1-yl}acetic acid methyl ester (479 mg, 1 mmol) was hydrolyzed according to General Procedure F and resulted {4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (247 mg, 0.5 mmol) was coupled with 4-(aminomethyl)-benzoic acid-methyl ester (83 mg, 0.5 mmol) following general procedure G.
LCMS: 640 (M+H)+
4-[(2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetylamino)-methyl]-benzoic acid methyl ester (160 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-[(2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetylamino)-methyl]-benzoic acid (99 mg, 63%).
LCMS: 626 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-fluoro-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (189 mg, 56%) was prepared according to General Procedure A using trans 4-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was alkylated with methyl bromo acetate (153 mg, 1 mmol) following general procedure E. The obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazol-1yl]-acetic acid methyl ester (466 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (138 mg, 1 mmol) following General Procedure B and resulting {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid methyl ester (240 mg, 0.5 mmol) was hydrolyzed according to General Procedure F. The resulted {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (233 mg, 0.5 mmol) was coupled with 4-fluoro benzylamine (63 mg, 0.5 mmol) following general procedure G and obtained 2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(4-fluoro-benzyl)-acetamide (286 mg, 0.5 mmol) was alkylated with 4-bromobutyric acid methyl ester (91 mg, 0.5 mmol) according to general procedure E.
LCMS: 672 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-fluoro-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (168 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-fluoro-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid (101 mg, 62%).
LCMS: 658 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-methoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (191 mg, 55%) was prepared according to General Procedure A using trans 4-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was alkylated with methyl bromoacetate (153 mg, 1 mmol) following general procedure E. Thus obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazol-1yl]-acetic acid methyl ester (466 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (138 mg, 1 mmol) following General Procedure B and resulting {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid methyl ester (240 mg, 0.5 mmol) was hydrolyzed according to General Procedure F. The resulted {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (233 mg, 0.5 mmol) was coupled with 4-methoxy benzylamine (69 mg, 0.5 mmol) following general procedure G and obtained 2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(4-methoxy-benzyl)-acetamide (292 mg, 0.5 mmol) was alkylated with 4-bromobutyric acid methyl ester (91 mg, 0.5 mmol) according to general procedure E.
LCMS: 684 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-methoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (171 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-methoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid (112 mg, 67%).
LCMS: 670 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-trifluoromethoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (201 mg, 54%) was prepared according to General Procedure A using trans 4-bromo cinnamic acid (227 mg, 1 mmol) and 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) and obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (394 mg, 1 mmol) was alkylated with methyl bromo acetate (153 mg, 1 mmol) following general procedure E. The obtained 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazol-1-yl]-acetic acid methyl ester (466 mg, 1 mmol) was coupled with 4-hydroxy phenyl boronic acid (138 mg, 1 mmol) following General Procedure B and resulting {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid methyl ester (240 mg, 0.5 mmol) was hydrolyzed according to General Procedure F. The resulted {4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-acetic acid (233 mg, 0.5 mmol) was coupled with 4-trifluoromethoxy benzylamine (96 mg, 0.5 mmol) following general procedure G and obtained 2-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl}-N-(4-trifluoromethoxy-benzyl)-acetamide (319 mg, 0.5 mmol) was alkylated with 4-bromobutyric acid methyl ester (91 mg, 0.5 mmol) according to general procedure E.
LCMS: m/z 738 (M+H)+
4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-trifluoromethoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid methyl ester (185 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-[4′-(2-{4-(2,4-Dichloro-phenyl)-1-[(4-trifluoromethoxy-benzylcarbamoyl)-methyl]-1H-imidazol-2-yl}-(E)-vinyl)-biphenyl-4-yloxy]-butyric acid (121 mg, 67%).
LCMS: 724 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 1.60 (m, 2H), 1.95 (m, 2H), 2.19 (m, 2H), 2.36 (m, 2H), 4.36 (m, 2H), 5.05 (s, 2H), 7.02 (d, 1H), 7.15-7.19 (m, 4H), 7.38 (d, 1H), 7.50 (d, 1H), 7.55-7.69 (m, 6H), 7.71 (d, 1H), 7.96 (s, 1H), 8.29 (d, 1H), 8.88 (s, 1H) ppm.
4-[2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (300 mg, 0.55 mmol) was treated with 6-fluoro-2-methoxyphenylboronic acid using general procedure B, followed by ester hydrolysis according to general procedure F to give 4-{4-(2,4-dichloro-phenyl)-2-[2-(6′-fluoro-2′-methoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (197 mg, 62% yield).
LCMS: m/z 573 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.74 (s, 3H), 5.62 (s, 2H), 7.08-7.20 (m, 3H), 7.30-7.37 (m, 3H), 7.48-7.53 (m, 3H), 7.56 (d, 1H), 7.63 (d, 1H), 7.69 (d, 2H), 7.93 (d, 2H), 8.10 (s, 1H), 8.27 (d, 1H) ppm.
4-[2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (300 mg, 0.55 mmol) was treated with 3-cyanophenyl boronic acid using general procedure B, followed by ester hydrolysis according to general procedure F to give 4-[2-[2-(3′-cyano-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (53 mg, 17% yield).
LCMS: m/z 550 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 5.64 (s, 2H), 7.33-7.41 (m, 3H), 7.50 (dd, 1H), 7.58 (d, 1H), 7.64 (d, 1H), 7.67 (d, 1H), 7.75-7.79 (m, 4H), 7.82 (d, 1H), 7.93 (d, 2H), 8.06 (d, 1H), 8.10 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H) ppm.
Step 1: 4-Bromophenylacetic acid (2.15 g, 10 mmol) is treated according to general procedure A using 2,4-dichlorophenacyl bromide to give the intermediate 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole, which is then treated as described in general procedure E using methyl 4-(bromomethyl)benzoate to give 4-[2-(4-bromobenzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (1.96 g, 37% total yield).
LCMS: m/z 531 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 4.11 (s, 2H), 5.36 (s, 2H), 7.46-7.50 (m, 4H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
Step 2: 4-[4-(2,4-Dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (41 mg, 34% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and 4-(trifluoromethyl)benzeneboronic acid (46 mg, 0.24 mmol).
LCMS: m/z 595 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (32 mg, 91% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (36 mg, 0.06 mmol).
LCMS: m/z 581 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 4.10 (s, 2H), 5.34 (s, 2H), 7.13 (d, 2H), 7.23 (d, 2H), 7.40 (d, 2H), 7.44 (dd, 1H), 7.48 (d, 2H), 7.60 (d, 1H), 7.68 (d, 2H), 7.81 (d, 2H), 7.94 (s, 1H), 8.18 (d, 1H) ppm.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (37 mg, 31% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and 3-(trifluoromethyl)benzeneboronic acid (46 mg, 0.24 mmol).
LCMS: m/z 595 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (26 mg, 89% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(3′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (30 mg, 0.05 mmol).
LCMS: m/z 581 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 4.12 (s, 2H), 5.35 (s, 2H), 7.14 (d, 2H), 7.26 (d, 2H), 7.44 (dd, 1H), 7.57 (d, 2H), 7.60 (d, 1H), 7.65-7.69 (m, 4H), 7.82 (d, 2H), 7.95 (s, 1H), 8.17 (d, 1H) ppm.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (93 mg, 78% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and 4-(trifluoromethoxy)benzeneboronic acid (50 mg, 0.24 mmol).
LCMS: m/z 611 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (54 mg, 90% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(4′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (61 mg, 0.1 mmol).
LCMS: m/z 597 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 4.11 (s, 2H), 5.34 (s, 2H), 7.13 (d, 2H), 7.23 (d, 2H), 7.39 (d, 2H), 7.43 (dd, 1H), 7.48 (d, 2H), 7.60 (d, 1H), 7.68 (d, 2H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (88 mg, 72% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and 3-(trifluoromethoxy)benzeneboronic acid (50 mg, 0.24 mmol).
LCMS: m/z 611 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (50 mg, 83% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(3′-trifluoromethoxy-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (61 mg, 0.1 mmol).
LCMS: m/z 597 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 4.14 (s, 2H), 5.37 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.44 (dd, 1H), 7.57 (d, 2H), 7.60 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (68 mg, 56% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and (3-methylsulfonylphenyl)boronic acid (48 mg, 0.24 mmol).
LCMS: m/z 605 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (51 mg, 86% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (61 mg, 0.1 mmol).
LCMS: m/z 591 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.28 (s, 3H), 4.14 (s, 2H), 5.37 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.44 (dd, 1H), 7.57 (d, 2H), 7.60 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (74 mg, 61% yield) is prepared according to general procedure B using 4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (106 mg, 0.2 mmol) and (4-methylsulfonylphenyl)boronic acid (48 mg, 0.24 mmol).
LCMS: m/z 605 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid (53 mg, 89% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (61 mg, 0.1 mmol).
LCMS: m/z 591 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.26 (s, 3H), 4.13 (s, 2H), 5.36 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.44 (dd, 1H), 7.57 (d, 2H), 7.60 (d, 1H), 7.65 (d, 2H), 7.72 (d, 2H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-(tert-Butoxycarbonylamino-methyl)-benzoic acid (502 mg, 2 mmol) is treated according to general procedure A using 2,4-dichlorophenacyl bromide to give {4-[4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-benzyl}-carbamic acid tert-butyl ester, which is then treated as described in general procedure E using methyl 4-(bromomethyl)benzoate to give 4-[2-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester, which is then treated with hydrogen chloride in ethyl ether and then coupled with 4-methylsulphonylphenylacetic acid according to general procedure G to afford the title compound 4-[4-(2,4-dichloro-phenyl)-2-(4-{[2-(4-methanesulfonyl-phenyl)-acetylamino]-methyl}-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (239 mg, 18% total yield).
LCMS: m/z 662 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4-{[2-(4-methanesulfonyl-phenyl)-acetylamino]-methyl}-phenyl)-imidazol-1-ylmethyl]-benzoic acid (92 mg, 71% yield) is prepared according to general procedure F using 4-[4-(2,4-dichloro-phenyl)-2-(4-{[2-(4-methanesulfonyl-phenyl)-acetylamino]-methyl}-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (133 mg, 0.2 mmol).
LCMS: m/z 648 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.16 (s, 3H), 3.51 (s, 2H), 4.25 (d, 2H), 5.38 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.46-7.58 (m, 3H), 7.60 (d, 1H), 7.65 (d, 2H), 7.72 (d, 2H), 7.81 (d, 2H), 7.94 (s, 1H), 8.15 (d, 1H) ppm.
Step 1: Trans-4-bromocinnamic acid (2.27 g, 10 mmol) is treated according to general procedure A using 2,4-difluorophenacyl bromide to give the intermediate 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-difluoro-phenyl)-1H-imidazole, which is then treated as described in general procedure E using methyl 4-(bromomethyl)benzoate to give 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-difluoro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (1.68 g, 33% total yield).
LCMS: m/z 510 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.60 (s, 2H), 7.13 (d, 1H), 7.46-7.50 (m, 5H), 7.61 (d, 2H), 7.65 (d, 2H), 7.69 (d, 2H), 7.74 (s, 1H), 7.81 (d, 1H) ppm.
Step 2: 4-{4-(2,4-Difluoro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (150 mg, 56% total yield) is prepared according to general procedure B using 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-difluoro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (255 mg, 0.5 mmol) and 4-ethoxyphenylboronic acid (100 mg, 0.6 mmol), followed by ester-hydrolysis according to general procedure F.
LCMS: m/z 537 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.34 (t, 3H), 4.06 (q, 2H), 5.63 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.33 (d, 1H), 7.39 (d, 1H), 7.47 (d, 2H), 7.58 (d, 1H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-{4-(2,4-Difluoro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-ethyl]-imidazol-1-ylmethyl}-benzoic acid (18 mg, 67% yield) is prepared according to general procedure V using 4-{4-(2,4-difluoro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (27 mg, 0.05 mmol).
LCMS: m/z 539 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.32 (t, 3H), 2.86 (m, 2H), 2.96 (m, 2H), 4.03 (q, 2H), 5.32 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.39 (d, 1H), 7.47 (d, 2H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-{4-(2,4-Difluoro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (72 mg, 71% total yield) is prepared according to general procedure C using 4-{4-(2,4-difluoro-phenyl)-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (107 mg, 0.2 mmol).
LCMS: m/z 509 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 5.62 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.33 (d, 1H), 7.39 (d, 1H), 7.47 (d, 2H), 7.58 (d, 1H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.16 (d, 1H) ppm.
4-[2-[2-(4′-Butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-difluoro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (28 mg, 49% total yield) is prepared according to general procedure E using 4-{4-(2,4-difluoro-phenyl)-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (51 mg, 0.1 mmol) and 1-bromobutane, followed by ester-hydrolysis according to general procedure F.
LCMS: m/z 565 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.04 (t, 3H), 1.46 (m, 2H), 1.90 (m, 2H), 4.18 (t, 2H), 5.61 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.33 (d, 1H), 7.39 (d, 1H), 7.47 (d, 2H), 7.58 (d, 1H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-{4-(2,4-Difluoro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (87 mg, 31% total yield) is prepared according to general procedure B using 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-difluoro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (255 mg, 0.5 mmol) and 3-(trifluoromethyl)benzeneboronic acid (114 mg, 0.6 mmol), followed by ester-hydrolysis according to general procedure F.
LCMS: m/z 561 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 5.60 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.33 (d, 1H), 7.39 (d, 1H), 7.47 (d, 2H), 7.58 (d, 1H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.18 (d, 1H) ppm.
4-{4-(2,4-Difluoro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-ethyl]-imidazol-1-ylmethyl}-benzoic acid (21 mg, 74% yield) is prepared according to general procedure V using 4-{4-(2,4-difluoro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (28 mg, 0.05 mmol).
LCMS: m/z 563 (M+H)+; 1H NMR (DMSO-d6, 400 MHz): δ 2.88 (m, 2H), 2.97 (m, 2H), 5.32 (s, 2H), 7.13 (d, 2H), 7.24 (d, 2H), 7.39 (d, 1H), 7.47 (d, 2H), 7.62 (d, 1H), 7.65-7.69 (m, 4H), 7.81 (d, 2H), 7.94 (s, 1H), 8.17 (d, 1H) ppm.
4-(2,4-Dichloro-phenyl)-2-[2-(4-nitro-phenyl)-(E)-vinyl]-1H-imidazole (1.98 g, 5.5 mmol) was treated with methyl 4-bromomethyl benzoate using general procedure E to provide 4-{4-(2,4-dichloro-phenyl)-2-[2-(4-nitro-phenyl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (753 mg, 27% yield). 30 mg (0.059 mmol) of the ester was hydrolyzed according to general procedure F to provide 4-{4-(2,4-dichloro-phenyl)-2-[2-(4-nitro-phenyl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (24 mg, 82% yield).
LCMS: m/z 494 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 5.53 (s, 2H), 7.18 (d, 1H), 7.31 (d, 2H), 7.38 (dd, 1H), 7.49 (d, 1H), 7.65-7.72 (m, 3H), 7.79 (s, 1H), 8.06 (m, 3H), 8.23 (d, 2H) ppm.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4-nitro-phenyl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (453 mg, 0.89 mmol) was reduced according to general procedure K to provide 4-[2-[2-(4-amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (350 mg, 82% yield).
LCMS: m/z 478 (M+H)+.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (17 mg, 0.036 mmol) was hydrolyzed according to general procedure F to provide 4-[2-[2-(4-amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (5.4 mg, 33% yield).
LCMS: m/z 464 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 5.52 (s, 2H), 6.54 (d, 2H), 6.90 (d, 1H), 7.25-7.34 (m, 4H), 7.38 (d, 1H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.90 (d, 2H), 8.05 (s, 1H), 8.27 (d, 1H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (69 mg, 0.14 mmol) was treated with n-butanesulfonyl chloride according to general procedure L to provide 4-[2-{2-[4-(butane-1-sulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (48 mg, 57% yield).
LCMS: m/z 598 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 0.90 (t, 3H), 1.42 (m, 2H), 1.80 (m, 2H), 3.10 (m, 2H), 3.93 (s, 3H), 5.34 (s, 2H), 6.66 (s, 1H), 6.73 (d, 1H), 7.17 (d, 2H), 7.23 (d, 2H), 7.34 (dd, 1H), 7.41 (d, 2H), 7.43 (d, 1H), 7.64 (d, 1H), 7.71 (s, 1H), 8.05 (d, 2H), 8.26 (d, 1H) ppm.
4-[2-{2-[4-(Butane-1-sulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (45 mg, 0.075 mmol) was hydrolyzed according to general procedure F to provide 4-[2-{2-[4-(butane-1-sulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (30 mg, 68% yield).
LCMS: m/z 584 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.83 (t, 3H), 1.35 (m, 2H), 1.64 (m, 2H), 3.12 (m, 2H), 5.60 (s, 2H), 6.66 (s, 1H), 7.17-7.23 (m, 3H), 7.34 (d, 2H), 7.46-7.53 (m, 2H), 7.62 (d, 2H), 7.65 (d, 1H), 7.93 (d, 2H), 8.09 (s, 1H), 8.28 (d, 1H), 9.93 (br s, 1H), 12.82 (br s, 1H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (71 mg, 0.15 mmol) was treated with 4-n-butylbenzenesulfonyl chloride according to general procedure L to provide 4-[2-{2-[4-(4-butyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (95 mg, 93% yield).
LCMS: m/z 674 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 0.90 (t, 3H), 1.30 (m, 2H), 1.57 (m, 2H), 2.62 (t, 2H), 3.92 (s, 3H), 5.31 (s, 2H), 6.69 (d, 1H), 6.98-7.05 (m, 3H), 7.21 (m, 4H), 7.28-7.33 (m, 3H), 7.42 (d, 1H), 7.58 (d, 1H), 7.68 (m, 3H), 8.03 (d, 2H), 8.24 (d, 1H) ppm.
4-[2-{2-[4-(4-Butyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (92 mg, 0.14 mmol) was hydrolyzed according to general procedure F to provide 4-[2-{2-[4-(4-butyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (82 mg, 91% yield).
LCMS: m/z 660 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.85 (t, 3H), 1.26 (m, 2H), 1.51 (m, 2H), 2.60 (t, 2H), 5.57 (s, 2H), 7.09 (d, 2H), 7.15 (d, 1H), 7.33 (d, 2H), 7.37 (d, 2H), 7.42 (d, 1H), 7.48-7.54 (m, 3H), 7.64 (d, 1H), 7.69 (d, 2H) 7.92 (d, 2H), 8.07 (s, 1H), 8.25 (d, 1H), 10.40 (S, 1H), 12.94 (br s, 1H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (70 mg, 0.15 mmol) was treated with 4-n-butylbenzaldehyde according to general procedure U to provide 4-[2-{2-[4-(4-butyl-benzylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (59 mg, 63% yield).
LCMS: m/z 624 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 0.92 (t, 3H), 1.35 (m, 2H), 1.58 (m, 2H), 2.60 (t, 2H), 3.90 (s, 3H), 4.29 (s, 2H), 5.28 (s, 2H), 6.54-6.60 (m, 3H), 7.15 (d, 2H), 7.20-7.30 (m, 6H), 7.32 (dd, 1H), 7.41 (d, 1H), 7.59 (d, 1H), 7.65 (s, 1H), 8.03 (d, 2H), 8.29 (d, 1H) ppm.
4-[2-{2-[4-(4-Butyl-benzylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (55 mg, 0.09 mmol) was hydrolyzed according to general procedure F to provide 4-[2-{2-[4-(4-butyl-benzylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (39 mg, 72% yield).
LCMS: m/z 610 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.90 (t, 3H), 1.29 (m, 2H), 1.53 (m, 2H), 2.55 (t, 2H), 4.24 (d, 2H), 5.55 (s, 2H), 6.56 (d, 2H), 6.89 (d, 1H), 7.13 (d, 2H), 7.25 (d, 2H), 7.31-7.40 (m, 5H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.92 (d, 2H), 8.02 (s, 1H), 8.27 (d, 1H), 12.95 (br s, 1H) ppm.
4-[2-{2-[4-(4-Butyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (16 mg, 0.024 mmol) was reduced according to general procedure V to provide 4-[2-{2-[4-(4-butyl-benzenesulfonylamino)-phenyl]-ethyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (8 mg, 50% yield).
LCMS: m/z 662 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 0.89 (t, 3H), 1.28 (m, 2H), 1.50 (m, 2H), 2.55 (t, 2H), 2.86 (m, 4H), 4.96 (s, 2H), 6.92 (d, 2H), 6.97 (d, 2H), 7.09 (d, 2H), 7.22 (d, 2H), 7.38 (dd, 1H), 7.51 (d, 1H), 7.58 (s, 1H), 7.63 (d, 2H) 7.88 (d, 1H), 7.97 (d, 2H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (66 mg, 0.14 mmol) was treated with 3-trifluoromethylbenzenesulfonyl chloride according to general procedure L to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(3-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (87 mg, 92% yield).
LCMS: m/z 686 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.92 (s, 3H), 5.34 (s, 2H), 6.67 (br s, 1H), 6.71 (d, 1H), 7.03 (d, 2H), 7.22 (d, 2H), 7.31-7.36 (m, 3H), 7.43 (d, 1H), 7.56-7.62 (m, 2H), 7.70 (s, 1H), 7.80 (d, 1H), 7.91 (d, 1H), 8.01-8.06 (m, 3H), 8.24 (d, 1H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (66 mg, 0.14 mmol) was treated with 4-trifluoromethylbenzenesulfonyl chloride according to general procedure L to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (87 mg, 92% yield).
LCMS: m/z 686 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 3.92 (s, 3H), 5.33 (s, 2H), 6.69-6.73 (m, 2H), 7.04 (d, 2H), 7.22 (d, 2H), 7.31-7.36 (m, 3H), 7.43 (d, 1H), 7.60 (d, 1H), 7.71 (m, 3H), 7.88 (d, 2H), 8.04 (d, 2H), 8.24 (d, 1H) ppm.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(3-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (79 mg, 0.12 mmol) was hydrolyzed according to general procedure F to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(3-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (46 mg, 59% yield).
LCMS: m/z 672 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 5.58 (s, 2H), 7.09 (d, 2H), 7.18 (d, 1H), 7.33 (d, 2H), 7.43 (d, 1H), 7.50 (dd, 1H), 7.56 (d, 2H), 7.64 (d, 1H), 7.82 (t, 1H) 7.93 (d, 2H), 8.01-8.06 (m, 3H), 8.08 (s, 1H), 8.25 (d, 1H), 10.59 (s, 1H), 12.96 (br s, 1H) ppm.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (79 mg, 0.12 mmol) was hydrolyzed according to general procedure F to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (54 mg, 70% yield).
LCMS: m/z 672 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 5.59 (s, 2H), 7.10 (d, 2H), 7.17 (d, 1H), 7.33 (d, 2H), 7.43 (d, 1H), 7.49 (dd, 1H), 7.55 (d, 2H), 7.64 (d, 1H), 7.92 (d, 2H) 7.97 (s, 4H), 8.08 (s, 1H), 8.25 (d, 1H), 10.68 (br s, 1H), 12.96 (br s, 1H) ppm.
4-[2-[2-(4-Amino-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (35 mg, 0.073 mmol) was treated with p-toluenesulfonyl chloride according to general procedure L to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(toluene-4-sulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (39 mg, 84% yield).
LCMS: m/z 632 (M+H)+; 1H NMR (CDCl3, 400 MHz): δ 2.36 (s, 3H), 3.90 (s, 3H), 5.30 (s, 2H), 6.68 (d, 1H), 7.03 (d, 2H), 7.20 (d, 4H), 7.26-7.32 (m, 3H), 7.41 (d, 1H), 7.57 (d, 1H), 7.65 (d, 2H), 7.68 (s, 1H), 8.03 (d, 2H), 8.23 (d, 1H) ppm.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(toluene-4-sulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (36 mg, 0.057 mmol) was hydrolyzed according to general procedure F to provide 4-(4-(2,4-dichloro-phenyl)-2-{2-[4-(toluene-4-sulfonylamino)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (26 mg, 74% yield).
LCMS: m/z 618 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 2.33 (s, 3H), 5.45 (s, 2H), 6.95 (d, 1H), 7.07 (d, 2H), 7.23 (d, 2H), 7.28 (d, 2H), 7.36 (m, 3H), 7.43 (d, 1H), 7.48 (d, 1H), 7.63 (d, 2H) 7.77 (s, 1H), 7.95-8.00 (m, 3H) ppm.
4-[2-{2-[4-(4-Butyl-benzenesulfonylamino)-phenyl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (24 mg, 0.036 mmol) was treated with sodium hydride and methyl iodide according to general procedure P, then the methyl ester which formed was hydrolyzed according to general procedure F to provide 4-[2-(2-{4-[(4-butyl-benzenesulfonyl)-methyl-amino]-phenyl}-(E)-vinyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (11 mg, 45% yield).
LCMS: m/z 674 (M+H)+; 1H NMR (CD3OD, 400 MHz): δ 0.95 (t, 3H), 1.38 (m, 2H), 1.64 (M, 2H), 2.70 (t, 2H), 3.18 (s, 3H), 5.48 (s, 2H), 6.95 (d, 1H), 7.09 (d, 2H), 7.28-7.33 (m, 4H), 7.37 (dd, 1H), 7.43-7.49 (m, 5H), 7.58 (d, 1H) 7.74 (s, 1H), 8.03-8.09 (m, 3H) ppm.
Trans-4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-(trifluoromethyl)-phenyl boronic acid (189 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (313 mg, 51%).
LCMS: 607 (M+H)+.
4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (303 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2[2-(4′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (197 mg, 67%).
LCMS: 593 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.82 (s, 2H), 7.48-7.50 (m, 2H), 7.56 (s, 1H), 7.60-7.64 (m, 3H), 7.81-7.88 (m, 4H), 7.91-7.99 (m, 4H), 8.14-8.19 (m, 3H), 8.32 (s, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-(trifluoromethoxy)-phenyl boronic acid (205 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-yl-methyl}benzoic acid methyl ester (324 mg, 52%).
LCMS: 623 (M+H)+
4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (311 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2[2-(4′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (198 mg, 65%).
LCMS: 609 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.66 (s, 2H), 7.36-7.40 (m, 2H), 7.44-7.46 (m, 2H), 7.51 (d, 1H), 7.52 (d, 1H), 7.53 (d, 1H), 7.59 (s, 1H), 7.63-7.66 (m, 2H), 7.70-7.72 (m, 2H), 7.76-7.84 (m, 2H), 7.93-7.95 (m. 2H), 8.13 (s, 1H), 8.27 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-butoxy-phenyl boronic acid (195 mg, 1 mmol) following General Procedure B to give 4-2-[2-(4″-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (315 mg, 51%).
LCMS: 611 (M+H)+.
4-2-[2-(4′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (305 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[2-[2-(4′-Butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (198 mg, 66%)
LCMS: 597 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 0.96 (t, 3H), 1.43-1.45 (m, 2H), 1.69-1.73 (m, 2H), 4.02 (q, 2H), 5.64 (s, 2H), 7.02 (d, 1H), 7.29 (s, 1H), 7.33-7.37 (m, 4H), 7.52-7.54 (m, 4H), 7.58-7.64 (m, 4H), 7.65 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.27 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-(trifluoromethyl)-phenyl boronic acid (189 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-dichloro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (312 mg, 52%).
LCMS: 607 (M+H)+ 1H NMR (CDCl3, 400 MHz): δ 3.91 (s, 3H), 5.37 (s, 2H) 6.87 (d, 1H), 7.33-7.7.36 (m, 4H), 7.43 (d, 1H), 7.53 (s, 1H), 7.55-7.61 (m, 4H), 7.72-7.75 (m, 4H), 7.83 (s, 1H), 8.05 (s, 1H), 8.30 (d, 1H) ppm.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (303 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (197 mg, 67%).
LCMS: 593 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.70 (s, 2H), 7.40-7.42 (m, 4H), 7.47 (s, 1H), 7.55 (d, 2H), 7.71 (d, 2H), 7.81 (s, 1H), 7.94 (d, 2H), 8.01-8.04 (m, 2H), 8.18-8.22 (m, 4H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-(trifluoromethoxy)-phenyl boronic acid (205 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-dichloro-phenyl)-2-[2-(3′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (321 mg, 51%).
LCMS: 623 (M+H)+.
4-{4-(2,4-dichloro-phenyl)-2-[2-(3′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (311 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2[2-(4′-trifluoromethoxy-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (198 mg, 65%).
LCMS: 609 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 4.81 (s, 2H), 6.51-6.55 (m, 2H), 6.66 (d, 2H), 6.72-6.75 (m, 4H), 6.76 (s, 1H), 6.77 (s, 1H), 6.81-6.93 (m, 4H), 7.10 (d, 2H), 7.27 (s, 1H), 7.45 (d, 1H) ppm.
Trans-4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-amino-phenyl boronic acid (137 mg, 1 mmol) following General Procedure B and obtained 4-{4-(2,4-dichloro-phenyl)-2-[2-(3′-amino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid methyl ester (277 mg, 0.5 mmol) was alkylated according to General Procedure P to give 4-{4-(2,4-Dichloro-phenyl)-2[2-(3-trifluoromethanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (228 mg, 66%).
LCMS: 686 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (343 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (238 mg, 70%).
LCMS: 672 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.61 (s, 2H), 6.93 (d, 1H), 7.05 (d, 1H), 7.12-7.14 (m, 2H), 7.24 (s, 1H), 7.30-7.34 (m, 4H), 7.50-7.57 (m, 4H), 7.64 (s, 1H), 7.70 (d, 1H), 7.92 (d, 2H), 8.10 (s, 1H), 8.30 (d, 1H) ppm.
Trans-4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with (4-Bromomethyl-phenyl)-acetic acid methyl ester (243 mg, 1 mmol) following general procedure E. The resulted {4-[2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-acetic acid methyl ester (556 mg, 1 mmol) was coupled with 3-methanesulfonyl-phenyl boronic acid (200 mg, 1 mmol) following General Procedure B to give (4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid methyl ester (321 mg, 50%).
LCMS: 631 (M+H)+
(4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid methyl ester (315 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give (4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid (198 mg, 64%).
LCMS: 617 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.31 (s, 3H), 3.46 (s, 2H), 5.51 (s, 2H), 7.23 (s, 1H), 7.45-7.49 (m, 2H), 7.51-7.57 (m, 2H), 7.61-7.64 (m, 2H), 7.75-7.76 (m, 2H), 7.79-7.82 (m, 2H), 7.84-8.07 (m, 4H), 8.10 (d, 1H), 8.19 (s, 1H), 8.25 (d, 1H) ppm.
Trans-4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-ethoxy-phenyl boronic acid (165 mg, 1 mmol) following General Procedure B to give 4-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (305 mg, 52%).
LCMS: 583 (M+H)+.
4-2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazo-1-yl-methyl}benzoic acid methyl ester (292 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[2-[2-(4′-ethoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (198 mg, 69%)
LCMS: 569 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 0.96 (t, 3H), 4.02 (q, 2H), 5.64 (s, 2H), 7.02 (d, 1H), 7.29 (s, 1H), 7.33-7.37 (m, 4H), 7.52-7.54 (m, 4H), 7.58-7.64 (m, 4H), 7.65 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.27 (d, 1H) ppm.
Step 1: Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-hydroxy-phenyl boronic acid (137 mg, 1 mmol) following General Procedure B to give 4-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (288 mg, 54%)
LCMS: 556 (M+H)+
Step 2: 4-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (278 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (168 mg, 62%)
LCMS: 541 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.68 (s, 2H), 7.12 (d, 1H), 7.36 (s, 1H), 7.37-7.40 (m, 4H), 7.52-7.54 (m, 4H), 7.58-7.64 (m, 4H), 7.66 (d, 1H), 7.91 (d, 1H), 8.09 (s, 1H), 8.21 (d, 1H) ppm.
Trans 5-bromo 2-methoxy cinnamic acid (257 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (424 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (572 mg, 1 mmol) was coupled with 4-ethoxy-phenyl boronic acid (165 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (298 mg, 49%).
LCMS: 613 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (154 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-ethoxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (117 mg, 78%).
LCMS: 599 (M+H)+. 1H NMR (DMSO, 400 MHz): δ 1.39 (t, 3H), 3.90 (s, 3H), 4.24 (q, 2H), 5.28 (d, 2H), 7.09 (d, 2H), 7.11-7.21 (m, 2H), 7.28-7.36 (m, 2H), 7.38 (d, 1H), 7.41-7.56 (m, 4H), 7.71 (d, 1H), 7.76-8.02 (m. 4H), 8.16 (d, 1H) ppm
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with (4-Bromomethyl-phenyl)-acetic acid methyl ester (243 mg, 1 mmol) following general procedure E. The resulted {4-[2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-acetic acid methyl ester (556 mg, 1 mmol) was coupled with 3-trifluoromethyl-phenyl boronic acid (189 mg, 1 mmol) following General Procedure B to give (4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid methyl ester (321 mg, 51%).
LCMS: 621 (M+H)+
(4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid methyl ester (310 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give (4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-phenyl)-acetic acid (198 mg, 65%).
LCMS: 607 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.81 (s, 2H), 5.56 (s, 2H), 7.44-7.48 (m, 2H), 7.50-7.53 (m, 2H), 7.58 (s, 1H), 7.61-7.64 (m, 2H), 7.75-7.76 (m, 2H), 7.79-7.82 (m, 2H), 7.83-8.07 (m, 4H), 8.09 (d, 1H), 8.19 (s, 1H), 8.27 (d, 1H) ppm.
Trans 5-bromo 2-methoxy cinnamic acid (257 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1H-imidazole (424 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(5-Bromo-2-methoxy-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (572 mg, 1 mmol) was coupled with 4-hydroxy-phenyl boronic acid (137 mg, 1 mmol) following General Procedure B to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (291 mg, 50%).
LCMS: 585 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (146 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-hydroxy-4-methoxy-biphenyl-3-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (107 mg, 75%).
LCMS: 571 (M+H)+. 1H NMR (DMSO, 400 MHz): 6, 3.87 (s, 3H), 5.26 (d, 2H), 7.13 (d, 2H), 7.16-7.22 (m, 2H), 7.28-7.36 (m, 2H), 7.39 (d, 1H), 7.41-7.56 (m, 4H), 7.70 (d, 1H), 7.76-8.11 (m. 4H), 8.14 (d, 1H) ppm
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-butoxy-phenyl boronic acid (195 mg, 1 mmol) following General Procedure B to give 4-2-[2-(3′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (325 mg, 53%).
LCMS: 611 (M+H)+
4-2-[2-(3′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (305 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[2-[2-(3′-Butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (192 mg, 64%)
LCMS: 597 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 0.94 (t, 3H), 1.41-1.44 (m, 2H), 1.68-1.72 (m, 2H), 4.01 (q, 2H), 5.66 (s, 2H), 7.10 (d, 1H), 7.29 (s, 1H), 7.31-7.36 (m, 4H), 7.51-7.56 (m, 4H), 7.59-7.66 (m, 4H), 7.67 (d, 1H), 7.91 (d, 1H), 8.11 (s, 1H), 8.29 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-3-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 3-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-butoxy-phenyl boronic acid (195 mg, 1 mmol) following General Procedure B to give 3-2-[2-(4′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (319 mg, 52%).
LCMS: 611 (M+H)+
3-2-[2-(4′-butoxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (305 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 3-[2-[2-(4′-Butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (191 mg, 64%)
LCMS: 597 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 0.97 (t, 3H), 1.42-1.46 (m, 2H), 1.69-1.71 (m, 2H), 4.01 (q, 2H), 5.67 (s, 2H), 7.04 (d, 1H), 7.27 (s, 1H), 7.34-7.38 (m, 4H), 7.51-7.55 (m, 4H), 7.57-7.63 (m, 4H), 7.64 (d, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.21 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-(methanesulfonyl)-phenyl boronic acid (200 mg, 1 mmol) following General Procedure B to give 4-2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (294 mg, 47%)
LCMS: 617 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (155 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (108 mg, 72%)
LCMS: 603 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.47 (s, 3H), 5.66 (s, 2H), 7.12 (d, 1H), 7.36 (s, 1H), 7.37-7.40 (m, 4H), 7.52-7.54 (m, 4H), 7.58-7.64 (m, 4H), 7.66 (d, 1H), 7.91 (d, 1H), 8.09 (s, 1H), 8.21 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-(methanesulfonyl)-phenyl boronic acid (200 mg, 1 mmol) following General Procedure B to give 4-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (299 mg, 48%)
LCMS: 617 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (155 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (101 mg, 67%)
LCMS: 603 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.31 (s, 3H), 5.51 (s, 2H), 7.23 (s, 1H), 7.45-7.49 (m, 2H), 7.51-7.57 (m, 2H), 7.61-7.64 (m, 2H), 7.75-7.76 (m, 2H), 7.79-7.82 (m, 2H), 7.84-8.07 (m, 4H), 8.10 (d, 1H), 8.19 (s, 1H), 8.25 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 1-(tert-butoxycarbonyl)-pyrrole-2-boronic acid (211 mg, 1 mmol) following General Procedure B to give 2-(4-{2-[4-(2,4-Dichloro-phenyl)-1-(4-methoxycarbonyl-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (278 mg, 44%)
LCMS: 628 (M+H)+.
2-(4-{2-[4-(2,4-Dichloro-phenyl)-1-(4-methoxycarbonyl-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (157 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 2-(4-{2-[1-(4-Carboxy-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (89 mg, 59%)
LCMS: 614 (M+H)+.
2-(4-{2-[1-(4-Carboxy-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-(E)-vinyl}-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (62 mg, 0.1 mmol) was de-protected according to General Procedure O to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(1H-pyrrol-2-yl)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (29 mg, 55%).
LCMS: 514 (M+H)+.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-hydroxy-phenyl boronic acid (137 mg, 1 mmol) following General Procedure B and obtained 4-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (278 mg, 0.5 mmol) was alkylated with 4-fluoronitro benzene (71 mg, 0.5 mmol) according to general procedure I to give 4-[2-{2-[4′-(4-Nitro-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (221 mg, 65%).
LCMS: 676 (M+H)+.
4-[2-{2-[4′-(4-Nitro-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (169 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-[2-{2-[4′-(4-Nitro-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid (125 mg, 75%).
LCMS: 662 (M+H)+.
4-[2-{2-[4′-(4-Nitro-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (169 mg, 0.25 mmol) was reduced according to general procedure K to give 4-[2-{2-[4′-(4-amino-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (112 mg, 69%).
LCMS: 646 (M+H)+.
4-[2-{2-[4′-(4-amino-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (65 mg, 0.1 mmol) was coupled with methanesulfonyl chloride (12 mg, 0.1 mmol) following general procedure L to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4-methanesulfonylamino-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (41 mg, 57%).
LCMS: 724 (M+H)+.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4-methanesulfonylamino-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (36 mg, 0.05 mmol) was hydrolyzed according to General Procedure F to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4-methanesulfonylamino-phenoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (20 mg, 64%).
LCMS: 710 (M+H)+
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-(methanesulfonylamino)-phenyl boronic acid (215 mg, 1 mmol) following General Procedure B to give 4-2-[2-(3′-methanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (304 mg, 48%)
LCMS: 632 (M+H)+.
4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (158 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(3′-methane-sulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (109 mg, 70%)
LCMS: 618 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 3.38 (s, 3H), 5.64 (s, 2H), 7.21 (d, 1H), 7.33-7.42 (m, 4H), 7.43-7.52 (m, 4H), 7.56-7.75 (m, 4H). 7.77 (d, 1H, 7.92 (d, 1H), 8.11 (s, 1H), 8.27 (d, 1H), 9.85 (s. 1H), 13.02 (s, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-(methanesulfonylamino)-phenyl boronic acid (215 mg, 1 mmol) following General Procedure B to give 4-2-[2-(4′-methanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (308 mg, 48%)
LCMS: 632 (M+H)+
4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid methyl ester (158 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-methanesulfonylamino-biphenyl-4-yl)-(E)-vinyl]-imidazol-1-ylmethyl}-benzoic acid (101 mg, 66%)
LCMS: 618 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.47 (s, 3H), 5.64 (s, 2H), 6.70 (d, 2H), 7.01 (d, 2H), 7.28-7.30 (m, 2H), 7.35-7.37 (m, 2H), 7.51-7.59 (m, 2H), 7.65-7.72 (m, 2H), 7.74 (d, 1H), 7.93 (s, 1H). 8.11 (s, 1H), 8.27 (d, 1H), 9.18 (s, 1H). 9.37 (s, 1H), 13.01 (s, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 3-(methoxycarbonyl)-phenyl boronic acid (179 mg, 1 mmol) following General Procedure B to give 4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-methoxycarbonyl-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-carboxylic acid methyl ester (289 mg, 48%)
LCMS: 597 (M+H)+.
4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-methoxycarbonyl-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-carboxylic acid methyl ester (149 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-methoxycarbonyl-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-3-carboxylic acid (99 mg, 69%)
LCMS: 569 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 5.70 (s, 2H), 7.39-7.45 (m, 4H), 7.54 (d, 1H), 7.61 (d, 1H), 7.70-7.74 (m, 4H), 7.76 (d, 1H), 7.79-7.96 (m, 4H), 7.98 (s, 1H), 8.17 (d, 1H), 8.22 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 4-hydroxy-phenyl boronic acid (137 mg, 1 mmol) following General Procedure B and obtained 4-2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-{4-(2,4-dichloro-phenyl)-imidazol-1yl-methyl}benzoic acid methyl ester (277 mg, 0.5 mmol) was alkylated with 1-bromo-4,4,4-trifluorobutane following general procedure E to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4,4,4-trifluoro-butoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (214 mg, 64%).
LCMS: 665 (M+H)+.
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4,4,4-trifluoro-butoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (166 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4′-(4,4,4-trifluoro-butoxy)-biphenyl-4-yl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (106 mg, 65%)
LCMS: 651 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 1.41-1.44 (m, 2H), 1.66-1.71 (m, 2H), 2.41-2.47 (m, 2H), 5.66 (s, 2H), 7.12 (d, 1H), 7.19 (s, 1H), 7.33-7.37 (m, 4H), 7.51-7.55 (m, 4H), 7.56-7.62 (m, 4H), 7.65 (d, 1H), 7.91 (d, 1H), 8.11 (s, 1H), 8.29 (d, 1H) ppm.
Trans-4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-imidazol-1yl-methyl]-benzoic acid methyl ester (542 mg, 1 mmol) was coupled with 2-methoxy-5-pyridine boronic acid (153 mg, 1 mmol) following General Procedure B to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(6-methoxy-pyridin-3-yl)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (289 mg, 50%)
LCMS: 570 (M+H)+
4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(6-methoxy-pyridin-3-yl)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid methyl ester (143 mg, 0.25 mmol) was hydrolyzed according to General Procedure F to give 4-(4-(2,4-Dichloro-phenyl)-2-{2-[4-(6-methoxy-pyridin-3-yl)-phenyl]-(E)-vinyl}-imidazol-1-ylmethyl)-benzoic acid (95 mg, 68%)
LCMS: 556 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.79 (s, 3H), 5.68 (s, 2H), 7.01 (d, 1H), 7.26 (s, 1H), 7.36-7.40 (m, 3H), 7.51-7.56 (m, 3H), 7.58-7.64 (m, 4H), 7.67 (d, 1H), 7.92 (d, 1H), 8.11 (s, 1H), 8.27 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with 4-(trifluoromethoxy)-benzyl bromide (255 mg, 1 mmol) following general procedure E. The resulted 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazole (284 mg, 0.5 mmol) was coupled with 4-butoxy-phenyl boronic acid (98 mg, 0.5 mmol) following General Procedure B to give 2-[2-(4′-Butoxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazole (155 mg, 48%).
LCMS: 637 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.92 (t, 3H), 1.43-1.47 (m, 2H), 1.69-1.72 (m, 2H), 4.02 (q, 1H), 5.59 (s, 2H), 7.02 (d, 2H), 7.34 (s, 1H), 7.39-7.42 (m, 4H), 7.50 (d, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.55-7.65 (m, 4H), 7.72 (d, 2H), 8.10 (s, 1H), 8.26 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with 4-(trifluoromethoxy)-benzyl bromide (255 mg, 1 mmol) following general procedure E. The resulted 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazole (284 mg, 0.5 mmol) was coupled with 4-hydroxy-phenyl boronic acid (69 mg, 0.5 mmol) following General Procedure B and obtained 2-[2-(4′-hydroxy-biphenyl-4-yl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazole (145 mg, 0.25 mol) was alkylated with 4-bromobutyric acid methyl ester (45 mg, 0.25 mmol) following general procedure E to give 4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (115 mg, 67%).
LCMS: 681 (M+H)+
4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid methyl ester (69 mg, 0.1 mmol) was hydrolyzed according to General Procedure F to give 4-(4′-{2-[4-(2,4-Dichloro-phenyl)-1-(4-trifluoromethoxy-benzyl)-1H-imidazol-2-yl]-(E)-vinyl}-biphenyl-4-yloxy)-butyric acid (46 mg, 68%)
LCMS: 667 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 1.97 (m, 2H), 2.38 (m, 2H), 4.03 (m, 2H), 5.61 (s, 2H), 7.01 (d, 2H), 7.35 (d, 1H), 7.40-7.44 (m, 4H), 7.52 (d, 1H), 7.60-7.67 (m, 6H), 7.74 (d, 2H), 8.14 (s, 1H), 8.23 (d, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with 4-(methanesulfonyl)-benzyl bromide (249 mg, 1 mmol) following general procedure E. The resulted 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-methanesulfonyl-benzyl)-1H-imidazole (281 mg, 0.5 mmol) was coupled with 3-(trifluoromethyl)-phenyl boronic acid (95 mg, 0.5 mmol) following General Procedure B to give 4-(2,4-Dichloro-phenyl)-1-(4-methanesulfonyl-benzyl)-2-[2-(3′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (155 mg, 49%).
LCMS: 627 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.35 (s, 3H), 5.71 (s, 2H), 7.41 (s, 1H), 7.45 (s, 1H), 7.51-7.77 (m, 6H), 7.79-7.93 (m, 4H), 7.95-8.12 (m, 4H), 8.28 (d, 1H), 8.39 (s, 1H) ppm.
Trans 4-bromo cinnamic acid (227 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-[2-(4-bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)}-1H-imidazole (412 mg, 1 mmol) was N-alkylated with 4-(methanesulfonyl)-benzyl bromide (249 mg, 1 mmol) following general procedure E. The resulted 2-[2-(4-Bromo-phenyl)-(E)-vinyl]-4-(2,4-dichloro-phenyl)-1-(4-methanesulfonyl-benzyl)-1H-imidazole (281 mg, 0.5 mmol) was coupled with 3-(methanesulfonyl)-phenyl boronic acid (100 mg, 0.5 mmol) following General Procedure B to give 4-(2,4-Dichloro-phenyl)-1-(4-methanesulfonyl-benzyl)-2-[2-(3′-methanesulfonyl-biphenyl-4-yl)-(E)-vinyl]-1H-imidazole (165 mg, 52%).
LCMS: 637 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.31 (s, 3H), 3.34 (s, 3H), 5.71 (s, 2H), 7.41 (s, 1H), 7.46 (s, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.53 (s, 1H), 7.65-7.81 (m, 4H), 7.83-7.85 (m, 4H), 7.93 (d, 1H), 7.95 (s, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.28 (d, 1H) ppm.
4-Hydroxy-4-biphenyl carboxylic acid (214 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 4′-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-biphenyl-4-ol (381 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E to give 4-[4-(2,4-Dichloro-phenyl)-2-(4′-hydroxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (312 mg, 59%).
LCMS: 529 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-hydroxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (264 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[4-(2,4-Dichloro-phenyl)-2-(4′-hydroxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid (186 mg, 72%).
LCMS: 515 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 5.54 (s, 2H), 6.81-6.86 (m, 5H), 7.23 (d, 1H), 7.41-7.57 (m, 5H), 7.74 (d, 1H), 7.89 (d, 1H), 7.94 (d, 1H), 8.11 (s, 1H), 8.27 (d, 1H) ppm.
4-Hydroxy-4-biphenyl carboxylic acid (214 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 4′-[4-(2,4-Dichloro-phenyl)-1H-imidazol-2-yl]-biphenyl-4-ol (381 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[4-(2,4-Dichloro-phenyl)-2-(4′-hydroxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (265 mg, 0.5 mmol) was alkylated with bromo ethane (55 mg, 0.5 mmol) following general procedure E to give 4-[4-(2,4-Dichloro-phenyl)-2-(4′-ethoxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (191 mg, 68%).
LCMS: 557 (M+H)+.
4-[4-(2,4-Dichloro-phenyl)-2-(4′-ethoxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (278 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[4-(2,4-Dichloro-phenyl)-2-(4′-ethoxy-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid (189 mg, 69%).
LCMS: 543 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.94 (t, 3H), 4.07 (q, 2H), 5.56 (s, 2H), 6.83-6.88 (m, 4H), 7.21 (d, 1H), 7.43-7.58 (m, 4H), 7.65-7.69 (m, 2H), 7.71 (d, 1H), 7.90 (d, 1H), 7.94 (d, 1H), 8.12 (s, 1H), 8.28 (d, 1H) ppm.
4-Bromo benzoic acid (201 mg, 1 mmol) was reacted with 2-bromo-2,4-dichloro acetophenone (267 mg, 1 mmol) according to general procedure A and obtained 2-(4-bromo-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (368 mg, 1 mmol) was N-alkylated with methyl-4-(bromomethyl)benzoate (229 mg, 1 mmol) following general procedure E. The resulted 4-[2-(4-Bromo-phenyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-benzoic acid methylester (516 mg, 1 mmol) was coupled with 3-(methanesulfonyl)-phenyl boronic acid (200 mg, 1 mmol) following General Procedure B to give 4-[4-(2,4-Dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (324 mg, 55%).
LCMS: 591 (M+H)+
4-[4-(2,4-Dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid methyl ester (295 mg, 0.5 mmol) was hydrolyzed according to General Procedure F to give 4-[4-(2,4-Dichloro-phenyl)-2-(3′-methanesulfonyl-biphenyl-4-yl)-imidazol-1-ylmethyl]-benzoic acid (201 mg, 69%).
LCMS: 577 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 3.31 (s, 3H), 5.64 (s, 2H), 7.25-7.33 (m, 4H), 7.60 (d, 1H), 7.76 (s, 1H), 7.82 (d, 1H), 7.84 (d, 1H), 7.90-7.96 (m, 4H), 8.10 (d, 1H), 8.18 (d, 1H), 8.23 (s, 1H), 8.30 (s, 1H) ppm.
4-{4-(2,4-dichloro-phenyl)-2-[2-(4′-trifluoromethyl-biphenyl-4-yl)-(E)-vinyl]-imidazol-1yl-methyl}benzoic acid (148 mg, 0.25 mmol) was reduced according to General Procedure V to give 4-{4-(2,4-Dichloro-phenyl)-2-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethyl]-imidazol-1-ylmethyl}-benzoic acid (79 mg, 53%).
LCMS: 595 (M+H)+ 1H NMR (DMSO, 400 MHz): δ 2.92-2.94 (m, 2H), 2.98-3.0 (m, 2H), 5.64 (d, 2H), 7.20 (d, 1H), 7.31-7.38 (m, 2H), 7.42-7.52 (m, 2H), 7.58-7.65 (m, 2H), 7.75-7.79 (m, 2H), 7.80-7.95 (m, 4H), 8.11 (s, 1H), 8.22 (d, 1H), 8.30 (d, 1H) ppm.
The following assay methods are utilized to identify compounds of formula I which are effective in inhibiting the activity of certain phosphatases, an example of which, as used herein, is PTP1B.
The assay for PTP1B inhibition is based on the detection of the complex between Malachite Green dye and free phosphate, liberated from the phosphopeptide substrate by PTPase action. To each well of a flat-bottom assay plate is added 45 μL assay buffer [-50 mM Imidazole, pH 7.2, 100 mM NaCl, 5 mM DTT, and 1 mM EDTA] and 10 μL of peptide substrate [Tyrosine Phosphopeptide-1, 80 μM FAC, Promega Cat #V256A] to a total volume of 55 μL. Test compound (10 μL in up to 50% DMSO) is then added. The mixture is incubated for 5 min, at 25° C., and 10 μL of PTP-1B [Protein Tyrosine Phosphatase 1B (PTP-1B); FAC 0.8 nM; Upstate Biotechnology, Cat #14-109 lot #19045] is then added. The mixture is incubated for 30 min at 25° C. Subsequently, 25 μL of Malachite Green reagent [10% (w/v) Ammonium Molybdate in water, Sigma Cat #A-7302, 0.2% (w/v) Malachite Green in 4 N HCl, Aldrich Cat #21, 302-0] is then added. After incubation for 15 min at 27° C., the reaction endpoint is measured at 640 nM.
The Malachite Green reagent is prepared by mixing one volume of 10% Ammonium Molybdate with 3 volumes of 0.2% Malachite Green solution, stirring at room temperature for 30 min and then filtering and collecting the filtrate. The Malachite Green reagent is treated with 10 μL of 5% Tween 20 per 990 μL of dye solution before use.
Test compounds are typically examined at six concentrations in the above assay. For this assay, the IC50 (microM) of the enzyme inhibition assay represents the concentration of compound at which 50% signal has been inhibited.
As illustrated by the Examples, embodiments of the present invention demonstrate utility in inhibiting protein tyrosine phosphatase PTP 1B. The compounds of the present invention set forth in the present examples are found to inhibit protein tyrosine phosphatase PTP1B with inhibitory potencies (IC50's) of about 0.01 microM to about 20 microM. In general, embodiments of the present invention useful for pharmaceutical applications will have inhibitory potencies (IC50's) for a protein of interest of below about 100, or in an embodiment below about 50 microM. For particular applications, lower inhibitory potencies are useful, thus compounds that inhibit protein tyrosine phosphatase PTP1B with inhibitory potencies (IC50's) in a range of about 0.01 microM to about 10 microM may be useful. In another embodiment, compounds that inhibit protein tyrosine phosphatase PTP1B with inhibitory potencies (IC50's) of about 0.01 microM to about 3 microM may be useful.
Embodiments of the compounds of the present invention demonstrate utility as inhibitors of protein tyrosine phosphatases (PTPases). Embodiments of the invention described herein are additionally directed to pharmaceutical compositions and methods of inhibiting PTPase activity in a mammal, which methods comprise administering, to a mammal in need of inhibition of PTPase activity, a therapeutically defined amount of a compound of formula (I), defined above, as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer, a mixture of diastereoisomers, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug, a biohydrolyzable ester, or a biohydrolyzable amide thereof.
Thus, the present invention provides a method of inhibiting a PTPase, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit a PTPase. A PTPase-inhibiting amount can be an amount that reduces or inhibits a PTPase activity in the subject.
Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat type I diabetes.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat type II diabetes.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat immune dysfunction.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat AIDS.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat autoimmune diseases
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat glucose intolerance.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat obesity.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat cancer.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat psoriasis.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat allergic diseases
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat infectious diseases.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat inflammatory diseases.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diseases involving the modulated synthesis of growth hormone.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diseases involving the modulated synthesis of growth factors or cytokines which affect the production of growth hormone.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat Alzheimer's disease.
The compounds of the present invention can be administered to subjects in need of inhibition of PTPase activity. Such subjects can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably humans.
The pharmaceutical compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example 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 monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the active compounds in an admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, poly-vinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or 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, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound 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.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.
For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles.
The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Also provided by the present invention are prodrugs of the invention. Pharmaceutically-acceptable salts of the compounds of the present invention, where a basic or acidic group is present in the structure, are also included within the scope of the invention. The term “pharmaceutically acceptable salts” refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. When an acidic substituent is present, such as —COOH, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate and the like, and include acids related to the pharmaceutically-acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p. 1-19.
Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the invention and these form a further aspect of the invention.
In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.
Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
The compounds of the present invention selectively act as inhibitors of one PTPase in preference to one or more other PTPases, and therefore may possess advantage in the treatment of one or more PTPase-mediated disease in preference to others.
Thus, in a further aspect, the present invention provides a method for the inhibition of PTPases. In an embodiment of this aspect, the present invention provides a method for treating a disease states including diabetes, cancer, inflammation, Alzheimer's disease, psoriasis, or graft versus host disease, which comprises administering to a subject in need thereof a compound of the present invention. In an embodiment, the amount of compound administered is a pharmacologically effective amount. In another embodiment, the compound administered is a therapeutically effective amount. In another embodiment, at least one compound of Formula (I) is utilized, either alone or in combination with one or more known therapeutic agents. In another embodiment, the present invention provides method of prevention and/or treatment of PTPase-mediated human diseases, treatment comprising alleviation of one or more symptoms resulting from that disorder, to an outright cure for that particular disorder or prevention of the onset of the disorder, the method comprising administration to a human in need thereof a therapeutically effective amount of a compound of the present invention of Formula (I).
In this method, factors which will influence what constitutes an effective amount will depend upon the size and weight of the subject, the biodegradability of the therapeutic agent, the activity of the therapeutic agent, as well as its bioavailability. As used herein, the phrase “a subject in need thereof” includes mammalian subjects, preferably humans, who either suffer from one or more of the aforesaid diseases or disease states or are at risk for such. Accordingly, in the context of the therapeutic method of the invention, this method also is comprised of a method for treating a mammalian subject prophylactically, or prior to the onset of diagnosis such disease(s) or disease state(s).
The following is a non-exhaustive listing of adjuvants and additional therapeutic agents which may be utilized in combination with the PTPase inhibitors of the present invention:
Pharmacologic Classifications of Anticancer Agents:
Pharmacologic Classifications of Treatment for Rheumatoid Arthritis (Inflammation)
Pharmacologic Classifications of Treatment for Diabetes Mellitus
Pharmacologic Classifications of Treatment for Alzheimer's Disease
Pharmacologic Classifications of Treatment for Hyperlipidemia
Generally speaking, the compound of the present invention or Formula (I), is administered at a dosage level of from about 0.003 to 500 mg/kg of the body weight of the subject being treated, a dosage range between 0.003 and 200 mg/kg, or a dosage range between 0.1 to 100 mg/kg of body weight per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1 mg to 2 grams of a compound of Formula (I) with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient. Also a dosage form intended for topical administration to the skin may be prepared at 0.1% to 99% compound to topical excipient ratio and a dosage form intended for inhaled administration of 0.01 to 200 mg of compound in a suitable carrier to deliver an inhaled dosage of compound. Dosage unit forms of systemically delivered compound will generally contain between from about 5 mg to about 500 mg of active ingredient. This dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level 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 and the severity of the particular disease undergoing therapy.
While the invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for PTPase-mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.
The present application is a continuation application of U.S. patent application Ser. No. 10/777,488, filed Feb. 12, 2004, which in turn claims the benefit of priority from U.S. Provisional Patent Application No. 60/446,977, filed Feb. 12, 2003. The disclosures of each of the aforementioned US patent applications is incorporated by reference into the present application as though each were fully set forth herein.
| Number | Date | Country | |
|---|---|---|---|
| 60446977 | Feb 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10777488 | Feb 2004 | US |
| Child | 12958237 | US |
