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WO2000033836A9 - 5-membered heterocycles for the treatment of human diseases involving modulators of selectins - Google Patents

5-membered heterocycles for the treatment of human diseases involving modulators of selectins

Info

Publication number
WO2000033836A9
WO2000033836A9 PCT/US1999/028692 US9928692W WO0033836A9 WO 2000033836 A9 WO2000033836 A9 WO 2000033836A9 US 9928692 W US9928692 W US 9928692W WO 0033836 A9 WO0033836 A9 WO 0033836A9
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
group
vinyl
imidazol
Prior art date
Application number
PCT/US1999/028692
Other languages
French (fr)
Other versions
WO2000033836A1 (en
Inventor
Deborah Helen Slee
Jei-Fei Cheng
Todd Kevin Jones
Adnan M M Mjalli
Truc Ngoc Nguyen
Raj Kumar Raheja
William Charles Ripka
Jinghua Yu
Original Assignee
Ontogen Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ontogen Corp filed Critical Ontogen Corp
Priority to AU20398/00A priority Critical patent/AU2039800A/en
Publication of WO2000033836A1 publication Critical patent/WO2000033836A1/en
Publication of WO2000033836A9 publication Critical patent/WO2000033836A9/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel selectin modulating compounds having the structural Formulas 1, 2. and 3, as. shown below, to methods of their preparation, to compositions comprising the compounds, to their use for treating human or animal disorders, to their use for purification of proteins, and to their use for in diagnostics.
  • These compounds are modulators of selectin (P-, E- and L-selectin) Ligand (e.g. Sialyl Lewis X (sLe )) interactions for the management, treatment, control, or as an adjunct of diseases in humans caused by selectins.
  • this invention relates to the administration of compounds according to Formulas 1, 2 and 3 which are selectin/ Ligand antagonists, for the management of diseases and disease states such as 1) acute respiratory distress syndrome (ARDS), 2) diseases that may be controlled via inhibition of angiogenesis, 3) asthma, 4) atherosclerosis, 5) atopic dermatitis, contact dermatitis, and cutaneous inflammation, 6) bowel inflammation, 7) diabetes/ diabetes-associated pathologies, 8) Grave's disease and associates conditions, 9) - multiple sclerosis (MS), 10) myocardial ischemia/ reperfusion injury, 11) organ transplantation, 12) psoriasis, 13) rheumatoid arthritis, 14) stroke and ischemic brain trauma, 15) trauma- induced organ injury, 16) thrombosis, 17) reduction of tumor metastasis and/ or tumor growth, and the like.
  • diseases and disease states such as 1) acute respiratory distress syndrome (ARDS), 2) diseases that may be controlled via inhibition of angiogenesis, 3) asthma,
  • the immune response relies on the ability of specialized immune cells— leukocytes and lymphocytes—to migrate to sites of tissue damage, infection, or other insult to the body. Once there, these cells mount a defense against the intruding organism, help to repair the injured tissue, and protect the body from further damage.
  • the immune system is also in constant "surveillance mode". Circulating lymphocytes monitor the body for pathogens by migrating through lymphoid tissues, where they can be exposed to antigens and become activated. In order for these processes to occur, various chemoattractants, cytokines, and cell adhesion molecules
  • CAMs act in a programmed, sequential manner to form what has been termed the leukocyte-endothelial cascade (Tedder et al, FASEB 9: 866 (1995), Albelda et al., FASEB 8: 1756, (1994)).
  • selectins Three known families of CAMs participate in this cascade: the selectins, the integrins and the immunoglobulin superfamily. The first step, rolling of leukocytes and lymphocytes along the blood vessel wall, is mediated by the selectins.
  • Selectins are a small family of transmembrane glycoproteins that bind to cell surface carbohydrate ligands (for reviews see: Lasky, Science 258: 964 (1992); McEver, Curr.
  • L-selectin binds to at least three different ligands: Glycam-1, CD34 and MAdCAM-1, each being expressed on different tissues.
  • P-selectin has been found to bind to PSGL- 1
  • E-selectin has been found to bind to ESL- 1.
  • These cell- surface selectin ligands are capped with clusters of oligosaccharides (for discussion see: Rosen et al, Curr. Opin. Cell Bi ⁇ l.
  • Selectin function can be modulated by altering cell- surface expression, by competitive inhibition, or by shedding/ cleavage from the cell surface (Diaz-Gonzalez, et al, J. Clin. Invest. 95: 1756 (1995); Whelan, Trends Biochem. Sci. 21 (1996)). While they have been identified as inhibitors of selectin-ligand interactions in vitro, compounds of Formulas 1 , 2 and 3 may reduce inflammation in vivo via any or all of these modes.
  • the compounds of the present invention which exhibit inhibitory activity against the selectins, are indicated in the treatment or management of the foregoing diseases (references supporting each indication are noted): 1) acute respiratory distress syndrome (ARDS) (Carraway et al, Am. J. Respir. Crit. Care Med. 157: 938 (1998); Moss et al, Crit. Care Med. 24: 1782 (1996) and others);
  • ARDS acute respiratory distress syndrome
  • Sialyl-Lewis x analogs/ mimetics reported in the literature include: 'GSC-150' (Kanebo) which has been reported to have IC50 values of 280 ⁇ M, 100 ⁇ M, and 30 ⁇ M against E-, P-, L-selectin respectively when assayed using an ELISA assay (Tsujishita et al, J. Med. Chem.
  • TBC-1269 (Texas Biotech) which has been reported to have IC50 values of 500 ⁇ M, 70 ⁇ M, and 560 ⁇ M against E-, P-, and L-selectin respectively, when assayed using a cell adhesion assay (Kogan et al, J. Med. Chem. 41: 1099 (1998)); a macrocyclic derivative, which has an IC50 of 390 ⁇ M against E-selectin (Kolb, Bioorg. Med. Chem. Lett. 7: 2629 (1997)); and C-mannose derivatives which have IC50 values of 100- 160 ⁇ M against E-selectin (Marron et al, Tet. Lett.
  • IP-6 inositol hexakisphosphate
  • sulfated galactocerebrosides sulfated galactocerebrosides
  • IP-6 has been reported to have IC50 values of 160 ⁇ M and 2 ⁇ M, against P- and L- selectin respectively, in competition ELISA assays (Cecconi et al., J. Biol Chem. 21: 15060 (1994)).
  • Sulfatides have IC50 values in the 0.1-12 ⁇ M range when tested in a P-selectin competition ELISA assay (Marinier et al, J. Med. Chem. 40: 3234 (1997)).
  • BMS- 190394 a sulfatide analog
  • IC50 values 18 ⁇ M and 10 ⁇ M
  • P-, and L-selectin cell adhesion assays respectively.
  • Mannose- containing natural products showed inhibition of P-selectin with an IC50 value of 60 ⁇ M (Ikeda et al, Bioorg. Med. Chem. Lett. 7: 2485 (1997)).
  • Non-carbohydrate inhibitors include peptides based on a conserved region of the lectin domain of the selectins, which have activity in P- and E-selectin cell adhesion assays with IC50 values of ⁇ 20 ⁇ M (Briggs et al, Glycobiology 5: 583 (1995)). Additional peptides, discovered by random screening, have IC50 values of 5-10 ⁇ M in an E-selectin cell adhesion assay (Martens et al, J. Biol Chem. 270: 21129 (1995)).
  • the present invention is based on the discovery that compounds of Formulas 1, 2 and 3 are inhibitors or modulators of selectins which render them particularly useful for the treatment or management of a large number of disease states in which the role of selectins has directly or indirectly been implicated.
  • the requisite selectin modulating activity can be obtained by employing a planar, rigid, five-membered ring template which acts as a scaffold, to which one can attach the necessary appendages that are required for activity.
  • the appendant groups that must be attached to the central template are 1) a carboxylic acid moiety as defined in Group I, or carboxylic acid isostere; or other calcium binding moiety which will be apparent to those skilled in the art; and 2) a hydrophobic moiety such as a C12H25 alkyl chain. Additional substitution about the central core is necessary to modify the potency, selectivity and physiological properties, of the compounds claimed herein.
  • the compounds of the present invention include any derivative with a rigid core when substituted with a carboxylic acid moiety as defined in Group I or a carboxylic acid isostere; or other calcium binding moiety which will be apparent to those skilled in the art, and a hydrophobic moiety as defined herein.
  • an object of the present invention is to provide a method for inhibiting or modulating selectins in a mammal by the administration of compound according to Formulas 1, 2 and 3.
  • Another object of the present invention relates to pharmaceutical compositions containing an effective inhibiting amount of compound according to Formulas 1, 2 and 3.
  • halogen or halo include fluorine, chlorine, bromine, and iodine.
  • alkyl includes C1-C16 straight chain saturated, C1-C16 branched saturated, C3-C8 cyclic saturated and Ci-Ci ⁇ straight chain or branched saturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr), isobutyl (i-Bu), tert- butyl (t-Bu), sec- butyl (s-Bu), isopentyl, neopenryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like.
  • alkenyl includes C2-C16 straight chain unsaturated, C2-C11 branched unsaturated, Cs-Cs unsaturated cyclic, and C2-C16 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Double bonds may occur in any stable point along the chain and the carbon- carbon double bonds may have either the cis or trans configuration.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl- 3-cyclohexenyl, and the like.
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkylthio (e.g. methylthio, ethylthio, propylthio, cyclohexylthio and the like) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
  • alkylamino represents one or two alkyl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci-Ci ⁇ alkyl, arylCo-Ci6alkyl, or Co-Ci6alkylaryl substituent. .
  • alkylamino alkyl represents an alkylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkyloxy (alkyl) amino e.g. methoxy (methyl) amine, ethoxy (propyl) amine
  • alkyloxy group as defined above attached through an amino group, the amino group itself having an alkyl substituent.
  • alkylcarbonyl e.g. cyclooctylcarbonyl, pentylcarbonyl, 3-hexylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen.
  • alkylcarboxyalkyl represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylamino e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl
  • alkylcarbonylamino represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.
  • the nitrogen group may itself be substituted with an alkyl or aryl group.
  • aryl represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g. 3-indolyl, 4-imidazolyl).
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, Ci-iealkyl, arylCi-i ⁇ alkyl, Co-i ⁇ alkyloxyCo- lealkyl, arylCo-i6alkyloxyCo-i6alkyl, Co-i ⁇ alkylthioCo-i ⁇ alkyl, arylCo-iealkylthioCo-i ⁇ alkyl, Co-i6alkylaminoCo-i6alkyl, arylCo- i6alkylaminoCo-i6alkyl, difaryld-iealkylJaminoCo-iealkyl, Ci- i6alkylcarbonylCo-i6alkyl, arylC ⁇ -i6alkylcarbonylCo-i6alkyl, Ci- l ⁇ alkylcarboxyCo-i ⁇ alkyl, arylCi-i ⁇ al
  • aryl includes but is not limited to phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl,
  • arylalkyl e.g. (4-hydroxyphenyl) ethyl, (2- aminonaphthyl)hexyl, pyridylcyclopentyl
  • carbonyloxy represents a carbonyl group attached through an oxygen bridge.
  • alkyl and “alkenyl” maybe used interchangeably in so far as a stable chemical entity is formed, as obvious to those skilled in the art.
  • the compounds of the present invention also includes racemic mixtures, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds (Goding; Monoclonal Antibodies Principles and Practice; Academic Press, p.104 (1986)).
  • Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral chromatography (Eliel, E. L. and Wilen S.H.; Stereochemistry in Organic Compounds; John Wiley & Sons, New York, (1993)).
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • an object of the present invention is to provide a method for inhibiting or modulating selectins in a mammal by the administration of a compound according to the general Formulas 1, 2 and 3 as defined below.
  • this application relates to the preparation of said compounds, to compositions comprising the compounds, to their use for treating human or animal disorders, to their use for purification of proteins, and to their use in diagnostics or medical devices.
  • the present invention relates to compounds having General Formula 1, General Formula 2, and General Formula 3 wherein at least one and no more than two of R 1 , R 2 , R 3 or R 4 must be selected from Group I.
  • the following substitution patterns are possible for the remaining R groups:
  • Case B When two of R 1 , R 2 , R 3 , R 4 ,or *R 5 (*in General Formula 3) are selected from Group I (templates 1-6), one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group II, and one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined below; Case C: When one of R 1 , R 2 , R 3 , R 4 , or *R 5 (*in General Formula 3) are selected from Group I (templates 1-6), one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group II, and one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where
  • Formula 3 is selected from Group I (template 7), one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group V, and one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group VI.
  • the remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined below;
  • Case D When two of R 1 , R 2 , R 3 , R 4 , or *R 5 (*in General Formula 3) are selected from Group I (template 7), one of R 1 , R 2 , R 3 , R 4 or *R 5 must be selected from Group V.
  • the remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, V, and VI are defined below; Definitions of Group I through Group IV
  • Group I is defined in Figure 1 , Table 1 , below:
  • Group II is defined as one of the following:
  • R 11 is C 8 -i6 alkyl,, or C3-8 alkylaiyl, in which the said aryl group such as phenyl, thienyl, imidazoyl, indolyl, furyl or pyridyl, is mono- or disubstituted with a member selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, C ⁇ -6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or Ci- 4 alkyloxy; or (ii) substituted or unsubstituted Cs-i6 alkyl or substituted
  • Group IV is defined as either: (i)hydrogen; or (ii) substituted or unsubstituted Ci-i ⁇ alkyl or C 2 -i2 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Ci- ⁇ alkyloxy, Ci- ⁇ alkylthio, C ⁇ -6 alkylamino, phenyl-Ci- ⁇ alkylamino, C ⁇ -6 alkoxycarbonyl; or (iv) mono, di or tri-substituted aryl C0-4 alkyl or substituted C0-4 alkyl aryl, wherein the aryl group is selected from phenyl, imidazolyl, indolyl, furyl, thienyl or pyridyl in which the substituents are selected from: (a)hydrogen; or (b) hydroxy or halo
  • Group V is defined as one of the following:
  • R 11 is hydrogen, Ci-i ⁇ alkyl, or Ci-i ⁇ alkyl aryl, in which the said aryl groups such as phenyl, or pyridyl, or alkyl groups are mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Ci- ⁇ alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, Ci- 4 alkyloxy, and aryl.
  • the present invention related to compounds of the general formula A.
  • Example 75 Example 76
  • Example 1 3- 4-(2-(4-Diethylamino-phenvH-5- ⁇ 4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -l.H r -imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 190
  • Example 2 3-r4-(2-(4-Diethylamino-phenyl)-5- ⁇ 4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyll-phenyl ⁇ -lJ f-imidazol-4-yl)-phenyl - 4,5-dihydro-isoxazole-5-carboxylic acid 191
  • Example 3 3-r4-(2-(4-Diethylamino-phenyl)-5- ⁇ 4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyll-phenyl ⁇ -lJ f-imidazol-4-yl)-phenyl - 4,5-dihydro-isoxazole-5-carboxylic acid 191
  • Example 3 3-r4-(2-(4-Diethylamino-phenyl)-5- ⁇ 4-r(E)-2-(3-phenyl- propylcarbam
  • Example 7 3- ⁇ 4-r5-f4-((E)-2-Dodecylcarbamoyl-vinyl)- ⁇ henyl]-2-(2- hydroxy-phenyl)-lH-imidazol-4-yl]-phenyl ⁇ -4,5-dihydro- isoxazole-5-carboxylic acid 196
  • Example 8 3-f4- ⁇ 5-r4-ffE)-2-Dodecylcarbamoyl-vinyl)- ⁇ henvn-lH- imidazol-4-yl)-phenyl)-4,5-dihvdro-isoxazole-5-carboxylic acid 197
  • Example 9 Example 9
  • Example 14 3- ⁇ 4-r2-(4-Diethylamino-phenyl)-5-(4- ⁇ (E)-2-r2-(lH-indol-3-y»- ethylcarbamoyn-vinyl)-phenyl)-lJFf-imidazol-4-yll-phenyl ⁇ - 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 203
  • Example 15 3- ⁇ 4-r2-(4-Diethylamino-phenvH-5-(4- ⁇ (E)-2-r2-(lH-indol-3-yl)- ethylcarbamoyl1-vinyl ⁇ -phenyl)-lH-imidazol-4-yl1-phenyl ⁇ - 4,5-dihydro-isoxazole-5-carboxylic acid 204
  • Example 16 3- ⁇ 4-r2-(4-Diethylamino-phenyl)-5-
  • Example 25 (4- ⁇ 5- ⁇ 4-f(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl ⁇ - 2-f4-((E)-2-ethoxycarbonyl-vinyl)-phenyl1-lff-imidazol-4-yl ⁇ - phenoxy)-acetic acid tert-butyl ester 214
  • Example 26 (4- ⁇ 5- ⁇ 4-f(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl ⁇ - 2-f4-((E)-2-ethoxycarbonyl-vinyl)-phenyl1-lff-imidazol-4-yl ⁇ - phenoxy)-acetic acid tert-butyl ester 214
  • Example 26 (4- ⁇ 5- ⁇ 4-f(E)-2-(3,3-Diphenyl-propylcarbamoyl)
  • Example 27 (4- ⁇ 5- ⁇ 4-f(E)-2-(3H-Benzotriazol-5-ylcarbamoyl)-vinyn- phenyl ⁇ -2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lff- imidazol-4-yl ⁇ -phenoxy)-acetic acid 216
  • Example 28 ⁇ 4-r2-r4-((E)-2-Ethoxycarbonyl-vinyl -phenvn-5-(4- ⁇ (E)-2-ri-(4- pentyl-phenyl)-ethylcarbamoyl1-vinyl ⁇ -phenyl)-lH-imidazol- 4-yl]-phenoxy ⁇ -acetic acid 217
  • Example 29 r4-(2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenvn-5- ⁇ 4-»E)-2-(2- methoxy-eth
  • Example 39 3-(4- ⁇ 5-(4-Carboxymethoxy- ⁇ henyl)-4-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1-l-methyl-lH-imidazol-2- yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228
  • Example 40 3-(4- ⁇ 5-(4-Carboxymethoxy- ⁇ henyl)-4-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1-l-methyl-lH-imidazol-2- yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228
  • Example 40 3-(4- ⁇ 5-(4-Carboxymethoxy- ⁇ henyl)-4-r4-((E)-2- dodecylcarbamoyl-vin
  • Example 45 ⁇ 4-(4-Carboxymethoxy-phenyl)-5-
  • Example 46 ⁇ 4-(4-Carboxymethoxy-phenyl)-5-
  • Example 46 ⁇ 4-(4-Carboxymethoxy-phenyl)-5-
  • Example 47 3-(4- ⁇ 4-(4-Carboxymethoxy- ⁇ henyl)-5-f4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1
  • Example 48 (4- ⁇ 5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2-pyridin-3- yl-lH-imidazol-4-yl ⁇ -phenoxy)-acetic acid tert-butyl ester 237
  • Example 49 4- ⁇ 5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2-pyridin-3- yl-lH-imidazol-4-yl ⁇ -phenoxy)-acetic acid tert-butyl este
  • Example 52 3- ⁇ 4-[5-f4-((E)-2-Dodecylcarbamoyl-vinyH- ⁇ henviy2-(4- pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]-phenyl ⁇ -4,5- dihydro-isoxazole-5-carboxylic acid 241
  • Example 53 3- ⁇ 4-[5-f4-((E)-2-Dodecylcarbamoyl-vinyH- ⁇ henviy2-(4- pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]-phenyl ⁇ -4,5- dihydro-isoxazole-5-carboxylic acid 241
  • Example 53 3- ⁇ 4-[5-f4-((E)-2-Dodecylcarbamoyl-vinyH- ⁇ henviy2-(4- pyrrolidin-l-yl-phenyl)-
  • Example 54 (4- ⁇ 2-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-((E)-2- dodecylcarbamoyl-vinyli-phenyl
  • Example 60 3- ⁇ 4-f5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2- (2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yll-phenyl ⁇ - acrylic acid 248
  • Example 61 3- ⁇ 4-f5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2- (2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yll-phenyl ⁇ - acrylic acid 248
  • Example 61 3- ⁇ 4-f5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2- (2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yll-phenyl ⁇ - acrylic acid 248
  • Example 61 3- ⁇ 4-f5-r4-((E)-2
  • Example 66 (E)-3-(4- ⁇ 2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-f4- (2-hexadecylcarbamoyl-vinyl)-phenyl -li-f-imidazol-4-yl ⁇ - phenyl)-acrylic acid tert-butyl ester 254
  • Example 67 (E)-3-(4- ⁇ 2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-f4- (2-hexadecylcarbamoyl-vinyl)-phenyl -li-f-imidazol-4-yl ⁇ - phenyl)-acrylic acid tert-butyl ester 254
  • Example 67 (E)-3-(4- ⁇ 2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-f4- (2-
  • Example 68 (E)-3-(4- ⁇ 2-f4-((E)-2-Carboxy-vinyl)-phenyn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenylj-l.ff-imidazol-4-yI ⁇ - phenyl)-acrylic acid 256
  • Example 69 3-(4- ⁇ 4-r4-((E)-2-Carboxy-vinvH-phenvn-5-r4-(2- dodecylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 257
  • Example 70 (E)-3-(4- ⁇ 2-f4-((E)-2-Carboxy-vinyl)-phenyn-5-r4-(2- hexadecylcarbamoyl-vinyl)-
  • Example 75 3.f4-(4-f4-((E)-2-Carboxy-vinyl)-phenyn-5- ⁇ 4-[2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-2-yl)- phenyl -4,5-dihydro-isoxazole-5-carboxylic acid 263
  • Example 76 3-(4- ⁇ 4-j4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyll-5-f4- (2-dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 264
  • Example 77 3-(4- ⁇ 4-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-(2- dihexylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 265
  • Example 78 3-(4- ⁇ 4-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-(2- dihexylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 265
  • Example 78 3-(4- ⁇ 4-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-(2- dihexylcarbamoyl
  • Example 80 (E)-3-(4- ⁇ 5-f4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyn-lH- imidazol-4-yl ⁇ -phenyl)-acrylic acid tert-butyl ester 268
  • Example 80 (E)-3-(4- ⁇ 5-f4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyn-lH- imidazol-4-yl ⁇ -phenyl)-acrylic acid tert-butyl ester 268
  • Example 80 (E)-3-(4- ⁇ 5-f4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyn-lH- imidazol-4-yl ⁇ -phenyl)-acrylic acid tert-butyl ester 268
  • Example 80 (E)-3-(4- ⁇ 5-f4-((E)
  • Example 83 3-r3-(4- ⁇ 5-r4-(fE)-2-Hexadecylcarbamoyl-vinyl)-phenvn- lH-imidazol-4-yl ⁇ -phenyl)-allanoylamino]-propionic acid 270
  • Example 84 3-f4-(5-Benzylcarbamoyl-l-hexadecyl-4-phenyl-lH- imidazol-2-yl)-pheny ⁇ -4,5-dihydro-isoxazole-5- carboxylic acid 147
  • Example 85 3-r3-(4- ⁇ 5-r4-(fE)-2-Hexadecylcarbamoyl-vinyl)-phenvn- lH-imidazol-4-yl ⁇ -phenyl)-allanoylamino]-propionic acid 270
  • Example 84 3-f4-(5-Benzylcarbamoyl
  • the compounds of the current invention When the compounds of the current invention have asymmetric centers they may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure are also included within the scope of this invention.
  • an acidic substituent such as -CU 2 H, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form.
  • Basic groups such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
  • esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, acetoxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • Substituted pyrroles can also be made through intermediates generated via the Ugi reaction (Mjalli et al, Tetrahedron Lett, 37, ⁇ 2943 (1996)).
  • the thiophene and furan templates can also be synthesized using similar chemistry to that shown for the pyrroles (Schemes 1 and 2).
  • the thiophene template can be made via the reaction of 1 ,4-dicarbonyl compounds and a source of sulfur (1,4- dicarbonyl synthesis illustrated in Scheme 3). Lawesson's reagent has been reported as the reagent of choice to effect this transformation (Shridar et al, Synthesis, 1061 (1982)).
  • the furan template can also be made from the dehydration of 1 ,4 dicarbonyl compounds (the Paal- Knorr synthesis), usually using non-aqueous acidic conditions (Nowlin et al, J. Am. Chem. Soc, 72, p5754 (1950); Traylelis et al, J. Org. Chem., 29, pl23, (1964); Scott et al, Synthesis, p209 (1973)) (Scheme 3).
  • reaction sequence shown in Scheme 4 can be utilized to synthesize tri- or tetra- substituted imidazole derivatives 18.
  • Scheme 5 illustrates a general methodology for the synthesis of dione 24, from readily available starting materials, utilizing a Wittig reaction.
  • General derivatization of intermediate diones such as 24 can be achieved via a Heck reaction for example.
  • the Heck reaction can be used to attach an acrylamide side chain as a desired R group to give compounds such as cinnamic acid 25, or a cinnamic acid ester.
  • the resulting acid or esters can themselves be derivatized, an example being via condensation with an amine (after hydrolyses of the ester if esterified) to form an amide 27, as illustrated in Scheme 6.
  • TAA t ⁇ butyl (methyl or ethyl) acrylate
  • t ⁇ butyl (methyl or ethyl) acrylate 32 to afford the 4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 33.
  • the diethyl acetal- protecting group of 33 is then removed via acid hydrolyses to reveal the aldehyde 34.
  • the isoxazole 37 can be synthesized in a similar manner using the alkyne 35 in place of the alkene 32.
  • Schemes 9, 10 and 11 illustrate specific examples of the synthesis of imidazoles, as described in the current invention, using the general methods outlined in Schemes 5 and 6.
  • alkene 40 This alkene is oxidized with mCPBA to the epoxide 41.
  • the epoxide 41 is opened to give the diol 42, which is in turn oxidized to the dione 43.
  • the dione 43 can be functionalized via a Heck reaction with acrylic acid, to give the cinnamic acid derivative 44.
  • This acid 44 can the be condensed with an amine 45 to give the derivatized dione 46, which can then be used to make the imidazole 47.
  • Scheme 10 illustrates a dione synthesis which includes a step for the derivatization of the intermediate alkene 49 to give ultimately a phenoxy acetic acid dione 54 which has been used routinely for the synthesis of imidazole compounds described in the current invention.
  • Scheme 11 illustrates the use of dione 54 for imidazole synthesis.
  • the dione can be derivatized to the acrylamide 59 and then converted to imidazole 60.
  • the imidazoles 55 and 56 can be derivatized by direct attachment of an acrylamide 57 (that is made in situ from the appropriate amine and acroyl chloride) to give imidazoles 60 and 58 respectively.
  • Imidazole 60 can be converted to imidazole 58 by ester hydrolysis.
  • Scheme 12 illustrates the synthesis of the acrylamide 57.
  • Acroyl chloride is reacted with the appropriate amine 45 to give the acrylamide 57 quantitatively in most cases.
  • This acrylamide 57 can be derivatized by alkylation of the amide NH with iodomethane to give the acrylamide 61 if required.
  • These acrylamides 57 and 61 can then be used directly in the Heck reactions without purification.
  • Unsymmetrical diones can also be synthesized through a process which starts with a Sonogashira palladium coupling reaction between an aryl halide 62 and an alkyne 70 or TMS- alkyne 63 to give compounds 71 and 64 respectively.
  • Alkyne 71 can be oxidized directly to the dione 72 using ruthenium tetroxide, then utilized for imidazole synthesis to give imidazole 73.
  • Scheme 14 shows the conversion of 4-iodobenzoic acid 74 to the acylchloride 75.
  • This acylchloride 75 is reacted without purification with the tert-butyl ester of glycine 76, to give the amide 77.
  • Compound 77 is then coupled to 1- dodecyne 78 to give the alkyne 79.
  • This alkyne 79 is then oxidized to the dione 80 with ruthenium tetroxide.
  • Dione 80 can then be used for the synthesis of imidazole 81 which after treatment with TFA gives the imidazole 82.
  • Scheme 15 shows the synthesis of the imidazoles 94 and 95 which contain a diol moiety.
  • Scheme 16 shows the synthesis of the imidazoles 104 and 105 which contain a mannose moiety.
  • the intermediate dione 88 is also used in Scheme 17.
  • the intermediate dione 88 is used in a different way in Scheme 17 than in Scheme 16, with derivatization of the carboxylic acid moiety to a hydrophobic side chain, instead of a polar or hydrophilic side chain, to give dione 108.
  • This dione 108 can be further derivatized via a Heck reaction to dione 109.
  • Dione 109 can then be used to synthesize imidazoles 110 and 111.
  • diones of interest are represented by the bis- cinnamate 115.
  • This type of dione can be synthesized in a number of ways.
  • Schemes 18 and 19 represent two appraoches.
  • Scheme 18 shows how dione 115 can be synthesized via the condensation of the two aldehydes 112 and 113.
  • the unsymmetrical diol 114 can be isolated and oxidized to the dione 115.
  • This dione 115 can be converted in two steps to dione 117.
  • This dione can then be used to synthesize imidazoles 118 and 119.
  • Scheme 19 shows how bis-cinnamates can be synthesized via sequential Heck reactions to give dione 123 which can then be used to synthesized imidazoles 124 and 119.
  • Tetrasubstituted imidazoles 134 can be synthesized regiospecifically via the keto-bromide intermediate 130 as illustrated in Scheme 20.
  • the N-substituted imidazoles are also readily accessible via direct alkylation or acylation of the imidazole nitrogen as illustrated in Scheme 21.
  • Scheme 21 shows the direct alkylation of the imidazole 135 nitrogen with iodomethane, to give a separable mixture of N-alkylated imidazoles 136 and 137.
  • a Heck reaction installs an acrylamide to give imidazoles 138 and 140 which after removal of the tert-butyl esters gives imidazoles 139 and 141 respectively.
  • the Ugi reaction can also be employed to synthesize Ugi intermediates that can be cyclized to give tetra-substituted imidazoles (Zhang et al, Tetrahedron Lett. , 37, p751 (1996)).
  • Zhang et al, Tetrahedron Lett. , 37, p751 (1996) A specific example of the use of this approach is shown below in Scheme 22.
  • Imidazoles can be further derivatized.
  • the double bond of imidazole 148 can be converted to the cyclopropyl via treatment with Pd II and diazomethane as shown in Scheme 23.
  • Double bonds can also be reduced on the imidazole 118 or the dione 115 for example, to give the saturated alkyl chain, using Pd/C and hydrogen gas in ethyl acetate as illustrated in Scheme 24.
  • Tosylmethyl isocyanide has been used in the synthesis of all three 1,3-azole types (oxazoles, thiazoles and imidazoles) (van Leusen et al; Tetrahedron Lett, p2369 (1972); van Leusen et al, ibid p2373; van Leusen et al, Synthesis, p501
  • the oxazole template can be synthesized through a common ⁇ -halocarbonyl intermediate as illustrated in Scheme 27 (Gauthier et al, Bioorg. & Med. Chem., 6, 87-92, (1996); Harris et al J. Org. Chem, 27, 2705 (1962); Helv. Chim. Acta, 33, 1271, (1950); B. Hulin et al. J. Med. Chem. 39, 3897-3907, (1996)).
  • the oxazole template can also be made from amino acid derivatives (Wipf et al, Bioorg. Med. Chem. Lett., 5, 165- 177 (1997)).
  • the required starting materials for the forgoing synthetic schemes are either commercially available or accessible from readily available starting materials. For example aldehydes and ketones and can be synthesized as shown below (Scheme 28):
  • Scheme 29 shows a general methodology for the synthesis of the pyrazole template (S. Bourrain et al, Bioorg. Med. Chem., 6, 1731-1743 (1998)) and the isoxazole template (Wiley et al, Org. Synth., Coll Vol TV, p351, (1963); Brederick, Chem. Ber., 97, p3407 (1964)).
  • the isoxazole and isothiazole templates can also be synthesized via an alkyne intermediate (Scheme 30) (Reviews:
  • Mass spectra were measured using Atmospheric Pressure Chemical Formation (APcI) looking at positive and negative modes on a Micromass LCZ (3 KeV with a probe temperature of 400 °C and a source block at 120 °C).
  • API Atmospheric Pressure Chemical Formation
  • LC spectra for LC/MS were measured using an eluant of CHsCN (0.1% CF 3 C0 2 H)/H 2 0 (0.1% CF3CO2H) (V:V) on a Hewlett Packard HP 1100 HPLC, in the range 200-300 nm with a Diode Array Detector (DAD); 5 ⁇ l per injection (Gilson 215 Autosampler) at an average concentration of 1 mg/ml; gradient: 10-100% CH3CN in 5 minutes, 100% CH3CN for 1 minute, 100- 10% CH3CN in 0.2 minutes, 10% CH3CN for 1.4 minutes; LC element split 1 :4 directly into ion source (500 ⁇ l/min).
  • DAD Diode Array Detector
  • the oxime 30 (24.9 g, 112 mmol) was dissolved in THF (200 mL).
  • t-Butyl acrylate 32 (28.6 g, 223 mmol) was added and the reaction mixture cooled to 0 °C.
  • Bleach (5.25% sodium hypochlorite aq.) (400 mL) was added and the reaction mixture allowed to warm to room temperature.
  • the reaction was worked up via addition of ethyl acetate (200 mL), followed by washing with 10% Na 2 S 2 0 3 (50 mL) and brine (50 mL), dried (Na 2 S0 4 ) and concentration in vacuo.
  • the t-butyl acrylate was removed by co-evaporation with toluene (monitored by NMR) to give
  • the alkene 40 (9.4 g, 22 mmol) was dissolved in DCM (100 mL) and then mCPBA (5 g, 22 mmol, (purity 57-86%)) in DCM (100 mL) was added. The reaction was stirred at 40°C for 10 hours then treated with 10% sodium sulfite until testing with starch paper was negative. The reaction mixture was then extracted with DCM. The combined organic extracts were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The product was concentrated to dryness. The product was purified via flash chromatography eluting with hexane: ethyl acetate (8: 1 then 6: 1). The desired epoxide 41 was obtained as a pale yellow foam (8.9 g, 91% yield) .
  • the diol 42 (1 g, 2.16 mmol) was dissolved in dichloromethane (12 mL). To this mixture was added 0.7M NaBr (1.47 mL, 1.03 mmol), and TEMPO (4 mg, 0.025 mmol) and the reaction mixture cooled to 0 °C. A freshly prepared buffered bleach solution (270 mg, NaHC ⁇ 3 dissolved in 16 mL bleach (5.25% sodium hypochlorite aq.)) was added dropwise to the reaction mixture. The reaction mixture was then stirred for a further 15 min. before work up. The reaction was quenched with 10% Na 2 S 2 ⁇ 3 aq. (30 mL), and extracted with ethyl acetate (3 x 60 mL) . The combined organic layers were then washed with water (30 mL), brine (40 mL), and dried (MgS ⁇ 4) and concentrated in vacuo, to afford the dione 43 (841 mg, quantitative), as a pale yellow solid.
  • the reaction was stirred at R.T. for 16 hours. Upon completion, the reaction mixture was extracted with ethyl acetate (500 mL) and washed with water, 1 N NaOH, water, 10% citric acid, water and dried over anhydrous magnesium sulfate. The product was concentrated to dryness to obtain the derivatized alkene 51 as a white solid (15.8g, >99% crude yield) which was used without further purification in subsequent steps.
  • the benzoate ester 52 (5.3 g, 10.9 mmol) was dissolved in methanol (50 mL). The solution was cooled in an ice bath, and R2CO3 (6.5 g) followed by 5mL DI water were added. The reaction was stirred at 0 °C for 30 minutes. On completion, the product was extracted into ethyl acetate (200mL), wash with saturated NH4CI, water, brine, dried under MgS ⁇ 4 and concentrated in vacuo to give a brownish residue. The product was purified by column chromatography, eluting with 20% EtOAc in Hexane, to give the desired diol 53 (3.5 g, 88%) as a light yellow oil.
  • the diol 53 (3.5 g, 8.3 mmol) was dissolved in dichloromethane (40 mL). To this mixture was added 0.7M NaBr (7 mL, 1.0 mmol, 0.5 eq,), and TEMPO (16.5 mg, 0.11 mmol, 0.01 eq) and the reaction mixture cooled to 0 °C. A freshly prepared buffered bleach solution (1.2 g, NaHC ⁇ 3 dissolved in 70 mL bleach (5.25% sodium hypochlorite aq.)) was added dropwise to the reaction mixture. The reaction mixture was then stirred for a further 15 min. before work up. The reaction was quenched with 10% Na 2 S 2 ⁇ 3 aq.
  • the dione 24 (1 equiv.) was dissolved in DMF (to make 0.14M solution), followed by addition of Pd(OAc) 2 (0.02 equiv.), TEA (3 equiv.), (o-Tolyl)sP (0.09 equiv.), and acrylic acid (or acrylamide) (1.2 equiv.).
  • the reaction mixture was heated to 100 °C for 2 hours.
  • the reaction was then quenched via addition of water and extraction with methylene chloride.
  • the combined organic layers were washed with IN HCI (aq.), water, dried (Na 2 S ⁇ 4), and concentrated in vacuo, to give the desired derivatized dione 25 (90% crude yield). This dione was used for subsequent reactions without further purification.
  • General Method 6 Coupling of amine 26 to dione acid 25 to give amide 27 (Scheme 6)
  • the dione 25 (1.0 equiv.) was suspended in CHCI3 (to make 0.55M solution).
  • EDCI 1.3 equiv.
  • HOBt 1.3 equiv.
  • TEA 2.0 equiv.
  • the amine 26 (1.2 equiv.) was then added and the reaction stirred overnight at room temperature.
  • the reaction was then worked up via addition of water and extraction with methylene chloride.
  • the combined organic layers were washed with IN HCI (aq.), water, dried (MgS0 4 ), and concentrated in vacuo.
  • the product was then purified via flash chromatography.
  • the Br imidazole 55 or 56 (1 equiv.) was dissolved in DMF (0.5-1.OM), followed by addition of Pd(OAc) 2 (0.2 equiv.), TEA (2 equiv.), (o-Tolyl)3P (0.4 equiv.), and an acrylamide 57 (1.2 equiv.).
  • the reaction mixture was heated to 100 °C for 1-2 hours.
  • Acrylamides 57 were prepared by adding acryloyl chloride (1 equiv.) to a cooled solution (0 °C) of the desired amine 45 (1.0 equiv.) in dichloromethane (0.5M) with triethylamine (1.0 equiv.) as base. These acrylamides were used directly, without purification in the Heck reaction (Scheme 11 for example).
  • Methyl 4-formylcinnamate 113 (5 g, 0.026 moles) and t- butyl 4-formylcinnamate 112 (3 g, 0.013 moles) were dissolved in dry THF (70 mL). Pyridine (6 mL) was then added followed by TiCl 3 (1.0 M in DCM/THF, 95 mL, 0.091moles). The reaction was allowed to stir for 1 hour at ambient then 18 hours at -20 °C. Additional TiCl 3 (1.0 M in DCM/THF, 20 mL) was added and the reaction stirred at ambient temperature for a further 5 hours. The reaction was then concentrated in vacuo by to remove approximately 60% of the solvent, then quenched via addition of sat.
  • the diol 114 (1.5 g, 3.21 mmoles) was dissolved in dichloromethane (10 mL). To this mixture was added 0.7 M NaBr (2.18 mL, 1.53 mmoles), TEMPO (5.9 mg, 0.037 mmoles) and the reaction mixture cooled to 0 °C. A freshly prepared buffer bleach solution (401 mg, NaHC ⁇ 3 dissoved in 24 mL bleach (5.25% sodium hydrochlorite aq.) was added dropwise to the reaction mixture was then srirred for futher 15 min. before work up. The reaction was quenched with 10% Na 2 S 2 ⁇ 3 aq.
  • Imidazole 191 was synthesized according to General Method 10 via hydrolyses of the methyl ester of imidazole 190 (Example 1), according to General Method 10 from imidazole 191 (methyl ester) (0.16 g, 0.23 mmol), IN LiOH (3.5 mL, 3.5 mmol), and 1,4-Dioxane (3.5 mL).
  • Compound 192 was synthesized according to General Method 7 from dione 46a (0.5 g, 0.88 mmol) in acetic acid (1 mL), with 2,4,6- trimethylbenzaldehyde (0.26 g, 1.76 mmol) and NH4OAC (2.0 g, 26.4 mmol), which gives 3- ⁇ 4-[5- ⁇ 4-[(E)-2-(3- Phenyl-propylcarbamoyl)-vinyl]-phenyl ⁇ -2-(2,4, 6-trimethyl- phenyl)- lH-imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5- carboxylic acid methyl ester.
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3- ⁇ 4-[5- ⁇ 4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -2-(2, 4, 6-trimethyl-phenyl)- 1 H- imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5-carboxylic acid 192 as a yellow solid (0.28 g, 50%).
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3- ⁇ 4-[5- ⁇ 4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -2-(4-pyrrolidin-l-yl-phenyl)-lH- imidazol-4-yl]-phenyl ⁇ -4, 5-dihydro-isoxazole-5-carboxylic acid 193 as a yellow solid (0.078 g, 33%).
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4-Carboxy-phenyl)-5- ⁇ 4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-4-yl) ⁇ phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 194 as a yellow solid (0.1 g, 45%).
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4- Diethylamino-2-hydroxy-phenyl)-5- ⁇ 4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-4-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 195 as a yellow solid (0.1 g, 41.8%).
  • Dione 46b (Scheme 9) was synthesized according to General Method 6 from dione 44a (1.5 g, 3.3 mmol) in CHCI3 (15 mL), EDCI (0.96 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol), DIEA (1.08 mL, 8.3 mmol), and dodecylamine 26b (0.93 g, 5.0 mmol).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3- ⁇ 4-[5-[4-((E)- 2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2-hydroxy-phenyl)-lH- imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5-carboxylic acid 196 as a yellow solid (0.1 g, 47%).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-(4- ⁇ 5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]- lH-imidazol-4-yl ⁇ -phenyl)-4, 5-dihydro-isoxazole-5- carboxylic acid 197 as a yellow solid (0.1 g, 48.7%).
  • Imidazole 199 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 199 (Example 10) according to General Method 11, to give 3-(4- ⁇ 5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4-((E)-2- ethoxy carbonyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 199, after recrystallization, as a pale yellow solid (0.05 g, 71.4%).
  • Compound 200 was synthesized according to General Method 7from dione 46b (0.3 g, 0.49 mmol) in acetic acid (4 mL), 5-formyluracil (0.072 g, 0.51 mmol) and NH 4 OAc (1.13 g, 14.61 mmol), which gives 3-(4- ⁇ 2-(2,4-Dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)-5-[4-((E)-2-dodecylcarbamoyl-vinyl)-phenyl]-lH- imidazol-4-yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester.
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-(4- ⁇ 2-(2,4- Dioxo-1,2, 3, 4-tetrahydro-pyrimidin-5-yl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-4,5- d ⁇ hydro-isoxazole-5-carboxylic acid 200 as a yellow solid (0.07 g, 21%).
  • the bis- tert-butyl ester of imidazole 202 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-[4-(2-[4-((E)-2- Carboxy-vinyl)-phenyl]-5- ⁇ 4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid 202 as a yellow solid (0.13 g, 36%).
  • Dione 46c (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (0.1 g, 0.25 mmol) in CHC1 3 (2 mL), EDCI (0.052 g, 0.27 mmol), HOBt (0.037, 0.27 mmol), DIEA (0.063g, 0.5 mmol), and tryptamine 26c (0.043g, 0.27 miriol).
  • Compound 203 was synthesized according to General Method 7 from dione 46c (0.066 g, 0.12 mmol) in acetic acid (1.5 mL) 4-diethylamino-benzaldehyde (0.024 g, 0.13 mmol) and NH4OAC (0.28 g, 3.6 mmol).
  • Imidazole 204 was synthesized according to General Method 10 from imidazole 203 (0.03 g, 0.04 mmol), IN LiOH (0.06 mL), and 1,4-Dioxane (0.6 mL). 3- ⁇ 4-[2-(4-Diethylamino- phenyl)-5-(4- ⁇ (E)-2-[2-(lH-indol-3-yl)-ethylcarbamoyl]-vinyl ⁇ - phenyl)-lH-imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5- carboxylic acid 204 was obtained, after recrystallization, as a pale yellow solid (0.02 g, 66.7%).
  • Dione 46d (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (0.1 g, 0.22 mmol) in CHC1 3 (1.5 mL), EDCI (0.064 g, 0.33 mmol), HOBt (0.045 g, 0.33 mmol), DIEA (0.11 g, 0.89 mmol), and phenylhydrazine 26d (0.04 g, 0.33 mmol).
  • I l l Compound 205 was synthesized according to General Method from dione 46d (0.11 g, 0.2 mmol) in acetic acid (2 mL), 2-hydroxy-4-diethylamino-benzaldehyde (0.06 g, 0.3 mmol) and NH4OAC (0.47 g, 6 mmol), which gives 3-[4-(2-(4- Diethylamino ⁇ 2-hydroxy-phenyl)-5- ⁇ 4-[(E)-2-(N-phenyl- hydrazinocarbonyl) -vinyl] -phenyl ⁇ - 1 H- imidazol-4-yl) -phenyl] - 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester.
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4- Diethylamino-2-hydroxy-phenyl)-5- ⁇ 4-[(E)-2-(N-phenyl- hydrazinocarbonyl)-vinyl]-phenyl ⁇ -lH-imidazol-4-yl)-phenyl]-4,5- d ⁇ hydro-isoxazole-5-carboxylic acid 205 as a yellow solid (0.02 g, 15.2%).
  • Dione 46e (Scheme 9) was synthesized according to General Method 6 from dione 44b (for synthesis of 44b see Example 7)(1 g, 2.2 mmol) in CHC1 3 (15 mL), EDCI (0.64 g, 3.3 mmol), HOBt (0.45 g, 3.3 mmol), DIEA (0.72 g. 5.6 mmol), and 4-fluorophenethylamine 26e (0.46 mL, 3.3 mmol).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3- ⁇ 4-[2-(4-Diethylamino-2-hydroxy-phenyl)-5- (4- ⁇ (E) -2- [2- (4-fluoro-phenyl) -ethylcarbamoyl] -vinyl ⁇ -phenyl) - 1 H- imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5-carboxylic acid 206 as a yellow solid (0.08 g, 55%).
  • Compound 207 was synthesized according to General Method 7 from dione 46e (0.5 g, 0.88 mmol) in acetic acid (7 mL), 4-pyrrolidin- l-yl-benzaldehyde (0.17 g, 0.96 mmol) and NH4OAC (2 g, 26.3 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1).
  • Imidazole 208 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 207 according to General Method 11, to give 3- ⁇ 4-[5-(4- ⁇ (E)-2-[2- (4-Fluoro-phenyl)-ethylcarbamoyl]-vinyl ⁇ -phenyl)-2-(4-pyrrolidin- l-yl-phenyl)-lH-imidazol-4-yl]-phenyl ⁇ -4,5-dihydro-isoxazole-5- carboxylic acid 208, after recrystallization as a pale yellow solid (0.19 g, 90%).
  • Example 7 (300 mg, 0.67 mmol) in CH 2 C1 2 (1.5 mL), EDCI (141 mg, 0.73 mmol), HOBt (99 mg, 0.73 mmol), DIEA (234 ⁇ L, 1.34 mmol), and tetrahydrofurfurylamine 26f (75.8 ⁇ L, 0.73 mmol).
  • Imidazole 210 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 209. After purification the desired imidazole 3- ⁇ 4-[2-(4- Hexadecylcarbamoyl-phenyl)-5-(4- ⁇ (E)-2-[(tetrahydro-furan-2- ylmethyl)-carbamoyl] ⁇ vinyl ⁇ -phenyl)-lH-imidazol-4-yl]-phenyl ⁇ - 4,5-dihydro-isoxazole-5-carboxylic acid 210, was obtained as a yellow solid (3.8 mg, 20%).
  • Dione 46g (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (180 mg, 0.44 mmol) in CH 2 C1 2 (3.5 mL), EDCI (127 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol), DIEA (193 ⁇ L, 1.1 mmol), and tetrahydrofurfurylamine 26f (68 ⁇ L, 0.66 mmol).
  • Compound 211 was synthesized according to General Method 7 from dione 46g (247 mg, 0.5 mmol) in acetic acid (1 mL + 250 ⁇ L DMSO), with 4-Formyl-N-dodecyl-benzamide (240 mg, 0.76 mmol) and NH 4 OAc (1.2 g, 15.1 mmol). The resulting imidazole was purified by flash column chromatography eluting with methanol/ dichloromethane.
  • Imidazole 212 was synthesized according to General Method 10 via hydrolyses of the methyl ester of imidazole 211, to give 3- ⁇ 4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4- ⁇ (E)-2- ](tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl ⁇ -phenyl)-lH- imidazol-4-yl]-phenyl ⁇ -4, 5-dihydro-isoxazole-5-carboxylic acid 212, after purification, as a white solid (12 mg, 31%).
  • Imidazole 56 was synthesized according to General Method 7 from dione 54 (4.6 g, 11 mmol) in acetic acid (11 mL), with 4-formylcinnamic acid ethyl ester (3.4 g, 16.5 mmol) and NH4OAC (25.4 g, 330 mmol), which gives imidazole 55a (5 g, 75%) (dione 54 was synthesized according to General Method 4).
  • Imidazole 215 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 214 (Example 25) according to General Method 11, to give (4- ⁇ 5- ⁇ 4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl ⁇ -2-[4-((E)-2- ethoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenoxy)-acetic acid 215, after purification, as a yellow solid (50 mg, 41%).
  • Compound 216 was synthesized according to General Method 8 from imidazole 56 (100 mg, 0.18 mmol) in DMF (1 mL), with Pd(OAc) 2 (8 mg, 0.036 mmol), TEA (50.2 ⁇ L, 0.36 mmol), (o-Tolyl)3P (22 mg, 0.072 mmol), and *acrylamide 57c (68 mg, 0.36 mmol) to (4- ⁇ 5- ⁇ 4-[(E)-2-(3H-Benzotriazol-5- ylcarbamoyl)-vinyl]-phenyl ⁇ -2-[4-((E)-2-ethoxycarbonyl-vinyl)- phenyl]-lH-imidazol-4-yl ⁇ -phenoxy)-acetic acid 216 as a light yellow solid (5 mg, 4%).
  • *Acrylamide 57c was synthesized according to General Method 9 from acryloyl chloride and 5- aminobenzo triazole .
  • Imidazole 55b was synthesized according to General
  • Imidazole 222 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 221 according to General Method 11, to give 3-[4-(4-(4- Carboxymethoxy-phenyl)-5- ⁇ 4-[(E)-2-(l -methyl- dodecylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-2-yl)-phenyl]-4,5- d ⁇ hydro-isoxazole-5-carboxylic acid 222, after recrystallization, as a yellow solid (13 mg, 15%).
  • Imidazole 224 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 223 according to General Method 11, to give 3- ⁇ 4-[4-(4- Carboxymethoxy-phenyl)-5-(4- ⁇ (E)-2-[l ⁇ (4-pentyl-phenyl) ⁇ ethylcarbamoyl]-vinyl ⁇ -phenyl)-lH-imidazol-2-yl]-phenyl ⁇ -4,5- dihydro-isoxazole-5-carboxylic acid 224, after recrystallization, as a pale yellow solid (50 mg, 42%).
  • Compound 225 was synthesized according to General Method 8 from imidazole 55b (300 mg, 0.44 mmol) in DMF (2.2 mL), with Pd(OAc) 2 (20 mg, 0.09 mmol), TEA (123 ⁇ L, 0.88 mmol), (o-Tolyl)3P (54 mg, 0.18 mmol), and *acrylamide 57g (127 mg, 0.53 mmol) to give after purification by flash column chromatography followed by recrystallization, 3-(4- ⁇ 4-(4-tert- Butoxycarbonylmethoxy-phenyl)-5-[4-((E)-2-dihexylcarbamoyl- vinyl)-phenyl]-lJf-imidazol-2-yl ⁇ -phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid tert-butyl ester as a yellow solid (300 mg, 80%).
  • the t-butyl ester 226 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-(4- ⁇ 5-(4-Carboxymethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l -methyl- lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228 as a yellow solid (33 mg, 77%).
  • the imidazole 134a was prepared from 132a according to General Method 7. Acetic acid (1 mL) was added to a mixture of the ⁇ -keto methylamine 132a (65 mg, 0.16 mmol), 3-(4-Formyl- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester (66 mg, 0.24 mmol), and NH 4 OAc (370 mg, 4.8 mmol) and heated to 100 °C for 2h. The reaction mixture was quenched with ice water, extracted with ethyl acetate (20 mL x 2). The organic layer was washed with water, sat.
  • Compound 230 was prepared according to General Method 11 from 229 (186 mg, 0.24 mmol). Purification via flash column chromatography eluting with 2% methanol/ dicholoromethane with 1% formic acid afforded 3- ⁇ 4- ]5-]4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)- 1 -methyl- 1 H-imidazol-2-yl]- phenyl ⁇ -4,5-dihydro-isoxazole-5-carboxylic acid 230 as a yellow solid (100 mg, 54%).
  • Compound 231 was prepared according to General Method 10 from imidazole 230 (40 mg, 0.052 mmol) after workup to obtain 3-(4- ⁇ 4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2-yl ⁇ - phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid 231 as a light yellow solid (31 mg, 82%).
  • Imidazole 233 (0.067 g, 0.1 mmol) was dissolved in 1,4- Dioxane (1 mL) and IN LiOH (1 mL, 1 mmol) was added. The reaction was stirred at RT for 2h, acidified with IN HCI (2 mL) and extracted with chloroform. After recrystallization, the desired product ⁇ 4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-imidazol-l-yl ⁇ -acetic acid 234 was obtained (0.035 g, 52%).
  • the t-butyl ester of imidazole 235 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-(4- ⁇ 4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl ⁇ -phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 236 as a yellow solid (0.12 g, 50%).
  • Compound 237 was hydrolyzed according to General Method 11 to give, after recrystallization from ethyl acetate/methanol, the desired imidazole (4- ⁇ 5-[4-((E)-2- Dodecylcarbamoyl-vinyl)-phenyl]-2-pyridin-3-yl-lH-imidazol-4- yl ⁇ -phenoxy) ⁇ acetic acid 238 as a yellow solid (0.06 g, 30%).
  • the methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-(4- ⁇ 2-(4-Diethylamino-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 239 as a yellow solid (0.02 g, 62%).
  • the tert-butyl ester of 240 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3- ⁇ 4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-2-(4-pyrrolidin- 1-yl-phenyl)- lH-imidazol-4-yl]-phenyl ⁇ - 4,5-dihydro-isoxazole-5-carboxylic acid 241 as a yellow solid (0.4 g, 29%).
  • the desired imidazole (4- ⁇ 5-[4 ⁇ ((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4- ((E)-2-tert-butoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ - phenoxy)-acetic acid tert-butyl ester 242 was obtained as a yellow solid (27 mg, 20%).
  • Compound 245 was synthesized according to General Method 11 from imidazole 244 to give after recrystallization from methanol/ ethyl acetate, 3-[4-(4-(4-Carboxymethoxy- phenyl)-5- ⁇ 4 ⁇ [(E)-2-(hexadecyl-methyl-carbamoyl)-vinyl]-phenyl ⁇ - 1 H-imidazol-2-yl)-phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid 245 as a yellow solid (30 mg, 60%).
  • Imidazole 246 was synthesized from imidazole 235 (Example 46) (40 mg, 0.05 mmol) via treatment with bis(benzonitrile)dichloropalladium (II) (1.5 mg, 0.04 mmol) and diazomethane (excess, ⁇ 0.332 mmol). The reaction was stirred for 15 minutes, filtered through celite and concentrated in vacuo.
  • the crude reaction mixture was added to a mixture of hexanes/ethyl acetate (4: 1, 200 mL), and washed with NH 4 C1 (200 mL) and brine (200 mL), dried over MgS ⁇ 4, filtered, and concentrated to dryness.
  • the crude material was dried in vacuo to provide a dark orange solid 87 (15.3 g). This crude was a mixture of 87 and 86, which was not purified further.
  • Imidazole 110 (Scheme 17, 60 mg) was added to a round- bottomed flask followed by 20% TFA in CH 2 C1 2 (3.0 mL). The reaction was stirred at rt for 2.5 h. The crude mixture was concentrated to dryness and purified by preparative chromatography (1.0 mm) using (2X) 10: 1 CH 2 Cl 2 /MeOH to provide (E)-3- ⁇ 4-[4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-(4- dodecylcarbamoyl-phenyl)-lH-imidazol-2-yl]-phenyl ⁇ -acrylic acid 111 (24 mg).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3- ⁇ 4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2, 3, 4- trimethoxy -phenyl)- lH-imidazol-4-yl] -phenyl ⁇ -acrylic acid 248 as a yellow solid (204 mg, 92%).
  • the starting dione 123b for compound 249 was synthesized according to General Method 15. Imidazole 249 was synthesized from dione 123b (1.5 g, 2.38 mmol, 1.0 eq) in acetic acid (14 mL), DMSO (4 mL), hexamethylenetetramine (1.67 g, 11.9 mmol, 5 eq) and 5.50 g, 71.4 mmol, 30 eq). The resulting imidazole was purified by flash column chromatography eluting with a gradient of 2% - 8% Methanol in DCM.
  • the imidazole (E)-3-(4- ⁇ 5-[4-((E)-2-Hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-acrylic acid tert-butyl ester 249 was obtained as a yellow solid (1.4 g, 92%).
  • Imidazole 250 was prepared according to General Method 11, form imidazole 249, to give after recrystallization from methanol/ ethyl acetate, (E) ⁇ 3-(4 ⁇ 5-[4 (E)-2- Hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)- acrylic acid 250 as a pale yellow solid (0.77g, 60%).
  • Imidazole 251 was obtained via reduction of the double bonds of imidazole 250 according to General Method 14. 3-(4- ⁇ 5- [4-(2-Hexadecylcarbamoyl-ethyl)-phenyl] ⁇ lH-imidazol-4-yl ⁇ - phenyl)-propionic acid 251 was obtained 15 mg (80%) after recrystallization as a white solid.
  • Example 65 3-(4- ⁇ 4-r4-(tE)-2-Carboxy-vinyl)-phenyq-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl ⁇ - phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 253
  • Imidazole 253 was prepared according to General Method 11, from imidazole 252, to give after recrystallization from methanol/ ethyl acetate, 3 ⁇ (4- ⁇ 4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)-phenyl]- 1 H- imidazol-2-yl ⁇ -phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid 253 as a pale yellow solid (0.3
  • Compound 254 was synthesized according to General Method 7 from dione 461 (1.1 g, 1.75 mmol) in acetic acid (20 mL), 4-formylcinnamic acid ethyl ester (0.53 g, 2.62 mmol) and NH 4 OAc (4 g, 52 mmol). The resulting imidazole was purified by flash column chromatography eluting with DCM/methanol (95:5).
  • the tert-butyl ester of imidazole 254 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole (E)-3-(4- ⁇ 2-[4-((E)-2- Ethoxycarbonyl-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-acrylic acid 255 as a yellow solid (0.4 g, 39 %).
  • the ethyl ester of imidazole 255 was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3- ⁇ 4-[5- ⁇ 4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl ⁇ -2-(4-pyrrolidin l-yl-phenyl)- 1 H-imidazol-4-yl]-phenyl ⁇ -4, 5-dihydro-isoxazole-5-carboxylic acid 256 as a yellow solid (0.23 g, 60%).
  • Imidazole 257 was synthesized according to General Method 7 (Scheme 19) from dione 123a (see General Method 15) ⁇ 1.3 g, 2.3 mmol) in acetic acid (4.6 mL), with 3-(4-Formyl- phenyl)-4,5-dihydro-isoxazole-5 ⁇ carboxylic acid tert-butyl ester (936 mg, 3.4 mmol) and NH 4 OAc (5.3 g, 69 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4-[4-((E)-2-tert- Butoxycarbonyl-vinyl)-phenyl]-5-[4-(2-dodecylcarbamoyl- vinyl) -phenyl] - 1 ff-imidazol-2-yl ⁇ -phenyl) -4 , 5-dihydro- isoxazole-5-carbox
  • the tert-butyl esters were hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol- 2-yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 257 200 mg (36%) as a yellow solid.
  • Imidazole 258 was synthesized according to General Method 7 (Scheme 19) from dione 123a (see General Method 15) (300 mg, 0.52 mmol) in acetic acid (2 mL), with 3-(4- Formyl-phenyl)-isoxazole-5-carboxylic acid ethyl ester 37 (synthesized according to General Method 1 using the appropriate alkyne) (192 mg, 0.78 mmol) and NH4OAC (1.2 g, 15.6 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4- [4-((E)-2- tert-Butoxycarbonyl -vinyl)-phenyl]-5-[4-(2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl ⁇ -phenyl)- isoxazole-5-carboxylic acid
  • the tert-butyl and ethyl esters are hydrolyzed according to General Method 10 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-
  • Imidazole 259 was synthesized according to General Method 7 (Scheme 19) from dione 123b (520 mg, 0.83 mmol) in acetic acid (2 mL), with 3-(4-formyl-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid ethyl ester (306 mg, 1.2 mmol) and NH4OAC (1.9 g, 25 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4-[4-((E)-2-tert-Butoxycarbonyl- vinyl) -phenyl] -5- [4-(2-hexadecylcarbamoyl-vinyl) -phenyl]- lH-imidazol-2-yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid ethyl ester (300 mg).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4- [4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-2-yl ⁇ -phenyl)-4, 5-dihydro- isoxazole-5-carboxylic acid ethyl ester 259, 200 mg (72%) as a yellow solid.
  • Imidazole 260 was synthesized according to General Method 7 (Scheme 19) from dione 123b (see General Method 15) (500 mg, 0.79 mmol) in acetic acid (4 mL), with 3-(4- Formyl-phenyl) -isoxazole- 5-carboxy lie acid ethyl ester (292 mg, 1.2 mmol) and NH4OAC (1.8 g, 24 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4-[4-((E)-2-tert-Butoxycarbonyl -vinyl) -phenyl] -5- [4- (2-hexadecylcarbamoyl-vinyl) -phenyl] - lH-imidazol-2-yl ⁇ -phenyl)-isoxazole-5-carboxylic acid ethyl ester (377 mg, 56%).
  • the tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)- phenyl]-lH-imidazol-2-yl ⁇ -phenyl)-isoxazole-5-carboxylic acid ethyl ester 260, 403 mg (100%) as a yellow solid.
  • Imidazole 261 was synthesized from imidazole 260 according to General Method 10 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl) ⁇ phenyl]- lH-imidazol-2-yl ⁇ -phenyl)-isoxazole-5-carboxylic acid 261, 217 mg (75%) as a yellow solid.
  • Imidazole 262 was synthesized according to General Method 7 (Scheme 19) from dione 123c (see General Method 15) (285 mg, 0.49 mmol) in acetic acid (3 mL), with 3-(4- Formyl-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester (162 mg, 0.59 mmol) and NH 4 OAc (758 mg, 9.9 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-[4-(4- [4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5- ⁇ 4-[2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl ⁇ - 1 H-imidazol-2-yl)-phenyl]- 4,5-d ⁇ hydro-isoxazole-5-carbox
  • Imidazole 263 was synthesized from imidazole 262 according to General Method 11 to give, after recrystallization from methanol/ ethyl .acetate, 3-[4-(4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5- ⁇ 4-]2-(4-heptyl-phenylcarbamoyl)- vinyl]-phenyl ⁇ -lH-imidazol-2-yl)-phenyl]-4, 5-dihydro- isoxazole-5-carboxylic acid 263, 200 mg (64%) as a yellow solid.
  • Imidazole 264 was synthesized according to General Method 7 (Scheme 19) from dione 123d (see General Method 15) (731 mg, 1.28 mmol) in acetic acid (4 mL), with 3-(4- Formyl-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester (422 mg, 1.54 mmol) and NH 4 OAc (1.97 g, 26 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4- [4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5-[4-(2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl ⁇ -phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-but
  • Imidazole 265 was synthesized from imidazole 264 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-dihexylcarbamoyl-vinyl)- phenyl]-lH-imidazol-2-yl ⁇ phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid 265, 300 mg (62%) as a yellow solid.
  • Imidazole 266 was synthesized according to General Method 7 (Scheme 19) from dione 123c (see General Method 15) (300 mg, 0.52 mmol) in acetic acid (6 mL), with hexamethylene tetramine (360 mg, 2.58 mmol) and NH4OAC (1.19 g, 15.5 mmol), which gives after purification via column chromatography eluting with DCM: methanol (95:5), (E)-3-[4-(5- ⁇ 4-[(E)-2-(4-Heptyl- phenylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol-4-yl)-phenyl]- acrylic acid tert-butyl ester 266 (110 mg, 36%).
  • Imidazole 267 was synthesized from imidazole 266 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, (E)-3-[4-(5- ⁇ 4- ](E)-2-(4-Heptyl-phenylcarbamoyl)-vinyl]-phenyl ⁇ -lH-imidazol- 4-yl)-phenyl]-acrylic acid 267, 31 mg (28%) as a yellow solid.
  • Imidazole 268 was synthesized according to General
  • Imidazole 269 was synthesized from imidazole 268 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, (E)-3-(4- ⁇ 5-[4-((E)-2-Dihexylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-acrylic acid 269, 50 mg (18 %) as a yellow solid.
  • Imidazole 270 was synthesized from imidazole 160a according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-[3-(4- ⁇ 5-[4-((E)-2-Hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl ⁇ -phenyl)-allanoylamino]-propionic acid 270, 62 mg (30%) as a yellow solid.
  • Carboxylic acid 142 300 mg, 1.03 mmol
  • amine 143 (248 mg, 1.03 mmol)
  • isocyanide 144 120 mg, 1.03 mmol
  • phenylglyoxal 145 138 mg, 1.03 mmol
  • the reaction mixture was concentrated and dried in vacuo to provide crude Ugi product 146 which was added to AcOH (10 mL) and NH 4 OAc (2.3 g , 30.9 mmol) and heated to 100 °C for 1.5 h.
  • Imidazole 81 was synthesized according to General Method 7 (Scheme 19) from dione 80 (336 mg, 0.78 mmol) in acetic acid (5 mL), with 3-(4-formyl-phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid tert-butyl ester (214 mg, 0.78 mmol) and NH4OAC (1.8 g, 23 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4- ⁇ 4-[4-(tert-Butoxycarbonylmethyl-carbamoyl)-phenyl]-5- decyl-lH-imidazol-2-yl ⁇ -phenyl)-4,5-dihydro-isoxazole-5 ⁇ carboxylic acid tert-butyl ester 81, 180 mg (34%).
  • Imidazole 82 was synthesized from imidazole 81 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4- ⁇ 4-[4-(Carboxymethyl- carbamoyl)-phenyl]-5-decyl-lH-imidazol-2-yl ⁇ -phenyl)-4, 5- dihydro-isoxazole-5-carboxylic acid 82, 119 mg (91%) as a pale yellow solid.
  • Glycoside 97 (Scheme 16, 4.0 g, 7.27 mmol) was added to a round-bottomed flask along with TMSalkyne (63) (5.14 mL, 36.3 mmol), bistriphenylphosphine palladium (II) dichloride (102 mg, 0.15 mmol), copper (I) iodide (14 mg, 0.073 mmol), * 0 triethylamine (3.0 mL, 21.8 mmol), and DMF (30 mL). The mixture was stirred at rt under N 2 for 10 h.
  • Alkyne 99 (Scheme 16, 2.0 g, 4.46 mmol) was charged to a round-bottomed flask along with DMF (20 mL), 4-bromo-l- iodobenzene 86 (1.5 g, 5.35 mmol), copper iodide (9.0 mg, 0.045 mmol), dichlorobis (triphenyl- phosphine) palladium(II) (63 mg, 0.09 mmol) and triethylamine (2.0 mL, 13.4 mmol). The reaction mixture was stirred at rt under an atmosphere of nitrogen for 8 h.
  • Alkyne 100 (Scheme 16, 430 mg, 0.7 mmol) was charged to a round-bottomed flask along with CC1 4 (4.0 mL), CH3CN (4.0 mL), H 2 0 (6.0 mL), and sodium periodate (610 mg, 2.85 mmol).
  • Dione 102 (Scheme 16, 250 mg, 0.32 mmol) was added to a round-bottomed flask along with 34a (81 mg, 0.35 mmol), NH 4 OAc (0.74 g, 9.6 mmol), and HO Ac (5 mL), and the mixture was heated to 100 °C under N 2 for 1.2 h.
  • the crude material was added to ethyl acetate (50 mL), washed with H 2 0 (50 mL) and brine (50 mL), dried over MgS ⁇ 4, filtered, and concentrated to dryness.
  • the crude material was eluted on a preparative TLC plate (1.0 mm) using 10: 1 CH 2 Cl 2 /MeOH to provide 103 (178 mg) as a yellow solid.
  • Imidazole 103 (Scheme 16, 150 mg) was added to a round-bottomed flask along with 20% TFA in CH 2 C1 2 (2 mL) and stirred at rt under N 2 for 1.5 h.
  • Data for compound 104 i H-NMR (300 MHz,
  • the crude was added to ethyl acetate (100 mL) and washed with H 2 0 (50 mL) and brine (50 mL), dried over MgS0 4 , filtered, and concentrated to dryness. Flash chromatography using 10: 1 CH Cl 2 /MeOH as eluent provided 93 as a yellow oil (248 mg) .
  • the complex-compound mixture was then added to the blocked, sialyl- Lewis x -ceramide coated plate and allowed to incubate for 45 minutes at 37°C. After washing 3-4 times with 50 mM imidazole, the bound complex was detected using the colorimetric phosphatase substrate, p- nitrophenylphosphate, at 1 mg/mL in 1 M diethanolamine containing 0.01% MgCl 2 . After developing for 1-2 hours at room temperature, the absorbance at 405 nM was measured in a Molecular Devices microplate reader. Percent inhibition was calculated by comparing the test compound result with the vehicle control after subtracting the background from each. IC50 values were calculated by in-house data analysis software (OntoASSAY; Ontogen, Corp.) using standard algorithms. Cell-Selectin Adhesion Assays
  • HL60 cells obtained from the ATCC (Manassas, VA) were cultivated in RPMI medium containing 10% heat- inactivated fetal bovine serum (FBS).
  • FBS heat- inactivated fetal bovine serum
  • cells were harvested by centrifugation, washed once with PBS + , and resuspended in PBS + at a concentration of 2 x 10 6 cells/mL.
  • Cells were added directly to the compound-containing wells in a volume of 50 ⁇ L per well, bringing the compound to its final test concentration in a total volume of 100 ⁇ L. Cells and compound were incubated on the selectin-coated wells for 45 minutes at 37°C.
  • Unbound cells were removed using a vacuum manifold and a single wash with 200 ⁇ L PBS + (added slowly using a manual multichannel pipettor) . Retained cells were labeled directly on the plate by adding 5 ⁇ g/mL of the membrane-permeable fluorescent dye, calcein-AM, and incubating for 30 minutes at 37°C. Signal was quantified in a Wallac Victor fluorescent microplate reader using 485 nM excitation and 535 nM emission. Percent inhibition and IC50 values were calculated as described above for the ELISA assay.
  • prodrugs of Formulas 1, 2 and 3 include, but are not limited to, compounds such as Formulas 4, 5 and 6, where R' can be methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • compositions of Formulas 1, 2 and 3, where a basic or acidic group is present in the structure are also included within the scope of this invention.
  • an acidic substituent such as - COOH there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methane sulfonate, ethanesul- fonate, picrate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) p.1-19 and incorporated herein by reference, can be used as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate,
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • therapeutically effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or others.
  • the present invention provides a method of administering a compound selected from those defined in Formulas 1 , 2 and 3 above in cases where inhibition or modulating selectin activity in a body is needed. These conditions include but are not limited to the foregoing described diseases.
  • the compounds may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • the tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • Coating may also be performed using techniques described in the U.S. Patent Nos. 4,256, 108; 4, 160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of ethylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylen-oxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
  • 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 can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidyl-cholines.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formulas 1, 2 and 3 are employed.
  • the compounds of Formulas 1 , 2 and 3 may also be administered directly into the lungs by inhalation or intranasal delivery when formulated in a solvent that is suitable for aerosol formation. Such delivery would be useful for direct delivery to the site of action, as in asthma. However, because administration to the lungs may result in significant blood levels of the compound, this route of administration can be also used in cases where systemic exposure is required.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg to about 100 mg per kilogram body weight, with a preferred dosage range between about 20 mg to about 50 mg per kilogram body weight per day (from about 25 mg to about 5 g's per patient 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.
  • a formulation intended for oral administration to humans may contain 5 mg to 1 g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient.
  • the specific dose 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, gender, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the dosage needs to be individualized by the clinician.

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Abstract

Compounds of formulas (1), (2) and (3) are disclosed, where at least one and no more than two of R?1, R2, R3, R4 or R5¿ are as defined in Group 1. In said formulas R1 is typically a moiety containing a terminal carboxylic acid group such as phenoxy acetic acid, R2 is typically a hydrophobic moiety such as functionalized alkyl chain or a functionalized aryl group, and R3 is typically a functionalized aryl group, and they are within the scope of this invention. These compounds exhibit inhibitory activity against the Selectins and are indicated in the treatment of human diseases involving Selectins.

Description

5-membered Heterocycles for the Treatment of Human Diseases Involving Modulators of Selectins This application claims the benefit of the filing date of provisional application serial no. 60/ 111,026, filed on December 4th 1998, and provisional application serial no. 60/ 111,025 filed on December 4th 1998, the disclosure of which is incorporated herein by reference. Field of the Invention
The present invention relates to novel selectin modulating compounds having the structural Formulas 1, 2. and 3, as. shown below, to methods of their preparation, to compositions comprising the compounds, to their use for treating human or animal disorders, to their use for purification of proteins, and to their use for in diagnostics. These compounds are modulators of selectin (P-, E- and L-selectin) Ligand (e.g. Sialyl Lewis X (sLe )) interactions for the management, treatment, control, or as an adjunct of diseases in humans caused by selectins. More particularly, this invention relates to the administration of compounds according to Formulas 1, 2 and 3 which are selectin/ Ligand antagonists, for the management of diseases and disease states such as 1) acute respiratory distress syndrome (ARDS), 2) diseases that may be controlled via inhibition of angiogenesis, 3) asthma, 4) atherosclerosis, 5) atopic dermatitis, contact dermatitis, and cutaneous inflammation, 6) bowel inflammation, 7) diabetes/ diabetes-associated pathologies, 8) Grave's disease and associates conditions, 9) - multiple sclerosis (MS), 10) myocardial ischemia/ reperfusion injury, 11) organ transplantation, 12) psoriasis, 13) rheumatoid arthritis, 14) stroke and ischemic brain trauma, 15) trauma- induced organ injury, 16) thrombosis, 17) reduction of tumor metastasis and/ or tumor growth, and the like. Background of the Invention The immune response relies on the ability of specialized immune cells— leukocytes and lymphocytes—to migrate to sites of tissue damage, infection, or other insult to the body. Once there, these cells mount a defense against the intruding organism, help to repair the injured tissue, and protect the body from further damage. The immune system is also in constant "surveillance mode". Circulating lymphocytes monitor the body for pathogens by migrating through lymphoid tissues, where they can be exposed to antigens and become activated. In order for these processes to occur, various chemoattractants, cytokines, and cell adhesion molecules
(CAMs) act in a programmed, sequential manner to form what has been termed the leukocyte-endothelial cascade (Tedder et al, FASEB 9: 866 (1995), Albelda et al., FASEB 8: 1756, (1994)). Three known families of CAMs participate in this cascade: the selectins, the integrins and the immunoglobulin superfamily. The first step, rolling of leukocytes and lymphocytes along the blood vessel wall, is mediated by the selectins.
Selectins are a small family of transmembrane glycoproteins that bind to cell surface carbohydrate ligands (for reviews see: Lasky, Science 258: 964 (1992); McEver, Curr.
Opin. Immun. 6: 75 (1994); McEver, J. Biol. Chem. 270: 11025 (1995)). To date, three members have been identified: P-selectin (expressed on platelets and vascular endothelial cells, L-selectin (on leukocytes), and E-selectin (on vascular endothelial cells). Common structural features include a calcium-dependent (C- type) lectin domain, an epidermal growth factor (EGF)-like domain, and a series of short consensus 'complement regulatory protein' repeat sequences. Rodent homologs have been cloned and they share a high degree of sequence homology with their human counterparts.
Several selectin counter-receptors have been identified (for review see: Lasky et al., in Cellular Adhesion: Molecular Definition to Therapeutic Potential, Metcalf et al., Eds. pp.37-53 (1994) and the like). L-selectin binds to at least three different ligands: Glycam-1, CD34 and MAdCAM-1, each being expressed on different tissues. P-selectin has been found to bind to PSGL- 1 , and E-selectin has been found to bind to ESL- 1. These cell- surface selectin ligands are capped with clusters of oligosaccharides (for discussion see: Rosen et al, Curr. Opin. Cell Biόl. 6: 663 (1994), and Bertozzi et al, Chemistry. & Biology 2: 703 (1995)). The specific carbohydrate moieties necessary for selectin binding have been identified: the sialylated and fucosylated tetrasaccharide sialyl Lewis X (sLex), and a related structure sialyl Lewis a (sLea), are common motifs recognized by all three selectins.
Although leukocyte recruitment into the tissue is a normal, indeed essential, component of the immune response, excessive and uncontrolled recruitment results in inflammatory disease. As adherence of immune cells to vascular endothelium is a critical event in the pathogenesis of acute inflammation, modulation of selectin function is indicated in the management of diseases and disease states as described below.
Selectin function can be modulated by altering cell- surface expression, by competitive inhibition, or by shedding/ cleavage from the cell surface (Diaz-Gonzalez, et al, J. Clin. Invest. 95: 1756 (1995); Whelan, Trends Biochem. Sci. 21 (1996)). While they have been identified as inhibitors of selectin-ligand interactions in vitro, compounds of Formulas 1 , 2 and 3 may reduce inflammation in vivo via any or all of these modes.
Accordingly, the compounds of the present invention, which exhibit inhibitory activity against the selectins, are indicated in the treatment or management of the foregoing diseases (references supporting each indication are noted): 1) acute respiratory distress syndrome (ARDS) (Carraway et al, Am. J. Respir. Crit. Care Med. 157: 938 (1998); Moss et al, Crit. Care Med. 24: 1782 (1996) and others);
2) diseases that may be controlled via inhibition of angiogenesis (Koch et al, Nature 376: 517-519 (1995); Detmar et al, J. Invest. Dermatol. 111: 1 (1998); Nguyen et al, Nature 365: 267-
269 (1993));
3) asthma (Gundal et al, J. Clin. Invest. 88: 1407 (1991); DeSanctis et al, J. Appl. Physiol. 83: 681, (1997); Kogan et al, J. Med. Chem. 41 : 1099 (1998); PRNewswire, Sept. 9, 1998);
4) atherosclerosis (Dong et al, J. Clin. Invest. 102: 145 (1998); Frijns et al, Stroke 28: 2214 (1997); Tenaglia et al, Am. J. Cardiol. 79: 742 (1997); Zeitler et al, Eur. J. Med. Res. 2: 389 (1997), and others); 5) atopic dermatitis, contact dermatitis, and cutaneous inflammation (Teixeira and Hellewell, J. Immunol. 161: 2516 (1998); Staite et al, Blood 88: 2973 (1996); Todderud et al, J. Pharmacol. Exp. Therap. 282: 1298 (1997); Ohnishi et al, Immunopharmacol 34: 161 (1996), and the like); 6) bowel inflammation (Schurmann et al, Gut 36: 411 (1995);
Koizumi et al., Gastroenterology 103: 840 (1992); Bhatti et al,
Gut 43: 40 (1998); Cellier et al, Eur.- J. Gastroenterol. Hepatol.
9: 1197 (1997)); 7) diabetes/ diabetes-associated pathologies (Kunt et al, Exp.
Clin. Endocήnol. Diabetes 106: 183 (1998); Kopp et al, Exp.
Clin. Endocrinol. Diabetes 106: 41 (1998); Albertini et al,
Diabetes Care 21 : 1008 (1998); Bannan et al, Diabetologica
41 : 460 (1998), and others); 8) Grave's disease and associates conditions (Hara et al, Endocr.
J. 43:709 (1996); Pappa et al, Clin Exp. Immunol. 108: 309
(1997); (Miyazaki et al, Clin. Exp. Immunol. 89: 52 (1992);
Aubert et a , Clin. Immunol. Immunopathol. 76: 170 (1995), and the like); 9) multiple sclerosis (MS) (McDonnell et al, J. Neuroimmunol.
85: 186 (1998)); Washington et al, Ann. Neurol 35: 89
(1994); Vora et al, Mult. Scler. 3: 171 (1997); Archelos et al,
J. Neurol Sci. 159: 127 (1998));
10) myocardial ischemia/ reperfusion injury (reviewed in Lefer, Ann Thorac Surg. 60: 773-777 (1995), also Yamada et al, Eur.
J. Pharmacol. 346: 217 (1998), Kilgore et al, J. Pharmacol. Exp. Ther. 284: 427 (1998); Lefer et al, Circulation 90: 2390 (1994));
11) organ transplantation (Naka et al, Proc. Natl Acad. Sci. 94: 757 (1997); Andreassen et al, Am. J. Cardiol. 81: 604
(1998); Koo et al Am. J. Pathol 153: 557 (1998); Dulkanchainun et al, Ann. Surg. 227: 832 (1998); Takada et al, Transplantation 64: 1520 (1997); Brandt et al, Eur. J. Cardiothorac. Surg. 12: 781 (1997); Garcia-Criado et al, J. Surg. Res. 70: 187 (1997)); 12) psoriasis (Veale et al, Br. J. Dermatol 132: 32 (1995); Bonifati et al, Dermatol. 190: 128 (1995); Danno et al, J. Dermatol Sci. 13: 49 (1996));
13) rheumatoid arthritis (Veale and Maple, Drugs Aging 9: 87 (1996); Hersmann et al, Cell Adhesion Comm. 6: 69 (1998);
Walter and Issekutz, Eur. J. Immunol 27: 1498 (1997); Ertenli et al, J. Rheumatol 25: 1054 (1998) and others);
14) stroke and ischemic brain trauma (Suzuki et al, Neurosci. Lett. 13: 151 (1997); Connolly et al, Circ. Res. 81 : 304 (1997); Morikawa et al, Stroke 27: 951 (1996));
15) trauma-induced organ injury (Simons et al, J. Trauma 41: 653 (1996), Cocks et al, J. Trauma 45: 1 (1998); Mulligan et al, Nature 359: 843 (1994); Rubio-Avilla et al, J. Trauma 43: 313 (1997) and others); 16) thrombosis (Minamino et al, J. Clin. Invest. 101 : 1643
(1998); (Downing et al, J. Vase. Surg. 25: 816 (1997) and the like); 17) reduction of tumor metastasis and /or tumor growth
(Hebbar et al, Proc. Amer. Assoc. Cancer Res. 39:501, (1998); Khatib et al, Proc. Amer. Assoc. Cancer Res. 39:501, (1998);
Kim et al., Proc. Natl Acad. Sci. USA. 95: 9325-9330 (1998); El-Hariry et al, Exp. Opin. Invest. Drugs 6: 1465-1478 (1997), and others). Comparison with other Selectin-Ligand Inhibitors /Antagonists
Sialyl-Lewisx analogs/ mimetics reported in the literature include: 'GSC-150' (Kanebo) which has been reported to have IC50 values of 280 μM, 100 μM, and 30 μM against E-, P-, L-selectin respectively when assayed using an ELISA assay (Tsujishita et al, J. Med. Chem. 40: 362 (1997)); TBC-1269 (Texas Biotech) which has been reported to have IC50 values of 500 μM, 70 μM, and 560 μM against E-, P-, and L-selectin respectively, when assayed using a cell adhesion assay (Kogan et al, J. Med. Chem. 41: 1099 (1998)); a macrocyclic derivative, which has an IC50 of 390 μM against E-selectin (Kolb, Bioorg. Med. Chem. Lett. 7: 2629 (1997)); and C-mannose derivatives which have IC50 values of 100- 160 μM against E-selectin (Marron et al, Tet. Lett. 37: 9037 (1996)). Some of the most potent derivatives that have been reported are multivalent sialyl-Lewisx analogs which have IC50 values of ~1 nM in an L-selectin cell adhesion assay (Renkonen et al, Glycobiology 7: 453 (1997)).
Some additional sugar based inhibitors of interest include inositol hexakisphosphate (IP-6) and sulfated galactocerebrosides ("sulfatides") . IP-6 has been reported to have IC50 values of 160 μM and 2 μM, against P- and L- selectin respectively, in competition ELISA assays (Cecconi et al., J. Biol Chem. 21: 15060 (1994)). Sulfatides have IC50 values in the 0.1-12 μM range when tested in a P-selectin competition ELISA assay (Marinier et al, J. Med. Chem. 40: 3234 (1997)). BMS- 190394, a sulfatide analog, has been reported to have IC50 values of 18 μM and 10 μM, in P-, and L-selectin cell adhesion assays respectively (Todderud et al, J. Pharmacol Exp. Therap. 282: 1298 (1997)). Mannose- containing natural products showed inhibition of P-selectin with an IC50 value of 60 μM (Ikeda et al, Bioorg. Med. Chem. Lett. 7: 2485 (1997)).
Non-carbohydrate inhibitors include peptides based on a conserved region of the lectin domain of the selectins, which have activity in P- and E-selectin cell adhesion assays with IC50 values of ~20 μM (Briggs et al, Glycobiology 5: 583 (1995)). Additional peptides, discovered by random screening, have IC50 values of 5-10 μM in an E-selectin cell adhesion assay (Martens et al, J. Biol Chem. 270: 21129 (1995)).
Summary of the Invention
The present invention is based on the discovery that compounds of Formulas 1, 2 and 3 are inhibitors or modulators of selectins which render them particularly useful for the treatment or management of a large number of disease states in which the role of selectins has directly or indirectly been implicated.
It has been found that the requisite selectin modulating activity can be obtained by employing a planar, rigid, five-membered ring template which acts as a scaffold, to which one can attach the necessary appendages that are required for activity. In order to obtain the desired selectin modulating activity the appendant groups that must be attached to the central template are 1) a carboxylic acid moiety as defined in Group I, or carboxylic acid isostere; or other calcium binding moiety which will be apparent to those skilled in the art; and 2) a hydrophobic moiety such as a C12H25 alkyl chain. Additional substitution about the central core is necessary to modify the potency, selectivity and physiological properties, of the compounds claimed herein. To this end, the compounds of the present invention include any derivative with a rigid core when substituted with a carboxylic acid moiety as defined in Group I or a carboxylic acid isostere; or other calcium binding moiety which will be apparent to those skilled in the art, and a hydrophobic moiety as defined herein.
Accordingly, an object of the present invention is to provide a method for inhibiting or modulating selectins in a mammal by the administration of compound according to Formulas 1, 2 and 3.
Another object of the present invention relates to pharmaceutical compositions containing an effective inhibiting amount of compound according to Formulas 1, 2 and 3.
These compounds have the following general structural
Formulas 1, 2 and 3:
Figure imgf000011_0001
X= N or O
Formula 1 Where at least one and no more than two of R1, R2, R3, R4 or R5 =
.Calcium binding moiety
Figure imgf000011_0002
Formula 2 as defined in Group 1
Figure imgf000011_0003
Formula 3
Formulas 1, 2 and 3 Definitions
As used herein, the term "attached" signifies a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art. The terms "halogen" or "halo" include fluorine, chlorine, bromine, and iodine.
The term "alkyl" includes C1-C16 straight chain saturated, C1-C16 branched saturated, C3-C8 cyclic saturated and Ci-Ciβ straight chain or branched saturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr), isobutyl (i-Bu), tert- butyl (t-Bu), sec- butyl (s-Bu), isopentyl, neopenryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like. The term "alkenyl" includes C2-C16 straight chain unsaturated, C2-C11 branched unsaturated, Cs-Cs unsaturated cyclic, and C2-C16 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Double bonds may occur in any stable point along the chain and the carbon- carbon double bonds may have either the cis or trans configuration. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl- 3-cyclohexenyl, and the like.
The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
The term "alkylthio" (e.g. methylthio, ethylthio, propylthio, cyclohexylthio and the like) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term "alkylamino" represents one or two alkyl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci-Ciβalkyl, arylCo-Ci6alkyl, or Co-Ci6alkylaryl substituent. .
The term "alkylamino alkyl" represents an alkylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "alkyloxy (alkyl) amino" (e.g. methoxy (methyl) amine, ethoxy (propyl) amine) represents an alkyloxy group as defined above attached through an amino group, the amino group itself having an alkyl substituent.
The term "alkylcarbonyl" (e.g. cyclooctylcarbonyl, pentylcarbonyl, 3-hexylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen.
The term "alkylcarboxyalkyl" represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "alkylcarbonylamino" (e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with an alkyl or aryl group.
The term "aryl" represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g. 3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, Ci-iealkyl, arylCi-iβalkyl, Co-iβalkyloxyCo- lealkyl, arylCo-i6alkyloxyCo-i6alkyl, Co-iβalkylthioCo-iβalkyl, arylCo-iealkylthioCo-iβalkyl, Co-i6alkylaminoCo-i6alkyl, arylCo- i6alkylaminoCo-i6alkyl, difaryld-iealkylJaminoCo-iealkyl, Ci- i6alkylcarbonylCo-i6alkyl, arylCι-i6alkylcarbonylCo-i6alkyl, Ci- lβalkylcarboxyCo-iβalkyl, arylCi-iθalkylcarboxyCo-iβalkyl, Ci- i6alkylcarbonylaminoCo-i6alkyl, arylCi-iδalkylcarbonylaminoCo- iβalkyl, -Co-iealkylCOORi, -C0-i6alkylCONR2R3 wherein Ri, R2 and R3 are independently selected from hydrogen, Ci-Cnalkyl, arylCo-Ciialkyl, or R2 and R3 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci- Ci6alkyl, arylCo-Ciβalkyl, or Co-Ciβalkylaryl substituent. The definition of aryl includes but is not limited to phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl.
The term "arylalkyl" (e.g. (4-hydroxyphenyl) ethyl, (2- aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.
In the above definitions, the terms "alkyl" and "alkenyl" maybe used interchangeably in so far as a stable chemical entity is formed, as obvious to those skilled in the art. The compounds of the present invention also includes racemic mixtures, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds (Goding; Monoclonal Antibodies Principles and Practice; Academic Press, p.104 (1986)). Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral chromatography (Eliel, E. L. and Wilen S.H.; Stereochemistry in Organic Compounds; John Wiley & Sons, New York, (1993)).
The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
Detailed Description This application relates to compounds having the general Formulas 1, 2 and 3. Accordingly, an object of the present invention is to provide a method for inhibiting or modulating selectins in a mammal by the administration of a compound according to the general Formulas 1, 2 and 3 as defined below. In addition, this application relates to the preparation of said compounds, to compositions comprising the compounds, to their use for treating human or animal disorders, to their use for purification of proteins, and to their use in diagnostics or medical devices.
Figure imgf000017_0001
Formula 1 Where at least one and no more than two of R1, R2, R3, R4 or R5 =
.Calcium binding moiety
Figure imgf000017_0002
Formula 2 as defined in Group 1
Figure imgf000017_0003
Formula 3
Formulas 1, 2 and 3
The present invention relates to compounds having General Formula 1, General Formula 2, and General Formula 3 wherein at least one and no more than two of R1, R2, R3 or R4 must be selected from Group I. The following substitution patterns are possible for the remaining R groups:
Case A: When one of R1, R2, R3, R , or *R5 (*in General Formula 3) is selected from Group I (templates 1-6), one of R1, R2, R3, R4 or *R5 must be selected from Group II, one of R1, R2, R3, R4 and *R5 must be selected from Group III and one of R1, R2, R3, R4 and *R5 must be selected from Group IV. The remaining R group must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined below;
Case B: When two of R1, R2, R3, R4,or *R5 (*in General Formula 3) are selected from Group I (templates 1-6), one of R1, R2, R3, R4 or *R5 must be selected from Group II, and one of R1, R2, R3, R4 or *R5 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined below; Case C: When one of R1, R2, R3, R4, or *R5 (*in General
Formula 3) is selected from Group I (template 7), one of R1, R2, R3, R4 or *R5 must be selected from Group V, and one of R1, R2, R3, R4 or *R5 must be selected from Group VI. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined below;
Case D: When two of R1, R2, R3, R4, or *R5 (*in General Formula 3) are selected from Group I (template 7), one of R1, R2, R3, R4 or *R5 must be selected from Group V. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, V, and VI are defined below; Definitions of Group I through Group IV
Group I is defined in Figure 1 , Table 1 , below:
Group I =
Figure imgf000018_0001
where R6 equals one of the following in Table 2: Figure 1
Table 1
Figure imgf000019_0001
Table l(cont.)
Figure imgf000020_0001
Table l(cont.)
Figure imgf000021_0001
(
Group II is defined as one of the following:
(i) C0-6CO2R11, Co-eCONHR11, Co-eNHCOR11, Co-
6NHC(0)NHR", C0-6NHSO2R11, wherein R11 is C8-i6 alkyl,, or C3-8 alkylaiyl, in which the said aryl group such as phenyl, thienyl, imidazoyl, indolyl, furyl or pyridyl, is mono- or disubstituted with a member selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, Cι-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or Ci- 4 alkyloxy; or (ii) substituted or unsubstituted Cs-i6 alkyl or substituted
Cs-ie alkenyl, wherein the substituents are selected from the group consisting of hydrogen, hydroxy, C1.-6 alkyloxy, amino, C1-6 alkylamino, or C1-6 dialkylamino, or aryl; or (iii) Unsubstituted, mono-, di-, or tri-substituted aryl-Co-11 alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of: (a) C0-6CO2R12, Co-eCON(*H)R12, Co-6NHS02R12, transCH=CHC02R12, rαns-CH=CHCON(*H)R12, or cyclopropylCON(*H)R12 wherein R12 is Cβ-iβ alkyl, bis- C4-16 alkyl (* no H), N-(methyl) C8-ι6 alkyl (* no H), C8-i6 alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaiyl, C 1-5 alkylaiyl C 1-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group such as phenyl, thienyl, imidazoyl, C or N-linked indolyl, furyl, benzo triazole, or pyridyl, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, C1-6 alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or Ci-4 alkyloxy; or R10 can be N-Boc-piperidino, or N- carboethoxypiperidino; Group III is defined as either: (i) Hydrogen; or (ii) Unsubstituted, mono or disubstituted Ci-iβ alkyl, Co-i6 alkylamino, amino Co-iβ alkyl, Co-6 alkylcarboxyl or Co-6 alkyl carboxyl ester, Co-iβ alkyloxyalkyl or C2-16 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Cι-8 alkyl, Cι-8 alkyloxyalkyl, Ci-β alkylthioalkyl, phenyl-Ci-s alkylamino,
C 1-8 alkoxycarbonyl; or Co-6 carboxyl, triazole, 2,3- (methylenedioxy) benzyl; or (iii) substituted or unsubstituted N or C-linked pyrrolidino, piperidino, piperidonyl, morpholino, piperazino, N-Boc- piperazino, N-Cι-10 alkylpiperazino, N-C3-6 alkenylpiperazino, N-(Cι-β aikoxy C1-6 alkyl) piperazino, N- (C1-6 aikoxy C3-6 alkenyl) piperazino, N-(Cι-6 alkylamino Ci- 6 alkyl) piperazino, N-(Cι-6 alkylamino C3-6 alkenyl) piperazino, uracil or other purine or pyrimidine heterocycles, wherein the substituents are N or C-linked as will be apparent to one skilled in the art, and are independently selected from:
(a) substituted Ci-iβ alkyloxy, C3-16 alkenyloxy, substituted C3-16 alkynyloxy; or (b) substituted Ci-e alkyl-amino, di(substituted Ci-β alkyl) amino; or (c) CONHC1-C16 alkyl, COOCi-Ciβ alkyl, Co-11 alkylC02H, C0-ιιNHC(O)NHR11, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHR wherein R11 is hydrogen, Ci-iβ alkyl, or C1-16 alkyl aryl, in which the said aryl group such as phenyl, or pyridyl, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and Cι-6 alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, Ci- 4 alkyloxy, and aryl; or
(iv) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl such as phenyl, imidazolyl, furanoyl, pyrimidino, pyridino, or N or C-linked pyrrole or imidazolyl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) unsubstituted or substituted C0-3 alkyloxy C0-3 alkyl, C3-16 alkenyloxy, substituted C3-16 alkynyloxy, aryl such as phenyl; or (c) mono or di-substituted C1-6 alkyl-amino, di(substituted Ci-β alkyl)amino; or (d) CONHC1-C16 alkyl, COOCi-Cie alkyl, Co-11 alkylC02H, C0-ιιNHC(O)NHRH, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRH wherein R11 is hydrogen, Cι-ι6 alkyl, or Ci-iβ alkyl aryl, in which the said aryl group such as phenyl, or pyridyl, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Cι-6 alkyl and C1-6 alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, Ci- 4 alkyloxy, and aryl.
(e) O- or C-linked hexose or furanose such as mannose or fucose. Group IV is defined as either: (i)hydrogen; or (ii) substituted or unsubstituted Ci-iβ alkyl or C2-i2 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Ci-β alkyloxy, Ci-βalkylthio, Cι-6 alkylamino, phenyl-Ci-β alkylamino, Cι-6 alkoxycarbonyl; or (iv) mono, di or tri-substituted aryl C0-4 alkyl or substituted C0-4 alkyl aryl, wherein the aryl group is selected from phenyl, imidazolyl, indolyl, furyl, thienyl or pyridyl in which the substituents are selected from: (a)hydrogen; or (b) hydroxy or halo
Group V is defined as one of the following:
(i) Unsubstituted, mono-, di-, or tri-substituted aryl- Co-11 alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of:
(a) C0-6CO2R12, Co-eCON(*H)R12, C0-6NHSO2R12, trans- CH=CHC02R12, irans-CH=CHCON(*H)Ri2, or cyclopropylCON(*H)R12 wherein R12 is Cβ-i6 alkyl, bis- C4-16 alkyl (* no H), N-(methyl) Cs-ie alkyl (* no H), C8-ι6 alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaiyl, C 1-5 alkylaiyl Cι-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group such as phenyl, thienyl, imidazoyl, C or N-linked indolyl, furyl, benzotriazole, or pyridyl, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Ci-e alkyl and Cι-6 alkyloxy, C1-6 cycloalkyloxy, C1-C4 alkyl. Group VI is defined as one of the following: (i) Hydrogen; or
(ii) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl such as phenyl, imidazolyl, furanoyl, pyrimidino, pyridino, or N or C-linked pyrrole or imidazolyl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) CONHC1-C16 alkyl, CONHCι-2 bis- C2-4 alkyl, COOC1-C16 alkyl, Co-11 alkylC02H, C0- ιιNHC(0)NHR , C0-11NHSO2R11, trans-
CH=CHC02RH, or trans- CH=CHCONHR" wherein R11 is hydrogen, Ci-iβ alkyl, or Ci-iβ alkyl aryl, in which the said aryl groups such as phenyl, or pyridyl, or alkyl groups are mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Ci-β alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, Ci- 4 alkyloxy, and aryl. (c) O- or C-linked hexose or furanose such as mannose or fucose. Detailed Description
The present invention related to compounds of the general formula A.
More particularly, the present invention relates to the compounds listed below in Figure 2 or pharmaceutically acceptable salts or esters thereof:
Example 1 Example 2
Figure imgf000028_0001
Example 3
Figure imgf000028_0003
Figure imgf000028_0002
Example 5 Example 6
Figure imgf000028_0004
Figure imgf000029_0001
Figure imgf000030_0001
Example 19 Example 20
Figure imgf000030_0002
Example 21
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000030_0005
Figure imgf000031_0001
Figure 2 (cont.)
Figure imgf000032_0001
Figure imgf000033_0001
Example 43
Figure imgf000033_0003
Example 45
Figure imgf000033_0004
Example 47
Figure imgf000033_0002
Figure imgf000033_0005
Figure 2 (cont.) Example 49 Example 50
Figure imgf000034_0001
Example 51
Figure imgf000034_0003
Figure imgf000034_0002
Example 53 Example 54
Figure imgf000034_0004
Figure imgf000035_0001
Example 61 Example 62
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000037_0001
Example 75 Example 76
Figure imgf000037_0002
Example 79 Example 80
Figure imgf000037_0003
Figure 2 (cont.) Example 74
Figure imgf000038_0001
Figure imgf000038_0002
Example 75
Exam le 76
Figure imgf000038_0003
Figure 2 (cont.) Example 89
Example 90
Figure imgf000039_0001
Figure 2 (cont.)
The compounds depicted in Figure 2 are named as follows:
Example 1 3- 4-(2-(4-Diethylamino-phenvH-5-{4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-l.Hr-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 190
Example 2 3-r4-(2-(4-Diethylamino-phenyl)-5-{4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyll-phenyl}-lJ f-imidazol-4-yl)-phenyl - 4,5-dihydro-isoxazole-5-carboxylic acid 191 Example 3
3-{4-f5-{4-f(E)-2-(3-Phenyl-ρropylcarbamoyl)-vinyll-phenyl}-2- (2,4,6-trimethyl-phenyl)-lff-imidazol-4-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 192
Example 4 3-{4-(5-{4-r(E)-2-(3-Phenyl-proρylcarbamoyl)-vinyl - phenyl}-2-(4-pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 193
Example 5 3-[4-(2-(4-Carboxy-phenyl)-5-{4-f(E)-2-(3-phenyl- propylcarbamoyl)-vinyl -phenyl}-lJEf-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid 194
Example 6 3-r4-(2-(4-Diethylamino-2-hydroxy-phenyl)-5-{4-r(E)-2- (3-phenyl-propylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-4- yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 195
Example 7 3-{4-r5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyl]-2-(2- hydroxy-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5-dihydro- isoxazole-5-carboxylic acid 196 Example 8 3-f4-{5-r4-ffE)-2-Dodecylcarbamoyl-vinyl)-ρhenvn-lH- imidazol-4-yl)-phenyl)-4,5-dihvdro-isoxazole-5-carboxylic acid 197 Example 9
3-(4-{5-r4-((E)-2-Dodecylcarbamoyl-vinv»-phenyl1-2-r4-((E)-2- ethoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 198
Example 10 3-(4-{5-r4-((E)-2-Dodecylcarbamoyl-vinyU-phenvn-2-r4-((E)-2- ethoxycarbonyl-vinyl)-phenyll-lJFf-imidazol-4-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 199
Example 11 3-(4-{2-(2,4-Dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl)-5-r4- ((E)-2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 200
Example 12 3-r4-(2-r4-((E)-2-tert-Butoxycarbonyl-vinyl)-ρhenyn-5-{4- f(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]-phenyl}-l.H'- imidazol-4-yl)-phenyl^-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 201
Example 13 3-r4-(2-r4-((E)-2-Carboxy-vinyl)-phenyn-5-{4-r(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-l.H:-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid 202
Example 14 3-{4-r2-(4-Diethylamino-phenyl)-5-(4-{(E)-2-r2-(lH-indol-3-y»- ethylcarbamoyn-vinyl)-phenyl)-lJFf-imidazol-4-yll-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 203 Example 15 3-{4-r2-(4-Diethylamino-phenvH-5-(4-{(E)-2-r2-(lH-indol-3-yl)- ethylcarbamoyl1-vinyl}-phenyl)-lH-imidazol-4-yl1-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid 204 Example 16
3-r4-(2-r4-Diethylamino-2-hvdroxy-phenyl)-5-{4-r(E)-2-(.V- phenyl-hydrazinocarbonyl)-vinyl]-phenyl}-lff-imidazol-4-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 205
Example 17 3-{4-r2-(4-Diethylamino-2-hvdroxy-phenyl)-5-(4-{(E)-2- 2-(4- fluoro-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lff-imidazol- 4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 206
Example 18 3-{4-f5-(4-{(E)-2-r2-(4-Fluoro-ρhenyl)-ethylcarbamoyn-vinyl}- phenyl)-2-(4-pyrrolidin- 1-yl-phenyl)- lff-imidazol-4-ylj- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 207
Example 19 3-{4-r5-(4-{(E)-2-r2-(4-Fluoro-ρhenyl)-ethylcarbamoyll-vinyl)- phenyl)-2-(4-pyrrolidin-l-yl-phenyl)-lff-imidazol-4-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 208
Example 20 3-{4-r2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2- [(tetrahydro-furan-2-ylmethyl)-carbamoyll-vinyl}-phenyl)- lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 209
Example 21 3-{4-[2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2- r(tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)- lH-imidazol-4-yl1-phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid 210
Example 22 3-{4-r2-f4-Dodecylcarbamoyl-ρhenyl)-5-(4-{|E)-2-r(tetrahydro- furan-2-ylmethyl)-carbamoyl|-vinyl}-phenyl)-lJ-r-imidazol-4- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 211
Example 23 3-{4-[2-(4-Dodecylcarbamoyl-ρhenyl)-5-(4-{(E)-2-r(tetrahydro- furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lff-imidazol-4- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 212
Example 24 r4-(2-r4-((E)-2-Ethoxycarbonyl-vinyH-phenyll-5-{4-r(E)-2-(l- methyl-dodecylcarbamoyl)-vinyl]-phenyl}-lJEf-imidazol-4-yl)- phenoxy]-acetic acid 213
Example 25 (4-{5-{4-f(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl}- 2-f4-((E)-2-ethoxycarbonyl-vinyl)-phenyl1-lff-imidazol-4-yl}- phenoxy)-acetic acid tert-butyl ester 214 Example 26
(4-{5-{4-f(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl}- 2- 4-((E)-2-ethoxycarbonyl-vinyl)-phenyll-l.H:-imidazol-4-yl}- phenoxy)-acetic acid 215
Example 27 (4-{5-{4-f(E)-2-(3H-Benzotriazol-5-ylcarbamoyl)-vinyn- phenyl}-2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lff- imidazol-4-yl}-phenoxy)-acetic acid 216 Example 28 {4-r2-r4-((E)-2-Ethoxycarbonyl-vinyl -phenvn-5-(4-{(E)-2-ri-(4- pentyl-phenyl)-ethylcarbamoyl1-vinyl}-phenyl)-lH-imidazol- 4-yl]-phenoxy}-acetic acid 217 Example 29 r4-(2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenvn-5-{4-»E)-2-(2- methoxy-ethylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-4-yl)- phenoxyl-acetic acid 218
Example 30 r4-(2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenvπ-5-{4-JΪE)-2- (2,2,3,3,4.4,5,5,6,6,7,7,8,8,8-pentadecafluoro- octylcarbamoyl)-vinyll-phenyl|-lH-imidazol-4-yl)-phenoxy|- acetic acid 219
Example 31 (E)-3-(4-{4-(4-Carboxymethoxy-ρhenyl)-5-f4-((E)-2- dihexylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl}-phenyl)- acrylic acid ethyl ester 220
Example 32 3-[4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-{4-JΪE)-2- ( l-methyl-dodecylcarbamoyl)-vinyl]-phenyl}- lH-imidazol-2- yl)-pheny!|-4,5-dih,ydro-isoxazole-5-carboxylic acid tert- butyl ester 221
Example 33 3-r4-(4-(4-Carboxymethoxy-phenyl)-5-{4-f(E)-2-(l-methyl- dodecylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-2-yl)-phenyll- 4,5-dihydro-isoxazole-5-carboxylic acid 222
Example 34 3-{4-r4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-(4-{(E)-2- fl-(4-pentyl-phenyl)-ethylcarbamoyl -vinyl}-phenyl)-li-f- imidazol-2-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 223
Example 35 3-{4-r4-f4-Carboxymethoxy-ρhenyl)-5-(4-{(E)-2-ri-(4-pentyl- phenyl)-ethylcarbamoyll-vinyl}-phenyl)-l. r-imidazol-2-yl1- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 224
Example 36 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-r4-((E1-2- dihexylcarbamoyl-vinyl)-phenyl1-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 225
Example 37 3-f4-(4-(4-Carboxymethoxy-phenyl)-5-{4-f(E)-2-(2-nonyloxy- ethylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl1- 4,5-dihydro-isoxazole-5-carboxylic acid 226 Example 38
3-(4-{5-(4-tert-Butoxycarbonylmethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyH- 1-methyl- lH-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 227
Example 39 3-(4-{5-(4-Carboxymethoxy-ρhenyl)-4-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1-l-methyl-lH-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228 Example 40
3-{4-r5-r4-((E)-2-Dodecylcarbamoyl-vinyH-phenyn-4-(4- ethoxycarbonylmethoxy-phenyl)-l-methyl-lH-imidazol-2- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 229 Example 41 3-{4-r5-r4-((E)-2-Dodecylcarbamoyl-vinv»-phenvn-4-(4- ethoxycarbonylmethoxy-phenyl)-l-methyl-lJEf-imidazol-2- yn-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 230 Example 42
3-(4-{4-(4-Carboxymethoxy-phenyl>-5-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 231
Example 43 r5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-phenvn-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol-l-yl]-acetic acid tert-butyl ester 232
Example 44 [5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenylI-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol- 1 -yl]-acetic acid 233
Example 45 {4-(4-Carboxymethoxy-phenyl)-5-|4-((E)-2-dodecylcarbamoyl- vinyl)-phenyl]-imidazol- l-yl}-acetic acid 234 Example 46
3-(4-{4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-f4-((E)-2- dodecylcarbamoyl-vinyl)-phenyll-lff-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 235
Example 47 3-(4-{4-(4-Carboxymethoxy-ρhenyl)-5-f4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1|-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 236 Example 48 (4-{5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2-pyridin-3- yl-lH-imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester 237 Example 49
(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenylj-2-pyridin-3- yl- l-UT-imidazol-4-yl}-phenoxy)-acetic acid 238
Example 50 3-(4-{2-(4-Diethylamino-phenyl)-5-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 239
Example 51 3-{4-f5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl1-2-(4- pyrrolidin-l-yl-phenyl)-lJ-T-imidazol-4-yl -phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 240
Example 52 3-{4-[5-f4-((E)-2-Dodecylcarbamoyl-vinyH-ρhenviy2-(4- pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 241 Example 53
(4-{5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyn-2-r4-((E)- 2-tert-butoxycarbonyl-vinyl)-phenyl]-lJ-r-imidazol-4-yl}- phenoxy)-acetic acid tert-butyl ester 242
Example 54 (4-{2-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-((E)-2- dodecylcarbamoyl-vinyli-phenyl|-lϋf-imidazol-4-yl}- phenoxy)-acetic acid 243
Example 55 3-f4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-{4-f(E)- 2-(hexadecyl-methyl-carbamoyl)-vinyl1-phenyl}-lH- imidazol-2-yl)-phenyl1-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 244
Example 56 3-[4-(4-(4-Carboxymethoxy-phenyH-5-{4-r(E)-2-(dodecyl- methyl-carbamoyl)-vinyl1-phenyl}-lH-imidazol-2-yl)- phenyl -4,5-dihydro-isoxazole-5-carboxylic acid 245
Example 57 3-(4-{4-(4-tert-butoxycarbonylmethoxy-phenyl)-5-|4-(2- hexadecylcarbamoyl-cyclopropyl)-phenyl)-lH-imidazol- 2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 246
Example 58 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-F4-(2- hexadecylcarbamoyl-cyclopropyl)-phenyl -lH-imidazol- 2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 247
Example 59 fE)-3-{4-r4-r4-J(E)-2-Carboxy-vinyl)-phenyll-5-(4- dodecylcarbamoyl-phenyl)-lff-imidazol-2-yl]-phenyl}- acrylic acid 111
Example 60 3-{4-f5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-2- (2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yll-phenyl}- acrylic acid 248 Example 61
(E)-3-(4-f5-r4-(fE)-2-Hexadecylcarbamoyl-vinyl)-phenyπ- lH-imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 249 Example 62 (E)-3-(4-{5-r4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl1- lH-imidazol-4-yl}-phenyl)-acrylic acid 250
Example 63 3-(4-{5-r4-(2-Hexadecylcarbamoyl-ethyl)-ρhenyiyiH- imidazol-4-yl}-phenyl)-propionic acid 251
Example 64 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyn-5-f4- (2-hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl)- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 252
Example 65 3-(4-f4-r4-((E)-2-Carboxy-vinyl)-phenyη-5-f4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 253
Example 66 (E)-3-(4-{2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-f4- (2-hexadecylcarbamoyl-vinyl)-phenyl -li-f-imidazol-4-yl}- phenyl)-acrylic acid tert-butyl ester 254 Example 67
(E)-3-(4-{2-r4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl1-5-r4- (2-hexadecylcarbamoyl-vinyl)-phenyl]-l,flr-imidazol-4-yl}- phenyl)-acrylic acid 255
Example 68 (E)-3-(4-{2-f4-((E)-2-Carboxy-vinyl)-phenyn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenylj-l.ff-imidazol-4-yI}- phenyl)-acrylic acid 256 Example 69 3-(4-{4-r4-((E)-2-Carboxy-vinvH-phenvn-5-r4-(2- dodecylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 257 Example 70
3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenvn-5-r4-(2- dodecylcarbamoyl-vinyl)-phenyl -lH-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid 258
Example 71 3-(4-{4-f4-((E)-2-Carboxy-vinyl)-phenyn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester 259
Example 72 3-(4-{4-f4-((E)-2-Carboxy-vinyl)-phenyn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid ethyl ester 260
Example 73 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyπ-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid 261
Example 74 3-f4-(4-f4-((E)-2-tert-Butoxycarbonyl-vinyl)-ρhenyl1-5-{4- [2-(4-heptyl-phenylcarbamoyl)-vinyl1-phenyl}-li-r- imidazol-2-yl)-phenyl]-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 262
Example 75 3.f4-(4-f4-((E)-2-Carboxy-vinyl)-phenyn-5-{4-[2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)- phenyl -4,5-dihydro-isoxazole-5-carboxylic acid 263 Example 76 3-(4-{4-j4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyll-5-f4- (2-dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 264
Example 77 3-(4-{4-f4-((E)-2-Carboxy-vinyl)-phenyl1-5-r4-(2- dihexylcarbamoyl-vinyl)-phenyll-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 265 Example 78
(E)-3-r4-(5-{4-r(E)-2-(4-Heptyl-phenylcarbamoy»-vinyn- phenyl}-lH-imidazol-4-yl)-phenyl|-acrylic acid tert-butyl ester 266
Example 79 (E)-3- 4-(5-{4-r(E)-2-(4-Heptyl-phenylcarbamoyl -vinvn- phenyl}- 1 H-imidazol-4-yl)-phenyl]-acrylic acid 267
Example 80 (E)-3-(4-{5-f4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyn-lH- imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 268 Example 81
(E)-3-(4-{5-r4-((E)-2-Dihexylcarbamoyl-vinyl)-phenvn-lH- imidazol-4-yl}-phenyl)-acrylic acid 269
Example 82 3-f3-(4-{5-r4-((E)-2-Hexadecylcarbamoyl-vinyl)-ρhenyll- lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid 160a
Example 83 3-r3-(4-{5-r4-(fE)-2-Hexadecylcarbamoyl-vinyl)-phenvn- lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid 270 Example 84 3-f4-(5-Benzylcarbamoyl-l-hexadecyl-4-phenyl-lH- imidazol-2-yl)-phenyπ-4,5-dihydro-isoxazole-5- carboxylic acid 147 Example 85
3-(4-{4-[4-(tert-Butoxycarbonylmethyl-carbamoyl)- phenyl]-5-decyl-liJ-imidazol-2-yl}-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 81
Example 86 3-(4-{4-[4-(Carboxymethyl-carbamoyl)-phenyl]-5-decyl- lH-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid 82
Example 87 Compound 104 Example 88
Compound 105 Example 89 (E)-3-(4-{5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyn-4- f4-(2-hydroxy-l-hydroxymethyl-ethylcarbamoyl|- phenyl]-! JET- imidazol-2-yl}-phenyl)-acrylic acid tert-butyl ester 94
Example 90 (E)-3-(4-{5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-phenvn-4- f4-(2-hydroxy-l-hydroxymethyl-ethylcarbamoyl)- phenyl]- 1 JET- imidazol-2-yl}-phenyl)-acrylic acid 95
When the compounds of the current invention have asymmetric centers they may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers, with all isomeric forms being included in the present invention as well as mixtures thereof. Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as -CU2H, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. Basic groups, such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
Also, in the case of the -CO2H being present, pharmaceutically acceptable esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, acetoxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
Synthetic Procedures
General references to methodologies for the synthesis of the compounds of the present invention are described in the following references 1) Drayton, C. J., Comprehensive Heterocyclic Chemistry, 1st ed; Pergamon: Oxford, 1984 and 2) Joule, J. A.; Mills, K.; and Smith, G.F., Heterocylic Chemistry, 3rd ed; Chapman and Hall, 1995.
The synthesis of the pyrrole, thiophene and furan templates is well documented. An example of the synthesis of the pyrrole 3 and 12 template {via the Paal Knorr) synthesis, which involves the reaction of 1 ,4 dicarbonyl compounds 1 and 9 and primary amines 2 is shown below (Schemes 1 and 2) (Wynberg, Ace. Chem. Res., 4, p65 (1971)).
2
Figure imgf000054_0001
Scheme 1
Figure imgf000054_0002
Works best when
Figure imgf000054_0003
Scheme 2
Substituted pyrroles can also be made through intermediates generated via the Ugi reaction (Mjalli et al, Tetrahedron Lett, 37, ρ2943 (1996)).
The thiophene and furan templates can also be synthesized using similar chemistry to that shown for the pyrroles (Schemes 1 and 2). The thiophene template can be made via the reaction of 1 ,4-dicarbonyl compounds and a source of sulfur (1,4- dicarbonyl synthesis illustrated in Scheme 3). Lawesson's reagent has been reported as the reagent of choice to effect this transformation (Shridar et al, Synthesis, 1061 (1982)). The furan template can also be made from the dehydration of 1 ,4 dicarbonyl compounds (the Paal- Knorr synthesis), usually using non-aqueous acidic conditions (Nowlin et al, J. Am. Chem. Soc, 72, p5754 (1950); Traylelis et al, J. Org. Chem., 29, pl23, (1964); Scott et al, Synthesis, p209 (1973)) (Scheme 3).
Figure imgf000055_0001
Scheme 3
More specific examples of, and references to, methodologies for the preparation of the oxazole and imidazole can be found in Gauthier et al, Bioorg. & Med. Chem., 6, 87-92, (1996); Maduskuie et al, J. Med. Chem., 38, 1067-1083 (1995); Mjalli et al, US. Patent, 5 753 687 (Application Number 766 114).
The reaction sequence shown in Scheme 4 can be utilized to synthesize tri- or tetra- substituted imidazole derivatives 18. The reaction of a dione 15 with an aldehyde 16, with the addition of an alkyl amine 17 for N-substituted imidazoles (this reaction is not regio selective and will give a mixture of two compounds) in the presence of ammonium acetate and acetic acid gives the imidazole 18 in good yield.
Figure imgf000056_0001
Scheme 4
A number of methods can be used to synthesize the dione intermediates. Scheme 5 illustrates a general methodology for the synthesis of dione 24, from readily available starting materials, utilizing a Wittig reaction.
Figure imgf000056_0002
Scheme 5 Aldehyde 19 is reacted with the Wittig reagent 20 to give the alkene 21. The double bond of 21 is then oxidized to the epoxide 22, which in turn is hydrolyzed to the diol 23 via treatment with formic acid and subsequent hydrolyses of the resulting formic acid ester intermediate during workup. The diol 23 is then oxidized to the required dione 24 via a TEMPO oxidation. This dione 24 can be used directly to form an imidazole as illustrated below in Scheme 6.
General derivatization of intermediate diones such as 24 can be achieved via a Heck reaction for example. The Heck reaction can be used to attach an acrylamide side chain as a desired R group to give compounds such as cinnamic acid 25, or a cinnamic acid ester. The resulting acid or esters can themselves be derivatized, an example being via condensation with an amine (after hydrolyses of the ester if esterified) to form an amide 27, as illustrated in Scheme 6.
Heck reaction acrylic acid
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
Scheme 6
An example of the synthesis of a non- commercially available aldehyde as a starting material for Scheme 5 is illustrated in Scheme 7. Terephthalaldehyde mono-diethyl acetal 30 is treated with hydroxylamine and triethylamine
(TEA) to give the corresponding oxime 31. This oxime 31 after oxidation with bleach undergoes a 3 + 2 cycloaddition reaction with t~butyl (methyl or ethyl) acrylate 32 to afford the 4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 33. The diethyl acetal- protecting group of 33 is then removed via acid hydrolyses to reveal the aldehyde 34. The isoxazole 37 can be synthesized in a similar manner using the alkyne 35 in place of the alkene 32.
Figure imgf000058_0001
Scheme 7
A general procedure for the synthesis of the Wittig reagent 39 as starting material for Scheme 5 is outlined in Scheme 8.
Figure imgf000058_0002
38 18 h 39
Scheme 8
Schemes 9, 10 and 11 illustrate specific examples of the synthesis of imidazoles, as described in the current invention, using the general methods outlined in Schemes 5 and 6.
In Scheme 9 aldehyde 34 is reacted with Wittig reagent
39, to give alkene 40. This alkene is oxidized with mCPBA to the epoxide 41. The epoxide 41 is opened to give the diol 42, which is in turn oxidized to the dione 43. The dione 43 can be functionalized via a Heck reaction with acrylic acid, to give the cinnamic acid derivative 44. This acid 44 can the be condensed with an amine 45 to give the derivatized dione 46, which can then be used to make the imidazole 47.
Figure imgf000059_0001
Scheme 9
Scheme 10 illustrates a dione synthesis which includes a step for the derivatization of the intermediate alkene 49 to give ultimately a phenoxy acetic acid dione 54 which has been used routinely for the synthesis of imidazole compounds described in the current invention.
Figure imgf000060_0001
Scheme 10
Scheme 11 illustrates the use of dione 54 for imidazole synthesis. The dione can be derivatized to the acrylamide 59 and then converted to imidazole 60. The imidazoles 55 and 56 can be derivatized by direct attachment of an acrylamide 57 (that is made in situ from the appropriate amine and acroyl chloride) to give imidazoles 60 and 58 respectively. Imidazole 60 can be converted to imidazole 58 by ester hydrolysis.
Figure imgf000061_0001
Scheme 11
Scheme 12 illustrates the synthesis of the acrylamide 57. Acroyl chloride is reacted with the appropriate amine 45 to give the acrylamide 57 quantitatively in most cases. This acrylamide 57 can be derivatized by alkylation of the amide NH with iodomethane to give the acrylamide 61 if required. These acrylamides 57 and 61 can then be used directly in the Heck reactions without purification. O
Cl o
NHR2' or NR2"
NH2R2'or NHR2" 57
45 Mel
0
N(Me)R" 61
Scheme 12
Unsymmetrical diones can also be synthesized through a process which starts with a Sonogashira palladium coupling reaction between an aryl halide 62 and an alkyne 70 or TMS- alkyne 63 to give compounds 71 and 64 respectively. Alkyne 71 can be oxidized directly to the dione 72 using ruthenium tetroxide, then utilized for imidazole synthesis to give imidazole 73. If TMS-alkyne 63 is used, removal of the TMS' group with TBAF to give alkyne 65 can be followed with a second Sonogashira coupling to aryl halide 66 followed by oxidation with ruthenium tetroxide to give an unsymmetrical diaryl dione 68 which can then be used for the synthesis of imidazole 69 as illustrated in Scheme 13.
Figure imgf000063_0001
Scheme 13
Specific examples of the synthesis of imidazole derivatives synthesized via the methodologies outlined in Scheme 13 are shown in Schemes 14, 15 and 16.
Scheme 14 shows the conversion of 4-iodobenzoic acid 74 to the acylchloride 75. This acylchloride 75 is reacted without purification with the tert-butyl ester of glycine 76, to give the amide 77. Compound 77 is then coupled to 1- dodecyne 78 to give the alkyne 79. This alkyne 79 is then oxidized to the dione 80 with ruthenium tetroxide. Dione 80 can then be used for the synthesis of imidazole 81 which after treatment with TFA gives the imidazole 82.
76
Figure imgf000064_0001
Scheme 14
Scheme 15 shows the synthesis of the imidazoles 94 and 95 which contain a diol moiety.
Figure imgf000065_0001
Scheme 15
Scheme 16 shows the synthesis of the imidazoles 104 and 105 which contain a mannose moiety. The intermediate dione 88 is also used in Scheme 17.
Figure imgf000066_0001
Scheme 16 The intermediate dione 88 is used in a different way in Scheme 17 than in Scheme 16, with derivatization of the carboxylic acid moiety to a hydrophobic side chain, instead of a polar or hydrophilic side chain, to give dione 108. This dione 108 can be further derivatized via a Heck reaction to dione 109. Dione 109 can then be used to synthesize imidazoles 110 and 111.
Figure imgf000067_0001
Scheme 17
Other diones of interest are represented by the bis- cinnamate 115. This type of dione can be synthesized in a number of ways. Schemes 18 and 19 represent two appraoches. Scheme 18 shows how dione 115 can be synthesized via the condensation of the two aldehydes 112 and 113. The unsymmetrical diol 114 can be isolated and oxidized to the dione 115. This dione 115 can be converted in two steps to dione 117. This dione can then be used to synthesize imidazoles 118 and 119.
Figure imgf000068_0001
LiOH (aq.; = H
Scheme 18
Scheme 19 shows how bis-cinnamates can be synthesized via sequential Heck reactions to give dione 123 which can then be used to synthesized imidazoles 124 and 119.
Figure imgf000069_0001
R = Ηu 124 ■ TFA:DCM 1 :1 R = H 119 -
Scheme 19
Tetrasubstituted imidazoles 134 can be synthesized regiospecifically via the keto-bromide intermediate 130 as illustrated in Scheme 20. The N-substituted imidazoles are also readily accessible via direct alkylation or acylation of the imidazole nitrogen as illustrated in Scheme 21.
Figure imgf000070_0001
BrCH2C02Et or BrCH2C02 fBu Cs2C03, 82%
Figure imgf000070_0002
Scheme 20
Scheme 21 shows the direct alkylation of the imidazole 135 nitrogen with iodomethane, to give a separable mixture of N-alkylated imidazoles 136 and 137. A Heck reaction installs an acrylamide to give imidazoles 138 and 140 which after removal of the tert-butyl esters gives imidazoles 139 and 141 respectively.
Figure imgf000071_0001
Heck Reaction, O
I ^ , 83 ,
~N IUHDR2z' or NR
Figure imgf000071_0002
R1 = fBu 138- TFA:DC R1 = *Bu 140
TFA:D
R1 H 139 1 :1 R1 = H 141 -D CM 1:1
Scheme 21
The Ugi reaction can also be employed to synthesize Ugi intermediates that can be cyclized to give tetra-substituted imidazoles (Zhang et al, Tetrahedron Lett. , 37, p751 (1996)). A specific example of the use of this approach is shown below in Scheme 22.
Figure imgf000071_0003
145
Scheme 22 Imidazoles can be further derivatized. The double bond of imidazole 148 can be converted to the cyclopropyl via treatment with Pd II and diazomethane as shown in Scheme 23.
Figure imgf000072_0001
R^' ^Bu 149-
TFA.DCM R1' = H 150 - 1 :1
Scheme 23
Double bonds can also be reduced on the imidazole 118 or the dione 115 for example, to give the saturated alkyl chain, using Pd/C and hydrogen gas in ethyl acetate as illustrated in Scheme 24.
Figure imgf000073_0001
Scheme 24
Figure imgf000073_0002
119
R= Εu 160 R= H 161 _
Scheme 25 The final imidazole can be further derivativatized to compounds of the current invention by reaction of the acid moiety with an amine for eample as shown in Scheme 25.
Alternative methodologies for the synthesis of the imidazole template include the reaction sequence shown in
Scheme 26, which illustrates a modified version of van Leusen's methodology for imidazole synthesis which proceeds via a 1,3- dipolar cycloaddition of the anion of tolyl sulfide isocyanides to imines. This approach leads to tri-substituted N-alkylated imidazoles (Gallagher et al, Bioorganic and Med.Chem. 5; 49-64
(1997)). Tosylmethyl isocyanide has been used in the synthesis of all three 1,3-azole types (oxazoles, thiazoles and imidazoles) (van Leusen et al; Tetrahedron Lett, p2369 (1972); van Leusen et al, ibid p2373; van Leusen et al, Synthesis, p501
(1977); van Leusen et al, J. Org. Chem., 42, pi 153 (1977)).
Figure imgf000074_0001
Scheme 26
Figure imgf000074_0002
NaHMDS oxaziridine
Figure imgf000074_0003
168 170 Scheme 27 The oxazole template can be synthesized through a common α-halocarbonyl intermediate as illustrated in Scheme 27 (Gauthier et al, Bioorg. & Med. Chem., 6, 87-92, (1996); Harris et al J. Org. Chem, 27, 2705 (1962); Helv. Chim. Acta, 33, 1271, (1950); B. Hulin et al. J. Med. Chem. 39, 3897-3907, (1996)). The oxazole template can also be made from amino acid derivatives (Wipf et al, Bioorg. Med. Chem. Lett., 5, 165- 177 (1997)). The required starting materials for the forgoing synthetic schemes are either commercially available or accessible from readily available starting materials. For example aldehydes and ketones and can be synthesized as shown below (Scheme 28):
171 172
R R R 173
-C02H C02H -C02H H2N HO carboxylic acids amino acids mandelic acids
For aldehydes:
Figure imgf000075_0001
Swern
R-C02H reduction R-CH2OH * R-CHO 174 175 Oxidation 176
For ketones (Schemes 3 and 11):
R AIMe R NMe(OMe) R'- i R R' v-C02H 177 HN e(OMe) O O 178 179 Scheme 28
General methodologies to synthesize the pyrazole, isothiazole, and isoxazole templates (1, 2-azoles), include those illustrated below in schemes 29 and 30. Scheme 29 shows a general methodology for the synthesis of the pyrazole template (S. Bourrain et al, Bioorg. Med. Chem., 6, 1731-1743 (1998)) and the isoxazole template (Wiley et al, Org. Synth., Coll Vol TV, p351, (1963); Brederick, Chem. Ber., 97, p3407 (1964)). 181
Figure imgf000076_0001
N-0
R" 185
Scheme 29
The isoxazole and isothiazole templates can also be synthesized via an alkyne intermediate (Scheme 30) (Reviews:
Quilico et al, ed. Wiley, Wiley Interscience, p. l (1962);
Kochetkov et al, Adv. Heterocycl. Chem., 14, p 43, (1972); Sokolov, Adv. Heterocycl. Chem., 2, p 365, (1963); Wakefield et al, Adv. Heterocycl Chem., 25, p 147, (1979); Wooldridge, Adv.
Heterocycl. Chem., 14, p 1, (1972)).
Figure imgf000076_0002
■R z= CHO or C(O)R"
186 187 NH2SS03- K+ N-S 189
R"^\^ R'
Scheme 30 Experimental Synthetic Description
To further illustrate the practice of this invention, the following examples are included along with the general methods employed to synthesize the compounds described. General Experimental Information
Nuclear magnetic resonance spectra (1H-NMR) were measured on either a Varian (300 MHz) or a Varian (400 MHz). Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS). Data are reported as follows: chemical shift, multiplicity (br=broad, s=singlet, d=doublet, t=triplet, q=quadruplet, m=multiplet), coupling constant (Hz), integration and peak assignment.
Mass spectra were measured using Atmospheric Pressure Chemical Formation (APcI) looking at positive and negative modes on a Micromass LCZ (3 KeV with a probe temperature of 400 °C and a source block at 120 °C).
LC spectra for LC/MS were measured using an eluant of CHsCN (0.1% CF3C02H)/H20 (0.1% CF3CO2H) (V:V) on a Hewlett Packard HP 1100 HPLC, in the range 200-300 nm with a Diode Array Detector (DAD); 5 μl per injection (Gilson 215 Autosampler) at an average concentration of 1 mg/ml; gradient: 10-100% CH3CN in 5 minutes, 100% CH3CN for 1 minute, 100- 10% CH3CN in 0.2 minutes, 10% CH3CN for 1.4 minutes; LC element split 1 :4 directly into ion source (500 μl/min).
The chromatography columns used for LC in LC/MS and HPLC were 50 x 4.6 mm C-8 with 5 μm particle sizes and Zorbax 150 x 4.6 mm C-8 with 5 μm particle sizes, respectively. The same gradient was used in HPLC as in LC for LC/MS. Reactions in solution phase were monitored by thin layer chromatography (TLC) using Merck silica gel 60F-254-coated plates (0.25 mm thickness). Flash chromatography was performed using E. Merck silica gel 60 (230-400 mesh ASTM). Synthetic Methods General Methods
General Method I. - Synthesis of Aldehyde 34 (Scheme 7) General procedure for synthesis of oxime 31 : The aldehyde 30 (10 g, 48 mmol) was dissolved in dioxane (40 mL). Triethylamine (20 mL) was added, followed by hydroxylamine hydrochloride (4 g, 58 mmol). The reaction mixture was sonicated for 3 hours then stirred at room temperature about 3 days. The progress of the reaction was monitored by lH NMR. The reaction was worked up by concentration in vacuo to about 50% of the original volume. Water (60 mL) was added and the reaction extracted with diethyl ether (3 x 40 mL) . The combined organic extracts were then dried (MgS04), and concentrated in vacuo. The oxime 30 was obtained and used crude in the next reaction (10 g, crude yield, 95%: quantitative by NMR).
Data for compound 30: *H NMR (400 MHz, CDC13); 8.0 (s, IH), 7.4 (d, 2H, J = 8), 7.3 (d, 2H, J = 8), 5.4 (s, IH), 3.5 (m, 4H), 1.1 (m, 6H). General procedure for synthesis of aldehyde 34:
The oxime 30 (24.9 g, 112 mmol) was dissolved in THF (200 mL). t-Butyl acrylate 32 (28.6 g, 223 mmol) was added and the reaction mixture cooled to 0 °C. Bleach (5.25% sodium hypochlorite aq.) (400 mL) was added and the reaction mixture allowed to warm to room temperature. When all of the starting material had been consumed, the reaction was worked up via addition of ethyl acetate (200 mL), followed by washing with 10% Na2S203 (50 mL) and brine (50 mL), dried (Na2S04) and concentration in vacuo. The t-butyl acrylate was removed by co-evaporation with toluene (monitored by NMR) to give
16 compound 33. The acetal protecting group of 33 was removed by dissolving the isoxazoline aldehyde 34 in THF/ ater {300 mL/50 mL) followed by addition of acidic amberlite IR-120 ion- exchange resin (2 g). The reaction mixture was stirred at room temperature for 5 hours. The resin was then removed via filtration and the product extracted with DCM. The combined organic extracts were dried (MgS04) and concentrated in vacuo. The aldehyde 34 was obtained as a pale yellow crystalline solid, which was recrystallized from DCM/Hexane (22 g, 92% yield). Data for compound 34: H NMR (400 MHz, CDC13); mixture of isomers: 10.01 (s, IH), 7.95 (d, 2H, J = 8.1), 7.85 (d, 2H, J = 8.1), 5.1 (t, IH, J = 9.6), 3.61 (d, 2H, J = 9.6), 1.5 (s, 9H). General Method 2: Synthesis of Wittig reagent 39 (Scheme 8) 4-Bromobenzyl bromide 38(10 g, 40 mmol) was added to triphenyl phosphine (11 g, 42 mmol), in o-xylene (50 mL). The mixture was heated to 150 °C overnight. The Wittig reagent 39 crystallizes out of solution and is collected by filtration as a white crystalline solid, which is washed with hexane and dried in a dessicator before use. The yield is quantitative. General Method 3: Synthesis of dione 43 via Wittig reaction (Scheme 9) Wittig reaction to give alkene 40:
To the Wittig reagent 39 (22.3 g, 43 mmol) in dry DMSO (65 mL), was added potassium tert-butoxide (5.14 g, 43 mmol) and the mixture was stirred at R.T. After 30 minutes, the aldehyde 34 (11.4 g, 41 mmol) was added in dry THF (150 mL). The reaction was stirred for 1 hour at R.T., then quenched by pouring into ice water (100 mL). This mixture was then extracted with DCM (3 x 100 mL). The combined DCM extracts were washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL). The mixture was dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by silica gel chromatography (eluting with Hexane: Ethyl acetate, 3: 1), to give the desired cis and trans alkenes 40 as a pale yellow oil (9.4 g, 52.9% yield). Data for compound 40: *H NMR (400 MHz, CDC13); cis isomer: 7.64 (d, 2H, J = 7.7), 7.55 (d, 2H, J = 8.2), 7.48 (d, 2H, J = 7.7), 7.40 (d, 2H, J = 8.5), 7.10 (s, 2H), 5.08 (t, IH, J = 9.6), 3.6 (d, . 2H, J = 9.6), 1.5 (s, 9H); trans isomer: 7.55 (d, 2H, J = 8.2), 7.35 (d, 2H, J = 8.5), 7.28 (d, 2H, J = 8.0), 7.10 (d, 2H, J = 8.2), 6.63 (d, IH, J = 12.0), 6.57 (d, IH, J = 12.0), 5.08 (t, IH, J = 9.6), 3.60 (d, 2H, J = 9.9), 1.50 (s, 9H). Preparation of epoxide 41:
The alkene 40 (9.4 g, 22 mmol) was dissolved in DCM (100 mL) and then mCPBA (5 g, 22 mmol, (purity 57-86%)) in DCM (100 mL) was added. The reaction was stirred at 40°C for 10 hours then treated with 10% sodium sulfite until testing with starch paper was negative. The reaction mixture was then extracted with DCM. The combined organic extracts were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The product was concentrated to dryness. The product was purified via flash chromatography eluting with hexane: ethyl acetate (8: 1 then 6: 1). The desired epoxide 41 was obtained as a pale yellow foam (8.9 g, 91% yield) .
Data for compound 41: H NMR (400 MHz, CDCI3); mixture of isomers 7.47 (m, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 7.01 (m, 2H), 4.97 (m, IH), 4.35 (m, 2H), 3.49 (m, 2H), 1.48 (s, 9H). Opening of epoxide 41 to give diol 42: The epoxide 41 (10.8 g) was dissolved in THF (15 mL). The solution was cooled in an ice bath, and formic acid (30 mL) was added slowly followed by water (0.5 mL). The reaction was stirred at 0 °C for 5 hours. On completion, the reaction was concentrated in vacuo. The residue was dissolved in THF (40 mL) and treated with IN NaOH (aq.) until a color change was observed (yellow to brown). The reaction was monitored carefully by tic. On completion, the product was extracted into ethyl acetate (200 mL), dried (MgSθ4) and concentrated in vacuo. The product was purified by column chromatography, eluting with 30% EtOAc in Hexane, to give the desired diol 42 (7.2 g, 64%).
Data for compound 42: XH NMR (400 MHz, CDC13); mixture of isomers (appears as two) 7.56 (d, 2H, J = 8.0), 7.52 (d, 2H, J = 8.0), 7.38 (d, 2H, J = 8.0), 7.35 (d, 2H, J = 8.0), 7.19 (d, 2H, J = 8.0), 7.12 (d, 2H, J = 8.0), 7.03 (d, 2H, J = 8.0), 6.96 (d, 2H, J = 8.0), 5.1-4.95 (m, IH), 4.90-4.80 (m, 3H), 4.70-4.55 ,(m, 2H), 3.60-3.49 (m, 4H), 1.50 (s, 18H). Oxidation of diol 42 to give dione 43:
The diol 42 (1 g, 2.16 mmol) was dissolved in dichloromethane (12 mL). To this mixture was added 0.7M NaBr (1.47 mL, 1.03 mmol), and TEMPO (4 mg, 0.025 mmol) and the reaction mixture cooled to 0 °C. A freshly prepared buffered bleach solution (270 mg, NaHCθ3 dissolved in 16 mL bleach (5.25% sodium hypochlorite aq.)) was added dropwise to the reaction mixture. The reaction mixture was then stirred for a further 15 min. before work up. The reaction was quenched with 10% Na2S2θ3 aq. (30 mL), and extracted with ethyl acetate (3 x 60 mL) . The combined organic layers were then washed with water (30 mL), brine (40 mL), and dried (MgSθ4) and concentrated in vacuo, to afford the dione 43 (841 mg, quantitative), as a pale yellow solid.
Data for compound 43: *H NMR (400 MHz, CDCls); 8.01 (d, 2H, J = 8.5), 7.86 (d, 2H, J = 8.2), 7.83 (d,lH, J = 8.0), 7.69 (d, 2H, J = 8.2), 5.12 (t, IH, J = 9.3), 3.62 (d, 2H, J = 9.4), 1.51 (s, 9H). This solid can be then treated with 50 % TFA in DCM to afford the free acid 43a in quantitative yield. Data for compound 43a: W NMR (300 MHz, DMSO-d6); 8.0 (d, 2H), 7.92 (m, 6H), 5.24 (m, IH), 3.80-3.65 (m, 2H). General Method 4: Synthesis of dione 54 via Wittig reacton (Scheme 10)
A Wittig reaction following the same procedure as outlined in General Method 3, using Wittig reagent 39 (25 g, 49 mmol) in dry THF (300 mL), with IM potassium tert-butoxide in THF (49 mL, 49 mmol) and 4-hydroxy benzaldehyde 48 (5.4 g, 44 mmol) gave the alkene 49 as a yellow solid (10.3 g, 85%). The alkene 49 (8.7 g, 31.6 mmol) and t-butyl bromoacetate 50 (4.9 mL, 33.2 mmol) was dissolved in DMF (80 mL) and then Cs2C0 (11.3 g, 34.8 mmol) was added. The reaction was stirred at R.T. for 16 hours. Upon completion, the reaction mixture was extracted with ethyl acetate (500 mL) and washed with water, 1 N NaOH, water, 10% citric acid, water and dried over anhydrous magnesium sulfate. The product was concentrated to dryness to obtain the derivatized alkene 51 as a white solid (15.8g, >99% crude yield) which was used without further purification in subsequent steps.
Data for compound 51. lH NMR (400MHz: CDCI3); cis isomer: 7.31 (d, 2H, J= 8.4), 7.13 (d, 2H J= 8.4), 7.09 (d, 2H, J= 8.4), 7.73 (d, 2H, J = 8.8) 6.53 (d, IH, J = 12.0), 6.40 (d, IH, J = 12.0), 4.47 (s, 2H), 1.46 (s, 9H). lH NMR (300MHz: CDCI3); trans isomer: 7.44 (d, 2H, J= 8.4), 7.42 (d, 2H, J= 8.4), 7.33 (d, 2H, J= 8.4), 7.02 (d, IH, J = 16.2), 6.89 (d, IH, J= 15.6), 6.87 (d, 2H, J = 8.7), 4.52 (s, 2H), 1.47 (s, 9H). Preparation of intermediate 52: The alkene 51 (3.7 g, 9.5 mmol) was dissolved in DCM
(50 mL) and then mCPBA (4.3 g, purity 57-86%.) was added. The reaction was stirred at 40°C for 8 hours then treated with 10% sodium sulfite until testing with starch paper was negative. The reaction mixture was then extracted with DCM. The combined organic extracts were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The product was concentrated to dryness to obtain the benzoate ester precursor 52 as a yellow foam (12.6g, >99% crude yield) and was used without further purification in subsequent steps.
Data for intermediate 52: *H NMR (300MHz: CDC13); mixture of isomers: 8.03-7.83 (m, 2H), 7.56-7.51 (m, IH), 7.42-7.32 (m, 3H), 7.24-7.00(m, 4H), 6.86-6.74 (m, 2H), 6.04-5.97 (m, IH), 5.06-5.00 (m, IH), 4.48-4.44 (m, 2H), 1.46-1.44 (m, 9H).
Removal of the benzoate ester of 52 to give diol 53:
The benzoate ester 52 (5.3 g, 10.9 mmol) was dissolved in methanol (50 mL). The solution was cooled in an ice bath, and R2CO3 (6.5 g) followed by 5mL DI water were added. The reaction was stirred at 0 °C for 30 minutes. On completion, the product was extracted into ethyl acetate (200mL), wash with saturated NH4CI, water, brine, dried under MgSθ4 and concentrated in vacuo to give a brownish residue. The product was purified by column chromatography, eluting with 20% EtOAc in Hexane, to give the desired diol 53 (3.5 g, 88%) as a light yellow oil.
Data for compound 53: *H NMR (300MHz: CDCI3); mixture of isomers: 7.45-7.32 (m, 2H), 7.16-6.95 (m, 4H), 6.87-6.75 (m, 2H), 4.82-4.57 (m, 2H), 4.52-4.50 (m, 2H), 1.46-1.44 (m, 9H). Oxidation of diol 53 to give dione 54:
The diol 53 (3.5 g, 8.3 mmol) was dissolved in dichloromethane (40 mL). To this mixture was added 0.7M NaBr (7 mL, 1.0 mmol, 0.5 eq,), and TEMPO (16.5 mg, 0.11 mmol, 0.01 eq) and the reaction mixture cooled to 0 °C. A freshly prepared buffered bleach solution (1.2 g, NaHCθ3 dissolved in 70 mL bleach (5.25% sodium hypochlorite aq.)) was added dropwise to the reaction mixture. The reaction mixture was then stirred for a further 15 min. before work up. The reaction was quenched with 10% Na2S2θ3 aq. (200 mL), and extracted with dichloromethane (250 mL). The organic layers was then washed with brine (150 mL), and dried (MgSθ4) and concentrated in vacuo, to afford the dione 54 (3.3g, quantitative), as a dark yellow oil. Compound 54: *H NMR (300MHz: CDCI3); 7.96 (d, 2H, J = 9.0), 7.85 (d, 2H, J = 9.0), 7.67 (d, 2H, J = 8.7), 6.98 (d, 2H, J = 9.0), 4.61 (s, 2H), 1.49 (s, 9H).
General Method 5: Heck Reaction on dione 24 to give dione 25 (Scheme 6)
The dione 24 (1 equiv.) was dissolved in DMF (to make 0.14M solution), followed by addition of Pd(OAc)2 (0.02 equiv.), TEA (3 equiv.), (o-Tolyl)sP (0.09 equiv.), and acrylic acid (or acrylamide) (1.2 equiv.). The reaction mixture was heated to 100 °C for 2 hours. The reaction was then quenched via addition of water and extraction with methylene chloride. The combined organic layers were washed with IN HCI (aq.), water, dried (Na2Sθ4), and concentrated in vacuo, to give the desired derivatized dione 25 (90% crude yield). This dione was used for subsequent reactions without further purification. General Method 6: Coupling of amine 26 to dione acid 25 to give amide 27 (Scheme 6)
The dione 25 (1.0 equiv.) was suspended in CHCI3 (to make 0.55M solution). EDCI (1.3 equiv.), HOBt (1.3 equiv.), and TEA (2.0 equiv.), were then added (mixture goes clear on addition of base) and stirred at room temperature for 1 hour. The amine 26 (1.2 equiv.) was then added and the reaction stirred overnight at room temperature. The reaction was then worked up via addition of water and extraction with methylene chloride. The combined organic layers were washed with IN HCI (aq.), water, dried (MgS04), and concentrated in vacuo. The product was then purified via flash chromatography.
General Method 7: Synthesis of Imidazole Core (Scheme 6)
Acetic acid (20 mL) was added to a mixture of the dione 27 (1.0 equiv.), aldehyde (1.5 equiv.) and NH4OAc (30 equiv.), and heated to 100 °C for ~ 2 hours. The reaction has to be monitored carefully if t-butyl groups are present, as these will be removed with prolonged heating. The reaction mixture was extracted with ethyl acetate and washed with water, then back extract with ethyl acetate. The organic layers were combined, dried (MgS04) and concentrated in vacuo. The imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1). The compound fluoresces as a yellow spot on TLC under long wave UV lamp. The desired imidazole is obtained as a yellow or white solid. General Method 8: Protocol for synthesis of imidazoles 58 and 60 via the Heck reaction (Scheme 11)
The Br imidazole 55 or 56 (1 equiv.) was dissolved in DMF (0.5-1.OM), followed by addition of Pd(OAc)2 (0.2 equiv.), TEA (2 equiv.), (o-Tolyl)3P (0.4 equiv.), and an acrylamide 57 (1.2 equiv.). The reaction mixture was heated to 100 °C for 1-2 hours.
The reaction was then quenched via addition of water, (acidified to pH 1-2 with IN HCI if starting from Br imidazole 56) and extracted with ethyl acetate (2x) . The combined organic layers were washed with water and brine, dried with (MgSθ4), and concentrated in vacuo to give a yellow oil. The crude was purified by column chromatography, eluting with hexane/ethyl acetate (methanol in dichloromethane with 1% formic acid if from 56), to give the desired imidazole. The purified compound was then recrystallized to give the desired compound as a yellow solid. General Method 9: Synthesis of Acrylamide 57 (Scheme 12). Acrylamides 57 were prepared by adding acryloyl chloride (1 equiv.) to a cooled solution (0 °C) of the desired amine 45 (1.0 equiv.) in dichloromethane (0.5M) with triethylamine (1.0 equiv.) as base. These acrylamides were used directly, without purification in the Heck reaction (Scheme 11 for example).
General Method 10: Hydrolyses of a methyl or ethyl ester
A mixture of ethyl or methyl ester (1 equiv.), IN LiOH (15 equiv.), and 1,4-Dioxane (0.3 M of ethyl ester) was stirred at rt. overnight. The reaction mixture was acidified with IN HCI and extracted with ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over MgSθ4 and concentrated to dryness. The final acid was reciystallized using isopropyl alcohol and ethyl acetate. General Method 11: Hydrolyses of a t-butyl ester The t-Butyl ester was dissolved in 50% TFA dichloromethane solution with ice bath. The reaction stirred at 0 °C for ~ 1 hour. The reaction mixture was then concentrated in vacuo. The product was precipitated with a mixture of acetonitrile (few drops) and ether, and collected via filtration. This product can be reciystallized from methanol/ ethyl acetate. General Method 12: Synthesis of dione 115 via condensation of two aldehydes 112 and 113 (Scheme 18)
Methyl 4-formylcinnamate 113 (5 g, 0.026 moles) and t- butyl 4-formylcinnamate 112 (3 g, 0.013 moles) were dissolved in dry THF (70 mL). Pyridine (6 mL) was then added followed by TiCl3 (1.0 M in DCM/THF, 95 mL, 0.091moles). The reaction was allowed to stir for 1 hour at ambient then 18 hours at -20 °C. Additional TiCl3 (1.0 M in DCM/THF, 20 mL) was added and the reaction stirred at ambient temperature for a further 5 hours. The reaction was then concentrated in vacuo by to remove approximately 60% of the solvent, then quenched via addition of sat. NaHC03. The mixture is then filtered through celite and the resulting solution extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were then washed with brine and concentrated in vacuo. The desired product was then purified via column chromatography eluting with a gradient of ethyl acetate in hexane (20-40%). To give the desired diol 114 (1.5g, 24.7%). Data for compound 114: Η-NMR (300 MHz, CDCI3): 7.51 (d, 2H, J= 8.4), 7.49 (d, IH, J = 15.6), 7.35 (d, 2H, J= 8.1), 7.14-7.08 (m, 4H), 6.30 (d, IH, J = 15.9), 5.20-5.14 (m, IH), 4.69 (br, t, 2H, J= 9.7), 3.82 (s, 3H), 3.61-3.58 (m, 2H), 3.19 (d, 2H, J = 18), 1.52 (s, 9H). Oxidation of diol 114 to give dione 115:
The diol 114 (1.5 g, 3.21 mmoles) was dissolved in dichloromethane (10 mL). To this mixture was added 0.7 M NaBr (2.18 mL, 1.53 mmoles), TEMPO (5.9 mg, 0.037 mmoles) and the reaction mixture cooled to 0 °C. A freshly prepared buffer bleach solution (401 mg, NaHCθ3 dissoved in 24 mL bleach (5.25% sodium hydrochlorite aq.) was added dropwise to the reaction mixture was then srirred for futher 15 min. before work up. The reaction was quenched with 10% Na2S2θ3 aq. (44 mL), and extracted with ethyl acetate (3 X 80 mL). The combined organic layers were then washed with water (40 mL), and brine (50 mL), and dried (MgSθ4) and concentrated in vacuo, to afford the dione 115 (1.5 g, quantitative), as a pale yellow solid. Data for compound 115: Η-NMR (300 MHz, CDCI3): 8.03 (d, 2H, J = 8.7), 7.99 (d, 2H, J = 8.1), 7.83 (d, 2H, J= 8.7), 7.64 (d, 2H, J= 8.4), 7.60 (d, IH, J = 16.0), 6.49 (d, IH, J = 15.9), 5.31-5.23 (m, IH), 4.03 (s, 3H), 3.70-3.65 (m, 2H), 1.54 (s, 9H). General Method 13: Synthesis of keto-bromide intermediate 130 (where R1 = Et) (Scheme 20)
4-Bromobenzyl-4-methoxyphenylketone 127 To a mixture of jp-bromo-phenylacetic acid 126 (51g, 237 mmol, 1 equiv.), and SOCl2 (35 mL, 480 mmol, 2 equiv.), was added 1 drop of DMF. The mixture was stirred at 60°C for 30 min. then concentrated under reduced pressure. The residue was dissolved in CHCI3 (140 mL), and AICI3 (35 g, 262 mmol, 1.1 equiv.) was added to the solution portionwise at 0° C. To this mixture was added anisole (30 g, 277 mmol, 1.2 equiv.) dropwise at 0° C, and the mixture stirred at 0° C for 15 min and r.t. for 1 h. The reaction mixture was poured onto ice- water, and extracted with CHCI3 (3 x 150 mL). The combined extracts were washed with sat. NaHCθ3 (aq.) (2 x 200 mL), and water (3 x 200 mL), dried (MgSθ4), and concentrated under reduced pressure. The residue was suspended in hexane, and the insoluble material collected by filtration to give 4- Bromobenzyl-4-methoxyphenylketone 127 65g (90%). Data for Compound 127: iH-NMR (300 MHz, CDCI3): 7.98 (d, 2H, J= 9.0), 7.45 (d, 2H, J= 8.4), 7.15 (d, 2H, J = 8.4), 6.94 (d, 2H, J = 9.0), 4.20 (s, 2H), 3.88 (s, 3H). 4-Bromobenzyl-4-hydoxyphenylketone 128
A mixture of 4-Bromobenzyl-4-methyloxyphenylketone 127 (65 g, 213 mmol), Lil (50 g, 374 mmol) and collidine (100 mL) was stirred at 180° C for 3 h. The reaction mixture was diluted with ethylene glycol (100 mL) and stirred at 180 ° C for 30 min. The mixture was cooled, acidified to pH 1 with dilute (IN) HCI, and extracted with EtOAc (3 x 150 mL). The combined extracts were washed with water (3 x 200 mL), Sat. NaHCθ3 (200 mL), and brine (3 x 200 mL), successively, dried (MgSθ4), and concentrated under reduced pressure. The residue was recrystallized using EtOAc to give 4-Bromobenzyl-4- hydoxyphenylketone 128 50 g (81%).
Data for compound 128: Η-NMR (300 MHz, CDCI3): 7.93 (d, 2H, J - 8.7), 7.50 (d, 2H, J = 8.4), 7.41 (d, 2H, J = 8.7), 6.89 (d, 2H, J = 9.0), 6.29 (s, 2H). 4-[4-Bromophenylacetyl]phenoxyacetic ethyl ester (R1 = Et) 129
A mixture of 4-Bromobenzyl-4-hydoxyphenylketone 128 (50 g, 172 mmol, 1.0 equiv.), ethyl bromoacetate (30 g, 180 mmol, 1.05 equiv.), CS2CO3 (60 g, 184 mmol, 1.07 equiv.) and DMF (300 mL) was stirred at r.t .for 1 hr. The reaction mixture was diluted with water (200 mL), and the resulting solid was collected by filtration. The solid was recrystallized from EtOH to give 4-[4-Bromophenylacetyl]phenoxy acetic ethyl ester (R1 = Et) 129 53 g (82%).
Data for Compound 129: Η-NMR (300 MHz, CDCI3): 7.98 (d, 2H, J= 9.3), 7.45 (d, 2H, J= 8.1), 7.13 (d, 2H, J= 8.4), 6.95 (d, 2H, J= 9.0), 4.69 (s, 2H), 4.29 (q, 2H, J= 7.2), 4.19 (s, 2H), 1.31 (t, 3H, J= 7.2). {4[Bromo-(4-bromophenyl) acetyl] phenoxy} acetic acid ethyl ester 130
To a mixture of 4-[(4-bromophenyl)acetyl]phenoxyacetic acid ethyl ester 129 (52 g, 136 mmol) and CHCI3 (400 mL) was added Br2 (7.5 mL) dropwise at 40° C, and the mixture was stirred at r.t. for 1 h. The reaction mixture was washed with Sat. NaHCOs (aq) (2x 200 mL) and water (3 x 200 mL), dried (MgSθ4), and concentrated under reduced pressure. The desire product was recrystallized using ethyl acetate and hexane to give (4[Bromo-(4-bromophenyl) acetyl] phenoxy} acetic acid ethyl ester 130 56 g (90%).
Data for compound 130; Η-NMR (300 MHz, CDCI3): 7.98 (d, 2H, J = 9.0), 7.50 (d, 2H, J = 8.4), 7.41 (d, 2H, J = 8.4), 6.94 (d, 2H, J = 8.7), 6.26 (s, 2H), 4.69 (s, 2H), 4.28 (q, 2H, J = 7.2), 1.30 (t, 3H, J= 7.2). General Method 14: Reduction of double bonds using 10% Pd/C under H2. (Scheme 24)
The compound is dissolved in ethyl acetate (with 10% methanol if necessary for dissolution) (to give ~0.1M solution). 10% Pd/C is added (10 -20 wt %). The reaction is stirred under an atmosphere of H2 gas at ambient pressure for ~ 1 hour. The catalyst is removed via filtration through celite. The resulting compound is purified via recrystallization. General Method 15: Synthesis of dione 123 (Scheme 19) To 4,4'-dibromobenzil 120 (5 g, 14 mmol, 1 equiv.) in
DMF (28 mL, 0.5M) was added Pd(OAφ (94 mg, 0.42 mmol, 0.03 equiv.), P(o-tolyl)3 (511 mg, 1.7 mmol, 0.12 equiv.), TEA (3.9 mL, 28 mmol, 2 equiv.), and t-butyl acrylate (2.9 mL, 20 mmol, 1.45 equiv.). The reaction was stirred at 100 C for lh. After, the acrylamide 57i (2.21 g, 7.5 mmol, 0.55 equiv.) was added and the mixture stirred an additional hour. Upon completion, the mixture was diluted with ethyl acetate. The mixture was extracted with ethyl acetate (400 mL), washed with water (200 mL). The aqueous layer was back extracted with an additional 250 mL ethyl acetate. The combine organic phase was washed with water, dried (MgS04), filtered and concentrated in vacuo to obtain a brown oil. The oil was purified by flash column chromatography eluting with a hexane/ethyl acetate/ dichloromethane mixture to afford the desired product (R2' = Cι H2s) as a light brown solid (1.8 g, 39%).
Data for 123a (R21 = Cι2H2s): Η-NMR (400 MHz, CDCls): 7.98 (d, 2H, J= 6.3), 7.97 (d, 2H, J = 6.0), 7.61-7.58 (m, 6H), 6.52 (d, IH, J= 11.7), 6.49 (d, IH, J= 12.0), 5.77 (t, IH, J = 4.2), 3.39 (q, 2H, J = 5.4), 1.70 (brs, 2H), 1.59-1.54 (m, 9H), 1.33- 1.30 (m, 18H), 0.88 (t, 3H, J = 5.1).
Data for 123b (R2' = Cι6H33): Η-NMR (300 MHz, CDC13): 7.98 (d, 4H, J = 7.2), 7.69-57 (m, 6H), 6.51 (d, IH, J = 15.9), 6.49 (d, IH, J = 15.9), 5.77 (brs, IH), 3.39 (q, 2H, J= 5.4), 1.82 (brs, 2H), 1.52 (s, 9H), 1.29 (s, 26H), 0.90 (t, 3H, J= 5.1). Data for 123c (R2' = PhCyHis): Η-NMR (300 MHz, CDCI3): 8.44 (s, IH), 7.97 (d, 2H, J = 8.7), 7.90 (d, 2H, J = 8.7), 7.71 (d, IH, J= 15.9), 7.66-7.48 (m, 7H), 7.12 (d, 2H, J= 8.7), 6.77 (d, IH, J = 15.9), 6.50 (d, IH, J = 15.9), 2.50 (m, 2H), 1.50 (br s, 11H), 1.30 ( br s ,4H), 0.88 (t, 3H, J = 6.9).
Data for 123d (R2' = (C6Hι3)2): Η-NMR (300 MHz, CDCI3): 7.98 (d, 4H, J = 8.1), 7.70 (d, IH, J = 15.3), 7.63 (d, 4H, J = 8.4), 7.59 (d, IH, J = 16.0), 6.95 (d, IH, J = 15.3), 6.48 (d, IH, J = 16.2), 3.40 (br q, 4H, J= 8.1), 1.68-1.50 (m, 4H), 1.4-1.24 (m, 12H), 0.96-0.82 (m, 6H).
Example 1 3-r4-f2-f4-Diethylamino-phenyl)-5-{4-r(E)-2-f3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-l-fir-imidazol-4-yl)-phenvn- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 190
Figure imgf000092_0001
Dione was synthesized according to General Method 12 followed by General Method 11 to give the free acid 44 (Using the methodology outlined in Scheme 18). The aldehyde input 34b was synthesized according to General Method 1, using methyl acrylate in place of tert-butyl acrylate to give aldehyde 34b (R = Me) g, (92%).
Figure imgf000093_0001
Data for aldehyde 34b: Η-NMR (300 MHz, CDC13); mixture of isomers: 10.06 (s, IH), 7.94 (d, 2H, J = 8.1), 7.86 (d, 2H, J = 8.4), 5.30-5.24 (m, IH), 3.85 (s, 3H), 3.72-3.67 (m, 2H). The t-butyl ester of dione 44 was converted to free acid 44b via treatment of with 50% TFA dichloromethane solution with ice bath. After two hours, the reaction was dried by vacuum. This gave, after work-up, 3-(4-{2-[4-((E)-2-Carboxy-vinyl)-phenyl]-2- oxo-ethanoyl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 44b (R1' = Me) (Quantitative).
Figure imgf000093_0002
Data for Compound 44b: iH-NMR (300 MHz, DMSO-d6): 8.04- 7.91 (m, 8H), 7.68 (d, IH, J = 15.9), 6.74 (d, IH, J = 15.9), 5.42-5.36 (m, IH), 3.90-3.63 (m, 2H), 3.71 (s, 3H).
Figure imgf000093_0003
3-[4-(2-Oxo-2-{4-[(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]- phenyl}-ethanoyl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 46a (Scheme 9) was synthesized according to General Method 6 from dione 44b (0.23 g, 0.57 mmol) in CHCI3 (2 mL), EDCI (0.13 g, 0.69 mmol), HOBt (0.093 g, 0.69 mmol), DIEA (0.3 mL, 1.71 mmol), and 3-phenylpropylamine 26a (0.098 mL, 0.69 mmol). After purification via column chromatography eluting with ethyl acetate:hexane the desired dione 3-[4-(2-Oxo-2-{4-[(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]~ phenyl}-ethanoyl)-phenyl]-4,5-dϊhydro-isoxazole-5-carboxylic acid methyl ester 46a was obtained (0.29 g, 97%).
Data for 3-[4-(2-Oxo-2-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-ethanoyl)-phenyl]-4,5-dihydro- isoxazole-5-carboxylic acid methyl ester 46a: iH-NMR (300 MHz, CDCI3): 8.01 (d, 2H, J = 6.6), 7.96 (d, 2H, J = 8.1), 7.81 (d, 2H, J = 9.0), 7.65-7.52 (m, 3H), 7.35-7.14 (m, 5H), 6.44 (d, IH, J = 15.6), 5.79 (t, IH, J = 5.0), 5.26 (dd, IH, J = 10.5, 7.2), 3.83 (s, 3H), 3.72-3.60 (m, 2H), 3.43 (q, 2H, J = 6.3), 2.70 (t, 2H, J = 7.5), 2.00-1.85 (m, 2H).
Compound 190 was synthesized according to General Method 7 from dione 46a (0.28 g, 0.53 mmol) in acetic acid (3 mL) with 4-diethylaminobenzaldehyde (0.1 g, 0.59 mmol) and NH4OAC (1.23 g, 16 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1). The desired imidazole 3-[4-(2-(4-Diethylamino-phenyl)-5-{4- l(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4- yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 190 was obtained as a yellow solid (0.16 g, 44%). Data for 3-[4-(2-(4-Diethylamino-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid methyl ester 190: iH-NMR (300 MHz, CDCls): 7.88 (br s, 2H), 7.50-7.05 (m, 15H), 6.67 (br s, 2H), 6.20 (br d, IH, J= 14.8), 5.13 (dd, IH, J= 10.0, 8.0), 3.77 (s, 3H), 3.62-3.50 (m, 2H), 3.50-3.20 (m, 6H), 2.58 (t, 2H, J= 7.6), 1.94-1.72 (m, 2H), 1.14 (t, 6H, J= 7.0).
Example 2 3-r4-(2-(4-Diethylamino-phenyl)-5-{4-f(E)-2-(3-phenyl- propylcarbamoyl)-vinyl -phenyl}-lff-imidazol-4-yl)-phenyl - 4,5-dihydro-isoxazole-5-carboxylic acid 191
Figure imgf000095_0001
Imidazole 191 was synthesized according to General Method 10 via hydrolyses of the methyl ester of imidazole 190 (Example 1), according to General Method 10 from imidazole 191 (methyl ester) (0.16 g, 0.23 mmol), IN LiOH (3.5 mL, 3.5 mmol), and 1,4-Dioxane (3.5 mL). 3-[4-(2-(4-Diethylamino- phenyl)-5-{4-[(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]-phenyl}-lH- imidazol-4-yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 191 was obtained, after recrystallization, as a pale yellow solid (0.11 g, 72%). Data for 3-[4-(2-(4-diethylamino-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 191: *H-NMR (300 MHz, CD3OD): 7.86 (d, 2H, J = 9.3), 7.71 (d, 2H, J = 8.4), 7.61 (d, 2H, J= 8.4), 7.58-7.48 (m, 5H), 7.30-7.10 (m, 5H), 6.84 (d, 2H, J = 9.3), 6.64 (d, IH, J= 15.9), 5.09 (dd, IH, J = 11.4, 7.2), 3.69 (dd, IH, J = 17.1, 11.7), 3.35 (dd, IH, J = 18.0, 7.8), 3.49 (q, 4H, J = 6.9), 3.38-3.24 (m, 2H), 2.68 (t, 2H, J = 7.7), 1.90-1.80 (m, 2H), 1.22 (t, 6H, J = 7.1); MS (APcI): 668.0 (100, [M]), 669.3 (38, [M+H]); calcd C41H41N5O4 ([M]) 667.8.
Example 3 3-{4-r5-{4-r(E)-2-(3-Phenyl-ρroρylcarbamoyl)-vinvn-ρhenyl}-2- (2,4,6-trimethyl-phenyl)-l-Hr-imidazol-4-yll-ρhenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 192
Figure imgf000096_0001
Compound 192 was synthesized according to General Method 7 from dione 46a (0.5 g, 0.88 mmol) in acetic acid (1 mL), with 2,4,6- trimethylbenzaldehyde (0.26 g, 1.76 mmol) and NH4OAC (2.0 g, 26.4 mmol), which gives 3-{4-[5-{4-[(E)-2-(3- Phenyl-propylcarbamoyl)-vinyl]-phenyl}-2-(2,4, 6-trimethyl- phenyl)- lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid methyl ester. The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-{4-[5-{4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl}-2-(2, 4, 6-trimethyl-phenyl)- 1 H- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 192 as a yellow solid (0.28 g, 50%).
Data for 3-{4-[5-{4-[(E)-2-(3-Phenyl-propylcarbamoyl)-vinyl]~ phenyl}-2-(2, 4, 6-trimethyl-phenyl)-lH-imidazol-4-yl]-phenyl}-4, 5- dihydro-isoxazole-5-carboxylic acid 192: MS (APcI): 639.5 (100, [M+H]); calcd C40H38N4O4 ([M+H]) 639.8.
Example 4 3-{4-r5-{4-^E)-2-(3-Phenyl-proρylcarbamovH-vinyn-phenyl>-2- (4-pyrrolidin-l-yl-phenyl)-lJEf-imidazol-4-yl1-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 193
Figure imgf000097_0001
Compound 193 was synthesized according to General Method 7 from dione 46a (0.2 g, 0.35 mmol) in acetic acid (2 mL), with 4-pyrrolidin-l-yl-benzaldehyde (0.07 g, 0.38 mmol) and NH4OAC (0.8 g, 10.5 mmol), which gives 3-{4-[5-{4-[(E)-2-(3- Phenyl-propylcarbamoyl) -vinyl] -phenyl}-2 - (4-pyrrolidin- 1 -yl- phenyl) - 1 H-imidazol-4-yl]-phenyl}-4 , 5-dihydro-isoxazole-5- carboxylic acid methyl ester. The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-{4-[5-{4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl}-2-(4-pyrrolidin-l-yl-phenyl)-lH- imidazol-4-yl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid 193 as a yellow solid (0.078 g, 33%). Data for 3-{4-[5-{4-[(E)-2-(3-Phenyl-propylcarbamoyl)-vinyl]- phenyl}-2-(4-pyrrolidin-l-yl~phenyl)-lH-imidazol-4-yl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid 193: iH-NMR (300 MHz, DMSO): 8.16 (t, IH, J = 5.4), 7.90 (d, 2H, J = 9.0), 7.70-7.56 (m, 8H), 7.43 (d, IH, J = 15.9), 7.32-7.18 (m, 5H), 6.67-6.61 (m, 3H), 5.17 (dd, IH, J= 11.4, J = 6.9), 3.79-3.55 (m, 2H), 3.35 (br s, 4H), 3.23-3.16 (m, 2H), 2.62 (t, 2H, J= 7.8), 1.98 (br s, 4H), 1.81-1.72 (m, 2H). MS (ESI): 666.7 (100, [M+H]); calcd C41H40N5O4 ([M+H]) 666.3.
Example 5 3-r4-(2-(4-Carboxy-phenyl)-5-{4-HE)-2-(3-phenyl- propylcarbamoyH-vinyl]-phenyl}-lir-imidazol-4-yl)-phenyl -
4,5-dihydro-isoxazole-5-carboxylic acid 194
Figure imgf000098_0001
Compound 194 was synthesized according to General Method 7 from dione 46a (0.2 g, 0.35 mmol) in acetic acid (2 mL), 4-formylbenzoic acid (0.08 g, 0.53 mmol) and NH4OAc (0.82 g, 10.6 mmol), which gives 3-[4-(2-(4-Carboxy-phenyl)-5- {4-[(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]-phenyl}- 1H- imidazol-4-yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester. The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4-Carboxy-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)~phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 194 as a yellow solid (0.1 g, 45%).
Data for 3-[4-(2-(4-Carboxy-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 194: iH-NMR (300 MHz, DMSO): 8.22 (d, 2H, J = 8.7), 8.16 (br s, IH), 8.05 (d, 2H, J = 8.7), 7.80-7.56 (m, 8H), 7.45 (d, IH, J = 16.0), 7.32-7.16 (m, 5H), 6.67 (d, IH, J = 16.0), 5.19 (br t, IH, J =8.7), 3.80-3.54 (m, 2H), 3.20 (dd, 2H, J = 12.6, 6.6), 2.62 (t, 2H, J = 7.7), 1.82-1.72 (m, 2H). MS (APcI): 641.3 (30, [M+H]), 553.3 (100); calcd C38H33N4O6 ([M+H]) 641.24.
Example 6 3-f4,(2-(4-Diethylamino-2-hvdroxy-phenv»-5-{4-r(E)-2-(3- phenyl-propylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-4-yl)- pheny!|-4,5-dihydro-isoxazole-5-carboxylic acid 195
Figure imgf000099_0001
Compound 195 was synthesized according to General Method 7 from dione 46a (0.2 g, 0.35 mmol) in acetic acid (2 mL), 2-hydroxy-4-diethylamino-benzaldehyde (0.1 g, 0.53 mmol) and NH4OAc (0.82 g, 10.59 mmol), which gives of 3-[4- (2-(4-Diethylamino-2-hydroxy-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-4-yl) -phenyl] -4 , 5- dihydro-isoxazole-5-carboxylic acid methyl ester. The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4- Diethylamino-2-hydroxy-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 195 as a yellow solid (0.1 g, 41.8%).
Data for 3-[4-(2-(4-Diethylamino-2-hydroxy-phenyl)-5-{4-[(E)-2-(3- phenyl-propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)~ phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 195: MS (ESI): 314.5 (100), 684.6 (54, [M+H]); calcd C41H41N5O5 ([M+H]) 684.8.
Example 7 3-{4-f5-f4-((E)-2-Dodecylcarbamoyl-vinvH-ρhenyll-2-(2- hydroxy-phenyl)-lH-imidazol-4-yl -phenyl}-4,5-dihydro- isoxazole-5-carboxylic acid 196
Figure imgf000100_0001
3-(4-{2-[4-((E)-2-Carboxy-vinyl)-ρhenyl]-2-oxo-ethanoyl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 44a (Ri' = tert-Bu, Scheme 9) was synthesized according to General Method 5 from dione 43a (43a - synthesized via General Method 3) . Dione 46b (Scheme 9) was synthesized according to General Method 6 from dione 44a (1.5 g, 3.3 mmol) in CHCI3 (15 mL), EDCI (0.96 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol), DIEA (1.08 mL, 8.3 mmol), and dodecylamine 26b (0.93 g, 5.0 mmol). After purification via column chromatography eluting with ethyl acetate: hexane the desired dione 3-(4-{2-[4- ((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-oxo-ethanoyl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 46b was obtained (1.52 g, 75%).
Figure imgf000101_0001
Data for dione 3-(4-{2-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]- 2-oxo-ethanoyl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 46b: iH-NMR (300 MHz, CDC13): 8.01 (d, 2H, J = 8.4), 7.96 (d, 2H, J = 8.4), 7.82 (d, 2H, J = 8.4), 7.64 (d, IH, J = 15.6), 7.61 (d, 2H, J = 8.1), 6.53 (d, IH, J= 15.6), 5.86 (brt, IH, J= 5.7), 5.14-5.08 (m, IH), 3.61-3.58 (m, 2H), 3.42-3.35 (m, 2H), 1.51 (brs, 11H), 1.26 (brs, 18H), 0.88 (t, 3H, J= 6.7).
Compound 196 was synthesized according to General Method 7 from dione 46b (0.2 g, 0.32 mmol) in acetic acid (3 mL) with 2-hydroxy-benzaldehyde (0.06 g, 0.53 mmol) and NH4OAc (0.8 g, 9.6 mmol), which gives 3-{4-[5-[4-((E)-2- Dodecylcarbamoyl- vinyl) -phenyl] -2 - (2 -hydroxy-phenyl) - 1 H- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester. The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-{4-[5-[4-((E)- 2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2-hydroxy-phenyl)-lH- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 196 as a yellow solid (0.1 g, 47%). Data for 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2- hydroxy-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole- 5-carboxylic acid 196: iH-NMR (300 MHz, DMSO-d6): 8.10 (t, IH, J = 5.4), 8.03 (d, IH, J =7.2), 7.76 (d, 2H, J = 8.1), 7.66- 7.55 (m, 6H), 7.43 (d, IH, J = 15.6), 7.32 (t, IH, J = 7.6), 7.01 (d, IH, J = 7.5), 6.98 (t, IH, J= 7.8), 6.65 (d, IH, J = 15.6), 5.19 (dd, IH, J = 11.4, 6.9), 3.80-3.56 (m, 2H), 3.20-3.13 (m, 2H), 1.50-1.40 (m, 2H), 1.24 (br s, 18H), 0.84 (t, 3H, J = 6.7). MS (ESI): 663.6 (100, [M+H]); calcd C40H46N4O5 ([M+H]) 663.4.
Example 8 3-(4-{5-r4-((E)-2-Dodecylcarbamoyl-vinylϊ-phenyn-lH- imidazol-4-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 197
Figure imgf000103_0001
Example 59 Example 60
Figure imgf000103_0002
Example 61 Example 62
Figure imgf000103_0003
Figure imgf000103_0004
Compound 197 was synthesized according to General Method 7 from dione 46b (0.22 g, 0.36 mmol) in acetic acid (3 mL) hexamethyltetramine (0.25 g, 1.78 mmol) and NH4OAC (0.8 g, 10.7 mmol), which gives 3-(4-{5-[4-((E)-2-Dodecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid tert-butyl ester. The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]- lH-imidazol-4-yl}-phenyl)-4, 5-dihydro-isoxazole-5- carboxylic acid 197 as a yellow solid (0.1 g, 48.7%). Data for 3-(4-{5-]4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 197: iH-NMR (300 MHz, DMSO-d6): 8.46 (br s, IH), 8.10 (t, IH, J = 5.4), 7.73 (d, 2H, J = 8.1), 7.60 (d, 2H, J = 8.4), 7.55 (d, 2H, J = 8.7), 7.49 (d, 2H, J = 8.1), 7.41 (d, IH, J = 15.6), 6.63 (d, IH, J = 15.9), 5.19 (dd, IH, J = 11.4, 6.6), 3.79-3.55 (m, 2H), 3.19- 3.12 (m, 2H), 1.50-1.40 (m, 2H), 1.24 (br s, 18H), 0.84 (t, 3H, J = 6.3). MS (ESI): 571.6 (100, [M+H]), 428.5 (50), 279.5 (60); calcd C34H43N4O4 ([M+H]) 571.3.
Example 9 3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinvU-ρhenvn-2-r4-((E)-2- ethoxycarbonyl-vinyl)-phenyll-lH-imidazol-4-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 198
Figure imgf000105_0001
Compound 198 was synthesized according to General Method 7 from dione 46b (0.14 g, 0.22 mmol) in acetic acid (2 mL), 4-formylcinnamic acid ethyl ester (0.047 g, 0.23 mmol) and NH4OAC (0.5 g, 6.6 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1). The desired imidazole 3-(4-{5-[4-((E)- 2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4-((E)-2-ethoxycarbonyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 198 was obtained as a yellow solid (0.07 g, 42.8%).
Data for 3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4- ((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)~ 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 198: H- NMR (300 MHz, DMSO-d6): 8.14 (d, 2H, J = 8.4), 8.86 (d, 2H, J = 8.1), 7.74 (d, IH, J= 15.9), 7.70-7.35 (m, 9H), 6.72 (d, IH, J = 15.9), 6.60 (d, IH, J = 15.9), 5.22-5.05 (m, IH), 4.21 (q, 2H, J = 7.1), 3.85-3.67 (m, IH), 3.67-3.46 (m, IH), 3.22-3.10 (m, 2H), 1.78- 1.45 (m, 2H), 1.55-1.35 (m, 11H), 1.48- 1.10 (m, 21H), 0.85 (t, 3H, J= 6.6); MS (APcI): 657.4 (100), 801.2 (40, [M]); calcd C49H61N4O6 ([M]) 801.0. Example 10 3-(4-{5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyn-2-r4-((E)-2- ethoxycarbonyl-vinyl)-phenyll-lff-imidazol-4-yl}-phenyl)-
4,5-dihydro-isoxazole-5-carboxylic acid 199
Figure imgf000106_0001
Imidazole 199 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 199 (Example 10) according to General Method 11, to give 3-(4- {5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4-((E)-2- ethoxy carbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 199, after recrystallization, as a pale yellow solid (0.05 g, 71.4%).
Data for 3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4- ((E)-2-ethoxycarbonyl-vinyl)-phenyl]~ 1 H-imidazol-4-yl} -phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 199: iH-NMR (400 MHz, CDCls + 5% CD3OD): 8.09 (d, 2H, J = 7.6), 7.67-7.56 (m, 3H), 7.51 (d, 2H, J= 7.6), 7.44 (d, 2H, J= 7.6), 7.42-7.34 (m, 5H), 6.45 (d, 2H, J = 16.0), 5.18-5.05 (m, IH), 4.30-4.15 (m, 2H), 3.62-3.40 (m, 2H), 3.38-3.15 (m, 2H), 1.78-1.45 (m, 2H), 1.35- 1.10 (m, 21H), 0.81 (t, 3H, J= 6.6); MS (APcI): 745.6 (100, [M+H]); calcd C45H53N4O6 ([M+H]) 745.9. Example 11 3-f4-{2-f2,4-Dioxo-l,2,3,4-tetrahydro-ρyrimidin-5-yH-5-r4- ((E)-2-dodecylcarbamoyl-vinyl)-phenyπ-lff-imidazol-4-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 200
Figure imgf000107_0001
Compound 200 was synthesized according to General Method 7from dione 46b (0.3 g, 0.49 mmol) in acetic acid (4 mL), 5-formyluracil (0.072 g, 0.51 mmol) and NH4OAc (1.13 g, 14.61 mmol), which gives 3-(4-{2-(2,4-Dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)-5-[4-((E)-2-dodecylcarbamoyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester. The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-(4-{2-(2,4- Dioxo-1,2, 3, 4-tetrahydro-pyrimidin-5-yl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4,5- dϊhydro-isoxazole-5-carboxylic acid 200 as a yellow solid (0.07 g, 21%).
Data for 3-(4-{2-(2, 4-Dioxo-l,2, 3, 4-tetrahydro-pyrimidin-5-yl)-5- [4-((E)-2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-4,5-dϊhydro-isoxazole-5-carboxylic acid 200: iH-NMR (300 MHz, DMSO-de): 12.09 (br s, IH), 12.05 (s, IH), 8.49 (d, 2H, J = 6.0), 8.30 (t, IH, J = 5.6), 7.95 (d, 2H, J= 8.4), 7.81 (d, 2H, J= 8.4), 7.75 (d, 2H, J= 8.4), 7.69 (d, 2H, J= 8.1), 7.60 (d, IH, J = 16.2), 6.84 (d, 2H, J = 15.9), 5.38 (dd, IH, J = 11.7, 6.6), 3.93 (dd, IH, J= 17.1, 11.4), 3.78 (dd, IH, = 17.4, 6.6), 3.40-3.30 (m, 2H), 1.70-1.55 (m, 2H), 1.42 (br s, 18H), 1.02 (t, 3H,
Figure imgf000108_0001
([M+H]) 681.8. Example 12
3-r4-(2-r4-((E)-2-tert-Butoxycarbonyl-vinvH-ρhenyn-5-{4- [(E)-2-(3-phenyl-propylcarbamoyl)-vinyll-phenyl}-lH- imidazol-4-yl)-phenyI|-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 201
Figure imgf000108_0002
Compound 201 was synthesized according to General Method 7 from dione 46i (Ri' = tert-butyl ester, R2' = - (CH2)3Ph) (0.73 g, 1.29 mmol) in acetic acid (6 mL), 4- formylcinnamic acid tert-butyl ester (0.36 g, 1.55 mmol) and NH40 Ac (3.0 g, 38.7 mmol). The resulting imidazole was purified by flash column chromatography eluting with DCM/MeOH (95:5). The desired imidazole 3-[4-(2-[4-((E)-2- tert-Butoxycarbonyl-vinyl)-phenyl]-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 201 was obtained as a yellow solid (0.42 g, 42%). Data for 3-[4-(2-[4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5-{4- [(E)-2-(3-phenyl-propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4- yl)-phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 201: iH-NMR (300 MHz, DMSO-d6): 8.15 (br s, 2H), 7.65- 7.40 (br m, 12H), 7.30-7.10 (br m, 5H), 6.40-6.20 (br m, 3H), 5.04 (t, IH, J = 7.5), 3.55 (d, 2H, J = 7.5), 3.34 (br s, 2H), 2.58 (br s, 2H), 1.84 (br s, 2H), 1.58 (s, 9H), 1.53 (s, 9H).
Example 13 3-r4-(2-r4-((E)-2-Carboxy-vinyl)-phenvn-5-{4-rtE)-2-(3- phenyl-propylcarbamoyl)-vinyπ-phenyl}-lH-imidazol-4- yl)-phenyl]|-4,5-dihydro-isoxazole-5-carboxylic acid 202
Figure imgf000109_0001
The bis- tert-butyl ester of imidazole 202 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-[4-(2-[4-((E)-2- Carboxy-vinyl)-phenyl]-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid 202 as a yellow solid (0.13 g, 36%).
Data for 3-[4-(2-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-{4-[(E)-2-(3- phenyl-propylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 202: iH-NMR (300 MHz, DMSO-de): 8.20-8.14 (m, 3H), 7.86 (d, 2H, J =7.8), 7.88 (d, 2H, J = 8.1), 7.69-7.57 (m, 7H), 7.45 (d, IH, J = 15.6), 7.32-7.18 (m, 5H), 6.67 (d, IH, J = 15.9), 6.63 (d, IH, J = 15.9), 5.22-5.16 (m, IH), 3.81-3.51 (m, 2H), 3.23- 3.17 (m, 2H), 2.65-2.60 (m, 2H), 1.82-1.72 (m, 2H).
Example 14 3-{4-r2-(4-Diethylamino-phenyH-5-(4-{(E)-2-r2-(lH-indol-3-vH- ethylcarbamoyl -vinyl}-phenyH-lH-imidazol-4-yl1-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 203
Figure imgf000110_0001
Dione 46c (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (0.1 g, 0.25 mmol) in CHC13 (2 mL), EDCI (0.052 g, 0.27 mmol), HOBt (0.037, 0.27 mmol), DIEA (0.063g, 0.5 mmol), and tryptamine 26c (0.043g, 0.27 miriol). After purification via column chromatography eluting with ethyl acetate: hexane the desired dione 3-{4-[2-(4-{(E)-2-[2-(lH-Indol-3-yl)- ethylcarbamoyl]-vinyl}-phenyl)-2-oxo-ethanoyl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid methyl ester 46c was obtained (0.08 g, 53.9%).
Figure imgf000110_0002
Data for 3-{4-[2-(4-{(E)-2-[2-(lH-Indol-3-yl)-ethylcarbamoyl]-vinyl}- phenyl)-2-oxo-ethanoyl]-phenyl}-4, 5-dihydro-isoxazole-5- carboxylic acid methyl ester 46c: iH-NMR (400 MHz, CDC1 ): 8.31 (s, IH), 7.99 (d, 2H, J= 8.4), 7.92 (d, 2H, J= 8.0), 7.79 (d, 2H, J = 8.8), 7.68-7.47 (m, 4H), 7.36 (d, IH, J = 8.0), 7.19 (t, IH, J = 7.4), 7.10 (t, IH, J = 7.4), 7.04 (s, IH), 6.41 (d, IH, J = 16.4), 5.96 (br t, IH, J = 5.6), 5.23 (dd, IH, J = 10.8, 7.2), 3.82 (s, 3H), 3.80-3.55 (m, 4H), 3.03 (t, 2H, J= 6.6).
Compound 203 was synthesized according to General Method 7 from dione 46c (0.066 g, 0.12 mmol) in acetic acid (1.5 mL) 4-diethylamino-benzaldehyde (0.024 g, 0.13 mmol) and NH4OAC (0.28 g, 3.6 mmol). Purification by column chromatography eluting with hexane /EtOAc gave 3-{4-[2-(4- Diethylamino-phenyl)-5-(4-{(E)-2-[2-(lH-indol-3-yl)- ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid methyl ester 203 (0.03 , 35.4%).
Data for 3-{4-[2-(4-Diethylamino-phenyl)-5-(4-{(E)-2-[2-(lH-indol- 3-yl)-ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 203: iH- NMR (300 MHz, CDCI3): 7.80 (d, 2H, J= 8.8), 7.60-7.24 (m, 11H), 7.14 (t, IH, J = 7.6), 7.06 (t, IH, J = 7.4), 7.02 (s, IH),
6.67 (br s, 2H), 6.47 (t, IH, J = 5.0), 6.24 (d, IH, J= 15.2), 5.12 (t, IH, J = 9.2), 3.78 (s, 3H), 3.65 (t, 2H, J = 6.2), 3.56 (d, 2H, J = 6.6), 3.53 (br s, 4H), 2.99 (t, 2H, J = 6.6), 1.41 (t, 6H, J = 7.0); MS (ESI): 707.6 (100, [M+H]); calcd C43H42N5O4 ([M+H]) 707.8. Example 15
3-{4-r2-(4-Diethylamino-phenvH-5-(4-{(E)-2-r2-(lH-indol-3-yl)- ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yll-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid 204
Figure imgf000112_0001
Imidazole 204 was synthesized according to General Method 10 from imidazole 203 (0.03 g, 0.04 mmol), IN LiOH (0.06 mL), and 1,4-Dioxane (0.6 mL). 3-{4-[2-(4-Diethylamino- phenyl)-5-(4-{(E)-2-[2-(lH-indol-3-yl)-ethylcarbamoyl]-vinyl}- phenyl)-lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid 204 was obtained, after recrystallization, as a pale yellow solid (0.02 g, 66.7%). Data for 3-{4-[2-(4-Diethylamino-phenyl)-5-(4-{(E)-2-[2-(lH-indol- 3-yl)-ethylcarbamoyl]~vinyl}-phenyl)-lH~imidazol-4-yl]-phenyl}~ 4, 5-dihydro-isoxazole-5-carboxy lie acid 204: : iH-NMR (300 MHz, CDCls): 8.09 (br s, 2H), 7.90-7.82 (m, 2H), 7.78-7.70 (m, 2H), 7.68-7.45 (m, 7H), 7.35-7.25 (m, IH), 7.10-7.02 (m, IH), 7.02-6.94 (m, IH), 6.89-6.80 (m, 2H), 6.66-6.55 (m, IH), 5.20- 5.10 (m, IH), 3.80-3.40 (m, 8H), 3.05-2.95 (m, 2H), 1.31-1.10 (m, 6H).
Example 16 3-f4-(2-(4-Diethylamino-2-hydroxy-phenyl)-5-{4-r(E)-2-(JV- phenyl-hydrazinocarbonyl)-vinyl]-phenyl}-lH-imidazol-4-yl)- phenyl|-4,5-dihydro-isoxazole-5-carboxylic acid 205
Figure imgf000113_0001
Dione 46d (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (0.1 g, 0.22 mmol) in CHC13 (1.5 mL), EDCI (0.064 g, 0.33 mmol), HOBt (0.045 g, 0.33 mmol), DIEA (0.11 g, 0.89 mmol), and phenylhydrazine 26d (0.04 g, 0.33 mmol). After purification via column chromatography eluting with ethyl acetate: hexane the desired dione 3-[4-(2-Oxo-2-{4-[(E)-2-(N'- phenyl-hydrazinocarbonyl)-vinyl]-phenyl}-ethanoyl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid methyl ester 46d was obtained (0.11 g, 92.7%).
Figure imgf000113_0002
Data for 3-[4-(2-Oxo-2-{4-[(E)-2-(N'-phenyl-hydrazinocarbonyl)- vinyl]-phenyl}-ethanoyl)-phenyl]-4,5-dihydro-isoxazole-5- carboxylic acid methyl ester 46d: iH-NMR (300 MHz, CDCI3):
8.76 (brs, IH), 7.97 (d, 2H, J= 8.4), 7.89 (d, 2H, J = 8.4), 7.77 (d, 2H, J= 8.4), 7.58-7.52 (m, 2H), 7.24-7.13 (m, 3H), 6.89-
6.77 (m, 3H), 6.71 (d, IH, J= 15.6), 6.48 (brs, IH), 5.10 (t, IH, J = 9.6), 3.57 (d, 2H, J = 9.3), 1.50 (s, 9H).
I l l Compound 205 was synthesized according to General Method from dione 46d (0.11 g, 0.2 mmol) in acetic acid (2 mL), 2-hydroxy-4-diethylamino-benzaldehyde (0.06 g, 0.3 mmol) and NH4OAC (0.47 g, 6 mmol), which gives 3-[4-(2-(4- Diethylamino~2-hydroxy-phenyl)-5-{4-[(E)-2-(N-phenyl- hydrazinocarbonyl) -vinyl] -phenyl}- 1 H- imidazol-4-yl) -phenyl] - 4,5-dihydro-isoxazole-5-carboxylic acid methyl ester. The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-[4-(2-(4- Diethylamino-2-hydroxy-phenyl)-5-{4-[(E)-2-(N-phenyl- hydrazinocarbonyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]-4,5- dϊhydro-isoxazole-5-carboxylic acid 205 as a yellow solid (0.02 g, 15.2%).
Data for 3-[4-(2-(4-Diethylamino-2-hydroxy-phenyl)-5-{4- [(E)-2-(N-phenyl~hydrazinocarbonyl)-vinyl]-phenyl}-lH-imidazol-4- yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 205: iH-NMR (400 MHz, DMSO-d6): 9.95 (s, IH), 7.77-7.51 (m, 11H), 7.13 (t, 2H, J= 7.6), 6.78-6.68 (m, 3H), 6.32 (br d, IH, J= 6.8), 6.18 (br s, IH), 7.74 (s, IH), 5.18 (dd, IH, J = 10.8, 6.4), 3.77-3.55 (d, 2H), 3.33 (br s, 4H), 1.11 (t, 6H, J = 7.0). MS (ESI): 657.6 (20, [M+H]), 579.6 (15), 301.5 (100); calcd CssHsyNeOs ([M+H]) 657.3.
Example 17 3-{4-r2-(4-Diethylamino-2-hydroxy-phenyl)-5-(4-{(E)-2-f2-(4- fluoro-phenyH-ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol- 4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 206
Figure imgf000115_0001
Dione 46e (Scheme 9) was synthesized according to General Method 6 from dione 44b (for synthesis of 44b see Example 7)(1 g, 2.2 mmol) in CHC13 (15 mL), EDCI (0.64 g, 3.3 mmol), HOBt (0.45 g, 3.3 mmol), DIEA (0.72 g. 5.6 mmol), and 4-fluorophenethylamine 26e (0.46 mL, 3.3 mmol). After purification via column chromatography eluting with ethyl acetate: hexane the desired dione 3-{4-[2-(4-{(E)-2-[2-(4-Fluoro- phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-2-oxo-ethanoyl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 46e was obtained (1.1 g, 87.7%).
Figure imgf000115_0002
Data for 3-{4-[2-(4-{(E)-2-[2~(4-Fluoro-phenyl)-ethylcarbamoyl]~ vinyl}-phenyl)-2-oxo-ethanoyl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 46e: iH-NMR (300 MHz, CDCI3): 8.02 (d, 2H, J = 8.4), 7.97 (d, 2H, J = 8.4), 7.82 (d, 2H, J = 8.4), 7.68 (d, IH, J= 15.6), 7.62 (d, 2H, J = 8.4), 7.21-7.16 (m, 2H), 7.05-6.99 (m, 2H), 6.45 (d, IH, J = 15.6), 5.70 (t, IH, J= 6.0), 5.15-5.09 (m, IH), 3.69-3.58 (m, 4H), 2.88 (t, 2H, J = 6.9), 1.51 (s, 9H).
Compound 206 was synthesized according to General Method 7 from dione 46e (0.11 g, 0.21 mmol) in acetic acid (2 mL), 2-hydroxy-4-diethylamino-benzaldehyde (0.06 g, 0.32 mmol) and NH4OAc (0.49 g, 6.4 mmol), which gives 3-{4-[2-(4- Diethylamino-2-hydroxy-phenyl)-5-(4-{(E)-2-[2-(4-fluoro- phenyl) -ethylcarbamoyl] -vinylj-phenyl) - 1 ff-imidazol-4-yl]- phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester. The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3-{4-[2-(4-Diethylamino-2-hydroxy-phenyl)-5- (4-{(E) -2- [2- (4-fluoro-phenyl) -ethylcarbamoyl] -vinyl}-phenyl) - 1 H- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 206 as a yellow solid (0.08 g, 55%).
Data for 3-{4-[2-(4-Diethylamino-2-hydroxy-phenyl)-5-(4-{(E)-2-[2- (4-fluoro-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-4- yl]-phenyl}-4,5-dϊhydro-isoxazole-5-carboxylic acid 206: iH-NMR (400 MHz, CDCI3/CD3OD): 8.33 (s, IH), 7.43-7.38 (m, 4H), 7.35 (d, 2H, J = 5.2), 7.32 (d, 2H, J= 6.4), 7.27 (d, 2H, J = 6.4), 7.00-6.97 (m, 2H), 6.77 (t, 2H, J= 8.4), 6.28 (d, IH, J= 16), 6.09 (d, IH, J = 9.6), 6.08 (s, IH), 4.83-4.78 (m, IH), 3.48-3.35 (m, 2H), 3.32 (t, 2H, J = 7.6), 3.18 (dd, 4H, J = 14.0, 7.2), 2.64 (t, 2H, J= 7.6), 0.98 (t, 6H, J = 6.8). MS (ESI): 688.6 (50, [M+H]), 333.5 (100); calcd C40H39FN5O5 ([M+H]) 688.3. Example 18 3-{4-r5-f4-{fE)-2-r2-(4-Fluoro-phenyl)-ethylcarbamoyl]-vinyl}- phenyll-2-(4-pyrrolidin-l-yl-phenyl)-lff-imidazol-4-yll- phenyl|-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 207
Figure imgf000117_0001
Compound 207 was synthesized according to General Method 7 from dione 46e (0.5 g, 0.88 mmol) in acetic acid (7 mL), 4-pyrrolidin- l-yl-benzaldehyde (0.17 g, 0.96 mmol) and NH4OAC (2 g, 26.3 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1). The desired imidazole 3-{4-[5-(4-{(E)-2-[2-(4-Fluoro- phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-2-(4-pyrrolidin-l-yl- phenyl)- lH-imidazol-4-y l]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 207 was obtained as a yellow solid (0.21 g, 32.8%).
Data for 3-{4-[5-(4-{(E)-2-[2-(4-Fluoro-phenyl)- ethylcarbamoyl]-vinyl}-phenyl)-2-(4-pyττolidin-l-yl-phenyl)-lH- imidazol-4-yl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 207: iH-NMR (300 MHz, DMSO): 7.92 (br s, 2H), 7.69-7.53 (br m, 5H), 7.40-7.20 (br m, 4H), 7.07 (br s, 2H), 7.00-6.88 (br m, 2H), 6.56 (d, 2H, J= 8.7), 6.40-6.14 (br m, 2H), 5.03 (t, IH, J= 9.15), 3.58 (br s, 2H), 3.54 (d, 2H, J = 9.3), 3.30 (br s, 4H), 2.80 (br s, 2H), 1.02 (t, 4H, J = 6.5).
Example 19 3-{4-r5-(4-{(E)-2-r2-(4-Fluoro-ρhenyl)-ethylcarbamovn-vinyl}- phenyl)-2-(4-pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 208
Figure imgf000118_0001
Imidazole 208 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 207 according to General Method 11, to give 3-{4-[5-(4-{(E)-2-[2- (4-Fluoro-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-2-(4-pyrrolidin- l-yl-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid 208, after recrystallization as a pale yellow solid (0.19 g, 90%). Data for 3-{4-[5-(4-{(E)-2-[2-(4-Fluoro-phenyl)-ethylcarbamoyl]- vinyl}-phenyl)-2-(4-pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 208: XH-NMR (300 MHz, DMSO): 8.20 (t, IH, J = 5.5), 7.96 (d, 2H, J = 9.0), 7.76 (d, 2H, J= 8.7), 7.63 (d, 2H, J = 8.4), 7.61 (d, 2H, J = 8.4), 7.55 (d, 2H, J = 8.7), 7.44 (d, IH, J = 15.9), 7.29 (d, IH, J =
8.7), 7.26 (d, IH, J = 8.7), 7.13 (d, IH, J = 9.0), 7.10 (d, IH, J = 9.0), 6.70 (d, 2H, J = 9.3), 6.64 (d, IH, J = 15.9), 5.20 (dd, IH, J = 11.7, J= 6.6), 3.80-3.56 (m, 2H), 3.34 (br s, 6H), 2.78 (t, 2H, J= 7.1), 1.99 (t, 4H, J= 7.5). MS (ESI): 670.7 (100, [M+H]); calcd C40H37FN5O4 [M+H] 670.3.
Example 20 3-{4-r2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2- f tetrahydro-furan-2-ylmethyl)-carbamoyl -vinyl}-phenyl)- lH-imidazol-4-yl|-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 209
Figure imgf000119_0001
Dione 46f (Scheme 9) was synthesized according to General Method 6 from dione 44a (for synthesis of 44a see
Example 7) (300 mg, 0.67 mmol) in CH2C12 (1.5 mL), EDCI (141 mg, 0.73 mmol), HOBt (99 mg, 0.73 mmol), DIEA (234 μL, 1.34 mmol), and tetrahydrofurfurylamine 26f (75.8 μL, 0.73 mmol). After purification via column chromatography eluting with ethyl acetate: hexane the desired dione 3-{4-[2-Oxo-2-(4-{(E)-2- [(tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)~ ethanoyl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 46f was obtained (150 mg, 41%).
Figure imgf000119_0002
Data for 3-{4-[2-Oxo-2-(4-{(E)-2-[(tetrahydro-fiιran-2-ylmethyl)- carbamoyl]-vinyl}-phenyl)-ethanoyl]-phenyl}-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 46f: 2H-NMR (300 MHz, CDCI3): 8.03 (d, 2H, J= 8.4), 7.98 (d, 2H, J= 8.4), 7.83 (d, 2H, J= 8.4), 7.69-7.62 (m, 3H), 6.56 (d, IH, J= 15.6), 6.21 (t, IH, J= 7.2), 5.12 (dd, IH, J= 10.2, 9.0), 4.07-4.03 (m, IH), 3.93-3.83 (m, IH), 3.90-3.72 (m, 2H), 3.61 (d, 2H, J = 9.9), 3.31-3.22 (m, IH), 2.26-2.89 (m, 4H), 1.52 (s, 9H).
Compound 209 was synthesized according to General Method from dione 46f (150 mg, 0.27 mmol) in acetic acid (2 mL), with 4-Formyl-N-hexadecyl-benzamide (154 mg, 0.41 mmol) and NH4OAc (634 mg, 8.22 mmol). The resulting imidazole was purified by flash column chromatography eluting with 0.5-5% methanol dichloromethane. The desired imidazole 3-{4-]2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2-[(tetrahydro- furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yl]- phenylj-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 209 was obtained as a yellow solid (200 mg, 82%).
Data for 3-{4-[2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2- [(tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 209: iH-NMR (400 MHz, CDCI3): 8.05 (brs, 2H), 7.68 (d, 2H, J= 6.8), 7.49 (brs, 4H), 7.36 (brs, 3H), 7.21 (brs, 2H), 6.71 (brs, IH), 6.56 (brs, IH), 6.30 (d, IH, J = 16.0), 5.02 (dd, IH, J = 10.0, 8.0), 3.98 (brs, IH), 3.85 (q, IH, J = 7.2), 3.74 (q, IH, J= 6.8), 3.70-3.61 (m, IH), 3.53-3.49 (m, 2H), 3.38-3.37 (m, 2H), 3.23-3.21 (m IH), 1.91-1.86 (m, 4H), 1.58-1.44 (m, 11H), 1.23 (brs, 26H), 0.86 (t, 3H, J= 6.8). Example 21 3-{4-r2-(4-Hexadecylcarbamoyl-ρhenyl)-5-(4-{(E)-2- f(tetrahydro-furan-2-ylmethyH-carbamoyl -vinyl}-phenyl)- l-H"-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid 210
Figure imgf000121_0001
Imidazole 210 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 209. After purification the desired imidazole 3-{4-[2-(4- Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2-[(tetrahydro-furan-2- ylmethyl)-carbamoyl]~vinyl}-phenyl)-lH-imidazol-4-yl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid 210, was obtained as a yellow solid (3.8 mg, 20%).
Data for 3-{4-[2-(4-Hexadecylcarbamoyl-phenyl)-5-(4-{(E)-2- ](tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 210: iH-NMR (300 MHz, DMSO-d6): 8.68 (t, IH, J= 5.1), 8.36- 8.33 (m, 3H), 8.13 (d, 2H, J= 8.4), 7.97-7.56 (m, 9H), 6.98-6.85 (m, IH), 5.35 (q, IH, J= 6.9), 4.30-4.20 (m, IH), 4.09-4.05 (m, IH), 4.00-3.89 (m, IH), 3.85-3.77 (m, IH), 3.70-3.34 (m, 5H), 2.11-2.00 (m, 4H), 1.71-1.70 (m, 2H), 1.47-1.30 (m, 26H), 1.02 (t, 3H, J = 6.3). Example 22 3-{4-r2-(4-Dodecylcarbamoyl-ρhenyl)-5-f4-{(E)-2-rftetrahydro- furan-2-ylmethyl)-carbamoyn-vinyl}-phenyl)-liH'-imidazol-4- yl1-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 211
Figure imgf000122_0001
Dione 46g (Scheme 9) was synthesized according to General Method 6 from dione 44b (see Example 1 for synthesis of 44b) (180 mg, 0.44 mmol) in CH2C12 (3.5 mL), EDCI (127 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol), DIEA (193 μL, 1.1 mmol), and tetrahydrofurfurylamine 26f (68 μL, 0.66 mmol). After purification via column chromatography eluting with ispropanol/ chloroform the desired dione 3-{4-[2-Oxo-2-(4-{(E)-2- ](tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)- ethanoyl]-phenyl}-4,5-dϊhydro-isoxazole-5-carboxylic acid methyl ester 46g was obtained (128 mg, 59%).
Figure imgf000122_0002
Data for 3-{4-[2-Oxo-2-(4-{(E)-2-[(tetrahydro-furan-2-ylmethyl)- carbamoyl]-vinyl}-phenyl)-ethanoyl]-phenyl}-4,5-dihydro- isoxazole-5-carboxylic acid methyl ester 46g: iH-NMR (400 MHz, CDCI3): 8.01 (d, 2H, J= 8.4), 7.98 (d, 2H, J= 8.4), 7.80 (d, 2H, J= 9.2), 7.66-7.60 (m, 3H), 6.51 (d, IH, J= 15.6), 6.08 (t, IH, J = 7.2), 5.24 (dd, IH, J= 10.2, 9.0), 4.04-3.98 (m, IH), 3.90- 3.84 (m, IH), 3.81 (s, 3H), 3.80-3.70 (m, 2H), 3.68-3.63 (m, 2H), 3.27-3.20 (m, IH), 2.05- 1.97 (m, 2H), 1.94- 1.87 (m, 2H). Compound 211 was synthesized according to General Method 7 from dione 46g (247 mg, 0.5 mmol) in acetic acid (1 mL + 250 μL DMSO), with 4-Formyl-N-dodecyl-benzamide (240 mg, 0.76 mmol) and NH4OAc (1.2 g, 15.1 mmol). The resulting imidazole was purified by flash column chromatography eluting with methanol/ dichloromethane. The desired imidazole 3-{4-[2- (4-Dodecylcarbamoyl-phenyl)-5-(4-{(E)-2-[(tetrahydro-fiιran-2- ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yl]-phenyl}- 4,5-dϊhydro-isoxazole-5-carboxylic acid methyl ester 211 was obtained as a yellow solid (44 mg, 11%).
Data for 3-{4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4-{(E)-2- ](tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester 211: iH-NMR (300 MHz, CDCI3): 8.06 (d, 2H, J = 7.2), 7.69 (d, 2H, J= 6.8), 7.52 (brs, 5H), 7.41-7.39 (m, 2H), 7.28-7.22 (m, 2H), 6.52 (brs, IH), 6.40 (brs, IH), 6.29 (d, IH, J = 15.6), 5.15 (t, IH, J= 9.0), 3.98 (brs, IH), 3.85-3.72 (m, 4H), 3.66-3.54 (m, 3H), 3.40-3.37 (m, 2H), 3.25-3.16 (m, IH), 1.98- 1.83 (m, 4H), 1.67-1.44 (m, 5H), 1.22 (brs, 18H), 0.83 (t, 6H, J = 5.6). Example 23 3-{4-f2-(4-Dodecylcarbamoyl-ρhenyH-5-(4-{(E)-2-F(tetrahvdro- furan-2-ylmethyl)-carbamoyl1|-vinyl|-phenyl)-lJ-r-imidazol-4- yiyphenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 212
Figure imgf000124_0001
Imidazole 212 was synthesized according to General Method 10 via hydrolyses of the methyl ester of imidazole 211, to give 3-{4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4-{(E)-2- ](tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid 212, after purification, as a white solid (12 mg, 31%). Data for 3-{4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4-{(E)-2- [(tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid 212: iH-NMR (300 MHz, DMSO-d6): 8.49 (t, IH, J= 5.4), 8.17 (d, 3H, J= 8.1), 7.91 (d, 2H, J= 8.1), 7.65-7.53 (m, 8H), 7.41 (d, IH, J= 15.6), 6.71 (d, IH, J= 15.6), 4.65 (t, IH, J= 9.0), 3.90-3.84 (m, IH), 3.77 (dd, IH, J= 14.4, 8.1), 3.62 (dd, IH, J = 14.7, 7.5), 3.42-3.22 (m, 6H), 1.88-1.77 (m, 4H), 1.59-1.49 (m, 2H), 1.23 (s, 18H), 0.84 (t, 3H, J = 5.6). Example 24 r4-(2-r4-((E)-2-Ethoxycarbonyl-vinv»-phenyll-5-{4-r(E)-2-(l- methyl-dodecylcarbamoyl)-vinyl -phenyl}-li-r-imidazol-4-yl)- phenoxyl-acetic acid 213
Figure imgf000125_0001
Imidazole 56 was synthesized according to General Method 7 from dione 54 (4.6 g, 11 mmol) in acetic acid (11 mL), with 4-formylcinnamic acid ethyl ester (3.4 g, 16.5 mmol) and NH4OAC (25.4 g, 330 mmol), which gives imidazole 55a (5 g, 75%) (dione 54 was synthesized according to General Method 4).
Figure imgf000125_0002
Data for 55a (R*' = tert-butyl): iH-NMR (300 MHz, CDCI3): 7.92 (d, 2H, J= 7.5), 7.64 (d, IH, J= 15.9), 7.53 (d, 2H, J= 8.1), 7.43-7.32 (m, 6H), 6.82 (d, 2H, J = 8.1), 6.43 (d, IH, J= 15.9), 4.51 (s, 2H), 4.24 (q, 2H, J= 6.9), 1.48 (s, 9H), 1.31 (t, 3H, J = 7.2).
The tert-butyl ester of 55a (4.2 g, 6.9 mmol)(Scheme 11) was hydrolyzed according to General Method 11 to give after recrystallization, imidazole 56a (3.2 g, 84%).
Figure imgf000126_0001
Data for 56a: iH-NMR (300 MHz, CDC13): 8.12 (d, 2H, J= 8.4), 7.93 (d, 2H, J= 8.7), 7.63 (d, IH, J = 15.9), 7.63 (d, 2H, J = 8.4), 7.49 (d, 2H, J= 9.0), 7.44 (d, 2H, J= 9.0), 7.02 (d, 2H, J = 8.7), 6.77 (d, IH, J = 16.2), 4.74 (s, 2H), 4.20 (q, 2H, J = 6.9), 1.26 (t, 3H, J = 7.2).
Compound 213 was synthesized according to General Method 8 from imidazole 56a (400 mg, 0.73 mmol) in DMF (5 mL), with Pd(OAc)2 (33 mg, 0.15 mmol), TEA (302 μL, 1.46 mmol), (o-Tolyl)3P (89 mg, 0.29 mmol), and *acrylamide 57a (222 mg, 0.88 mmol) to give after purification by flash column chromatography and recrystallization [4-(2-[4-((E)-2- Ethoxycarbonyl-vinyl)-phenyl]-5-{4-[(E)-2-(l-methyl- dodecylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenoxy]- acetic acid 213 as a yellow solid (30 mg, 38%). * Acrylamide 57a was synthesized according to General Method 9 from acryloyl chloride and 1 -methyl dodecylamine. Data for [4-(2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5-{4- [(E)-2-(l-methyl-dodecylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4- yl)-phenoxy]-acetic acid 213: iH-NMR (400 MHz, DMSO-d6): 8.12 (d, 2H, J= 7.7), 7.92-7.87 (m, 3H), 7.68 (d, IH, J = 16.0), 7.59-7.53 (m, 4H), 7.45 (d, 2H, J= 8.0), 7.38 (d, IH, J= 16.0), 7.00 (d, 2H, J
= 8.4), 6.72 (d, IH, J = 16.0), 6.60 (d, IH, J = 16.0), 4.73 (s, 2H), 4.20 (q, 2H, J = 7.2), 3.85 (m, IH, J = 6.4), 1.39 (brs, 2H), 1.28- 1.22 (m, 21H), 1.06 (d, 3H, J = 6.4), 0.83 (t, 3H, J = 6.4). LC/MS: LC: retention time 3.78 minutes; MS (APcI): 720.5 (100, [M+H]); calcd C44H53N3O6 [M+H] 720.9.
Example 25 (4-{5-{4-r(E)-2-(3,3-Diρhenyl-propylcarbamovH-vinvn-phenyl}- 2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyll-lH-imidazol-4-yl}- phenoxy)-acetic acid tert-butyl ester 214
Figure imgf000127_0001
Compound 214 was synthesized according to General Method 8 from imidazole 55a (200 mg, 0.33 mmol) in DMF (2 mL), with Pd(OA (15 mg, 0.07 mmol), TEA (70 μL, 0.5 mmol), (o-Tolyl) P (40 mg, 0.13 mmol), and *acrylamide 57b (0.88 mmol) to give after recrystallization (4-{5-{4-[(E)-2-(3,3-Diphenyl- propylcarbamoyl)-vinyl]-phenyl}-2-[4-((E)-2-ethoxycarbonyl-vinyl)- phenyl]-lH-imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester 214 as a yellow solid 130mg, (50%). *Acrylamide 57b was synthesized according to General Method 9 from, acryloyl chloride and 3,3-Diphenyl-propylamine.
Data for (4-{5-{4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)- vinyl]-phenyl}~2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester 214: iH-NMR (300 MHz, CDCls): 8.04 (d, 2H, J= 7.5), 7.60 (d, IH, J= 15.9), 7.45-7.31 (m, 7H), 7.21-7.10 (m, 12H), 6.66 (d, 2H, J = 8.7), 6.36 (d, IH, J = 15.9), 6.22 (brs, IH), 6.13 (d, IH, J= 15.3), 4.44 (s, 2H), 4.24 (q, 2H, J = 6.9), 3.86 (t, IH, J = 6.9), 3.22 (q, 2H, J = 6.0), 2.22 (q, 2H, J = 6.9), 1.46 (s, 9H), 1.32 (t, 3H, J = 7.2).
Example 26 (4-{5-{4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl|-phenyl}- 2-r4-((E)-2-ethoxycarbonyl-vinyl1-phenvn-lH-imidazol-4-yl}- phenoxy)-acetic acid 215
Figure imgf000128_0001
Imidazole 215 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 214 (Example 25) according to General Method 11, to give (4-{5- {4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinyl]-phenyl}-2-[4-((E)-2- ethoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenoxy)-acetic acid 215, after purification, as a yellow solid (50 mg, 41%). Data for (4-{5-{4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)- vinyl]-phenyl}-2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenoxy)-acetic acid 215: iH-NMR (300 MHz, DMSO-de): 8.21 (t, IH, J= 8.2), 8.14 (d, 2H, J= 8.4), 7.95 (d, 2H, J = 8.1), 7.70 (d, IH, J = 15.9), 7.62 (d, 2H, J = 8.1), 7.57 (d, 2H, J = 8.4), 7.47 (d, 2H, J = 8.7), 7.41 (d, IH, J= 15.9), 7.33-7.25 (m, 8H), 7.19-7.14 (m, 2H), 7.03 (d, 2H, J = 8.7), 6.78 (d, IH, J = 15.9), 6.64 (d, IH, J= 15.9), 4.75 (s, 2H), 4.20 (q, 2H, J= 6.6), 4.02 (t, IH, J= 8.1), 3.06 (q, 2H, J= 5.4), 2.23 (q, 2H, J = 7.5), 1.26 (t, 3H, J = 7.2). LC/MS: LC: retention time 3.30 minute; MS (APcI): 732.7 (100, [M+H]); calcd C46H4ιN3θ6 [M+H] 732.8.
Example 27 (4-{5-{4-HE)-2-(3H-Benzotriazol-5-ylcarbamoyl)-vinyn- phenyl}-2-r4-f El-2-ethoxycarbonyl-vinyl)-phenvn-lg- imidazol-4-yl}-phenoxy)-acetic acid 216
Figure imgf000129_0001
Compound 216 was synthesized according to General Method 8 from imidazole 56 (100 mg, 0.18 mmol) in DMF (1 mL), with Pd(OAc)2 (8 mg, 0.036 mmol), TEA (50.2 μL, 0.36 mmol), (o-Tolyl)3P (22 mg, 0.072 mmol), and *acrylamide 57c (68 mg, 0.36 mmol) to (4-{5-{4-[(E)-2-(3H-Benzotriazol-5- ylcarbamoyl)-vinyl]-phenyl}-2-[4-((E)-2-ethoxycarbonyl-vinyl)- phenyl]-lH-imidazol-4-yl}-phenoxy)-acetic acid 216 as a light yellow solid (5 mg, 4%). *Acrylamide 57c was synthesized according to General Method 9 from acryloyl chloride and 5- aminobenzo triazole .
• Data for (4-{5-{4-[(E)-2-(3H-Benzotriazol-5-ylcarbamoyl)- vinyl]-phenyl}-2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenoxy)-acetic acid 216: iH-NMR (300 MHz, CDCls + CD3OD): 8.12 (d, 2H, J = 7.7), 7.65-7.55 (m, 5H), 7.42- 7.28 (m, 9H), 6.85 (d, 2H, J = 7.7), 6.44 (d, IH, J = 16.0), 4.53 (s, 2H), 4.20 (q, 2H, J = 7.2), 1.15 (d, 3H, J = 6.4). LC/MS: LC: retention time 2.53 minute; MS (APcI): 655.8 (100, [M+H]); calcd C37H30N6O6 [M+H] 655.7. Example 28
{4-r2-r4-((E)-2-Ethoxycarbonyl-vinyl)-pheny -5-(4-{(E)-2-fl-(4- pentyl-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lff-imidazol- 4-yI|-phenoxy}-acetic acid 217
Figure imgf000131_0001
Example 59 Example 60
Figure imgf000131_0002
Example 61 Example 62
Figure imgf000131_0003
Figure imgf000131_0004
Compound 217 was synthesized according to General Method 8 from imidazole 56a (100 mg, 0.18 mmol) in DMF (1 mL), with Pd(OAc)2 (8 mg, 0.036 mmol), TEA (50.2 μL, 0.36 mmol), (o-Tolyl)3P (22 mg, 0.072 mmol), and *acrylamide 57d (0.88 mmol) to give after purification by flash column chromatography and recrystallization {4-[2-[4-((E)-2- Ethoxycarbonyl-vinyl)-phenyl]-5-(4-{(E)-2-[l-(4-pentyl-phenyl)~ ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-4-yl]-phenoxy}-acetic acid 217 as a yellow solid (30 mg, 23%). *Acrylamide 57d was synthesized according to General Method 9 from acryloyl chloride and l-(4-pentylphenyl)-ethylamine hydrochloride.
Data for {4-[2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5-(4- {(E)-2-[l-(4-pentyl-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH- imidazol-4-yl]-phenoxy}-acetic acid 217: iH-NMR (300 MHz, DMSO-dδ): 8.53 (d, IH, J= 8.4), 8.27 (d, 2H, J= 8.4), 7.92 (d, 2H, J = 8.4), 7.69 (d, IH, J = 15.9), 7.58 (s, 4H), 7.47 (d, 2H, J = 8.4), 7.41 (d, IH, J = 15.9), 7.23 (d, 2H, J = 8.1), 7.12 (d, 2H, J= 8.1), 7.02 (d, 2H, J = 9.0), 6.75 (d, IH, J = 15.6), 6.70 (d, IH, J= 15.6), 5.01 (t, IH, J= 6.6), 4.74 (s, 2H), 4.20 (q, 2H, = 6.9), 2.52 (t, 2H, J= 7.5), 1.53 (m, 2H), 1.38 (d, 3H, J= 6.9), 1.29-1.23 (m, 7H), 0.84 (t, 3H, J = 6.9). LC/MS: LC: retention time 3.37 minutes; MS (APcI): 712.5 (100, [M+H]); calcd C44H45N3O6 [M+H] 712.8. Example 29 r4-(2-r4-(lE)-2-Ethoxycarbonyl-vinyl)-phenvn-5-{4-r(E)-2-f2- methoxy-ethylcarbamoyl)-vinyl]-phenyl}-lJ-r-imidazol-4-yl)- phenoxy]-acetic acid 218
Figure imgf000133_0001
Compound 218 was synthesized according to General Method 8 from imidazole 56 (400 mg, 0.73 mmol) in DMF (5 mL), with Pd(OAc)2 (33 mg, 0.15 mmol), TEA (203 μL, 1.46 mmol), (o-Tolyl)3P (89 mg, 0.29 mmol), and *acrylamide 57e (114 mg, 0.88 mmol) to give after purification by flash column chromatography recrystallization [4-(2-[4-((E)-2-Ethoxycarbonyl- vinyl)-phenyl]-5-{4-[(E)-2-(2-methoxy-ethylcarbamoyl)-vinyl]- phenyl}-lH~imidazol-4-yl)-phenoxy]-acetic acid 218 as a yellow solid (62 mg, 14%). * Acrylamide 57e was synthesized according to General Method 9 from acryloyl chloride and 2-methoxy- ethylamine.
Data for [4-(2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5-{4-[(E)-2- (2-methoxy-ethylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)- phenoxy]-acetic acid 218: iH-NMR (300 MHz, DMSO-d6): 8.22 (t, IH, J = 5.1), 8.17 (d, 2H, J = 8.4), 8.01 (d, 2H, J = 8.4), 7.72 (d, IH, J = 15.9), 7.66 (d, 2H, J = 8.4), 7.58 (d, 2H, J = 8.4), 7.50- 7.42 (m, 3H), 7.06 (d, 2H, J = 9.0), 6.83 (d, IH, J= 6.83), 6.72 (d, IH, J = 15.9), 4.76 (s, 2H), 4.21 (q, 2H, J= 7.2), 3.41-3.26
(m, 4H), 3.26 (s, 3H), 1.27 (t, 3H, J= 7.2). LC/MS: LC: retention time 2.41 minutes; MS (APcI): 596.7 (100, [M+H]); calcd
C34H33N3O7 [M+H] 596.6. Example 30
[4-(2-r4-((E)-2-Ethoxycarbonyl-vinvH-phenvn-5-H-r(E)-2-
(2,2,3,3,4,4,5,5,6,6,7, 7,8,8,8-ρentadecafluoro- octylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenoxy]- acetic acid 219
Figure imgf000134_0001
Compound 219 was synthesized according to General Method 8 from imidazole 56 (224 mg, 0.37 mmol) in DMF (4 mL), with Pd(OAc)2 (17 mg, 0.074 mmol), TEA (103 μL, 0.74 mmol), (o-Tolyl)3P (45 mg, 0.15 mmol), and *acrylamide 57f (200 mg, 0.44 mmol) to give after purification by flash column chromatograhpy and recrystallization [4-(2-[4-((E)-2- Ethoxycarbonyl-vinyl)-phenyl]-5-{4-[(E)-2-
(2, 2, 3, 3, 4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 8-pentadecafluoro-octylcarbamoyl)- vinyl]-phenyl}-lH-imidazol-4-yl)-phenoxy]-acetic acid 219 as a yellow solid (12 mg, 13%). *Acrylamide 57f was synthesized according to General Method 9 from acryloyl chloride and 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-octylamine. Data for [4-(2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5-{4-[(E)-2- (2, 2, 3, 3, 4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 8-pentadecafluoro-octylcarbamoyl)- vinyl]-phenyl}-lH-imidazol-4-yl)-phenoxy]-acetic acid 219: iH- NMR (300 MHz, DMSO-de): 8.76 (t, IH, J= 5.1), 8.13 (d, 2H, J = 8.4), 7.91 (d, 2H, J= 8.4), 7.69 (d, IH, J= 15.9), 7.64-7.58 (m, 4H), 7.53 (d, IH, J= 15.9), 7.46 (d, 2H, J= 8.7), 7.02 (d, 2H, J = 8.7), 6.75 (d, IH, J = 16.2), 6.74 (d, IH, J= 15.9), 4.74 (s, 2H), 4.24-4.07 (m, 4H), 1.27 (t, 3H, J= 7.2). LC/MS: LC: retention time 3.99 minutes; MS (APcI): 920.3 (100, [M+H]); calcd C39H28Fi5N3θ6 [M+H] 920.6.
Example 31 (E)-3-(4-{4-(4-Carboxymethoxy-phenyl)-5-r4-(JE)-2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- acrylic acid ethyl ester 220
Figure imgf000135_0001
Compound 220 was synthesized according to General Method 8 from imidazole 56 (400 mg, 0.73 mmol) in DMF (5 mL), with Pd(OAφ (33 mg, 0.15 mmol), TEA (203 μL, 1.46 mmol), (o-Tolyl)3P (89 mg, 0.29 mmol), and *acrylamide 57g (210 mg, 0.88 mmol) to give after purification by column chromatograhpy and recrystallization (E)-3-(4-{4-(4- Carboxymethoxy-phenyl)-5-[4-((E)-2-dihexylcarbamoyl-vinyl)- phenyl]-lH-imidazol-2-yl}-phenyl)-acrylic acid ethyl ester 220 as a yellow solid (33 mg, 6.4%). *Acrylamide 57g was synthesized according to General Method 9 from acryloyl chloride and dihexylamine.
Data for (E)-3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-acrylic acid ethyl ester 220: iH-NMR (300 MHz, DMSO-de): 8.13 (d, 2H, J= 8.4), 7.89 (d, 2H, J = 8.7), 7.71-7.66 (m, 3H), 7.57 (d, 2H, J =7.8), 7.49-7.45 (m, 3H), 7.12 (d, IH, J = 15.6), 7.01 (d, 2H, J = 8.4), 6.73 (d, IH, J = 15.9), 4.73 (s, 2H), 4.20 (q, 2H, J = 6.9), 3.44 (t, 2H, J = 4.8), 3.31 (t, 2H, J = 6.9) 1.50 (brs, 4H), 1.26 (s, 15H), 0.84 (d, 6H, J= 6.6). LC/MS: LC: retention time 3.57 minutes; MS (APcI): 706.2 (100, [M+H]); calcd C43H51N3O6 [M+H] 706.9.
Example 32 3-f4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-{4-r(E)-2- (l-methyl-dodecylcarbamoyl)-vinyl|-phenyl}-lH-imidazol-2- yl)-pheny!|-4,5-dih,ydro-isoxazole-5-carboxylic acid tert- butyl ester 221
Figure imgf000136_0001
Imidazole 55b was synthesized according to General
Method 7 (Scheme 1 1) from dione 54 (8.0 g, 19.1 mmol) in acetic acid (20 mL), with 3-(4-Formyl-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester (7.9g, 28.6 mmol) and NH4OAC (44.2 g, 573 mmol), which gives imidazole 55b (6.3 g, 49%) . Dione 54 was synthesized according to General Method 4.
Figure imgf000137_0001
Data for compound 55b (Ri* = tert-butyl): iH-NMR (300 MHz, CDCI3): 7.93 (d, 2H, J = 6.9), 7.64 (d, 2H, J = 7.8), 7.39 (s, 2H), 7.34 (d, 2H, J = 8.1), 6.82 (d, 2H, J= 7.8), 5.06 (t, IH, J= 8.7), 4.52 (s, 2H), 3.59 (d, 2H, J= 8.1), 1.51 (s, 19H).
Compound 221 was synthesized according to General Method 8 from imidazole 55b (300 mg, 0.44 mmol) in DMF (5 mL), with Pd(OAc)2 (20 mg, 0.09 mmol), TEA (123 μL, 0.88 mmol), (o-Tolyl)3P (54 mg, 0.18 mmol), and *acrylamide 57a (135 mg, 0.53 mmol) to give, after purification via column chromatography eluting with Ethyl Acetate: Hexane followed by recrystallization, 3-[4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)- 5-{4-[(E)-2-(l-methyl-dodecylcarbamoyl)-vinyl]-phenyl}-lH- imidazol-2-yl)-phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 221 as a yellow solid (60 mg, 16%). * Acrylamide 57a was synthesized according to General Method 9 from acryloyl chloride and 1 -methyl dodecylamine. Data for 3-[4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-{4-[(E)- 2-(l -methyl-dodecylcarbamoyl)-vinyl]~phenyl}-l H-imidazol-2-yl)- phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 221: iH-NMR (300 MHz, CDCls): 8.07 (d, 2H, J= 7.8), 7.69 (d, 2H, J= 7.8), 7.53-7.43 (m, 5H), 7.33 (d, 2H, J= 8.4), 6.84 (d, 2H, J= 8.4), 6.30 (d, IH, J= 15.3), 5.69 (brs, IH), 5.08 (t, IH, J = 9.3), 4.52 (s, 2H), 4.12-4.06 (m, IH), 3.59 (d, 2H, J= 9.3), 1.58-1.47 (m, 2H), 1.52 (s, 9H), 1.50 (s, 9H), 1.25 (brs, 18H), 1.17 (d, 3H, J= 6.3), 0.88 (t, 3H, J = 6.6).
Example 33 3-r4-(4-(4-Carboxymethoxy-phenyl)-5-{4-r(E)-2-(l-methyl- dodecylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-2-yl)-phenyl1- 4,5-dihydro-isoxazole-5-carboxylic acid 222
Figure imgf000138_0001
Imidazole 222 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 221 according to General Method 11, to give 3-[4-(4-(4- Carboxymethoxy-phenyl)-5-{4-[(E)-2-(l -methyl- dodecylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]-4,5- dϊhydro-isoxazole-5-carboxylic acid 222, after recrystallization, as a yellow solid (13 mg, 15%). Data for 3-[4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)-2-(l -methyl- dodecylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 222: iH-NMR (300 MHz, DMSO-de): 8.16 (d, 2H, J= 8.4), 7.80 (d, 2H, J = 8.4), 7.63-7.45 (m, 7H), 7.36 (d, IH, J = 16.5), 7.05-6.89 (m, 2H), 6.67-6.56 (m, IH), 5.20 (dd, IH, J = 11.7, 6.9), 4.76-4.69 (m, 2H), 3.87-3.83 (m, IH), 3.79-3.73 (m, IH), 3.63 (dd, IH, J = 6.9, 6.6), 1.40 (bs, 2H) 1.23 (s, 18H), 1.07 (d, 3H, J= 6.6), 0.84 (t, 3H, J = 6.6). LC/MS: LC: retention time 3.24 and 3.42 minutes (micelle aggregation); MS (APcI): 735.6 (100, [M+H]); calcd C43H50N4O7 [M+H] 735.9.
Example 34 3-{4-r4-(4-tert-Butoxycarbonylmethoxy-ρhenyU-5-(4-{(E)-2- l-(4-pentyl-phenyl)-ethylcarbamoyll-vinyl)-phenyl)-lH- imidazol-2-yll-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 223
Figure imgf000139_0001
Compound 223 was synthesized according to General Method 8 from imidazole 55b (300 mg, 0.44 mmol) in DMF (2.5 mL), with Pd(OAc)2 (20 mg, 0.09 mmol), TEA (123 μL, 0.88 mmol), (o-Tolyl)3P (54 mg, 0.18 mmol), and *acιylamide 57d (130 mg, 0.53 mmol) to give, after purification via column chromatography eluting with Ethyl Acetate: Hexane followed by recrystallization, 3-{4-[4-(4-tert-Butoxycarbonylmethoxy-phenyl)- 5-(4-{(E)-2-[l-(4-pentyl-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH- imidazol-2-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 223 as a yellow solid (200 mg, 54%).
*Acrylamide 57d was synthesized according to General Method 9 from acryloyl chloride and l-(4-pentylphenyl)-ethylamine hydrochloride.
Data for 3-{4-[4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-(4-{(E)- 2-[l-(4-pentyl-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH- imidazol-2-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 223:
iH-NMR (300 MHz, CDC1 ): 8.05 (d, 2H, J = 7.8), 7.69 (d, 2H, J = 8.4), 7.48-7.44 (m, 5H), 7.34-7.21 (m, 4H), 7.14 (d, 2H, J = 7.8), 6.84 (d, 2H, J = 8.4), 6.31 (d, IH, J= 15.3), 6.13 (brs, IH), 5.20 (t, IH, J= 6.9), 5.07 (t, IH, J= 9.3), 4.51 (s, 2H), 3.57 (d, 2H, J = 9.3), 2.57 (t, 2H, J= 7.5) 1.59-1.43 (m, 5H), 1.52 (s, 9H), 1.50 (s, 9H), 1.33-1.30 (m, 4H), 0.83 (t, 3H, J= 6.6).
Example 35 3-{4-r4-(4-Carboxymethoxy-phenyl)-5-f4-{(E)-2-ri- -ρentyl- phenyl)-ethylcarbamoyll-vinyl}-phenylϊ-lff-imidazol-2-yl|- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 224
Figure imgf000141_0001
Imidazole 224 was synthesized according to General Method 11 via hydrolyses of the tert-butyl ester of imidazole 223 according to General Method 11, to give 3-{4-[4-(4- Carboxymethoxy-phenyl)-5-(4-{(E)-2-[l~(4-pentyl-phenyl)~ ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-2-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 224, after recrystallization, as a pale yellow solid (50 mg, 42%).
Data for 3-{4-[4-(4-Carboxymethoxy-phenyl)-5-(4-{(E)-2-[l-(4- pentyl-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH-imidazol-2-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 224: iH-NMR (300 MHz, CDCI3/CD3OD): 8.12 (d, 2H, J = 8.7), 8.00 (d, 2H, J = 8.4), 7.66 (d, 2H, J= 8.7), 7.58 (d, 2H, J = 8.7), 7.54 (d, IH, J = 15.9), 7.50 (d, 2H, J = 8.7), 7.26 (d, 2H, J = 8.4), 7.15 (d, 2H, J = 8.1), 7.08 (d, IH, J = 8.7), 6.73 (d, IH, J = 15.9) 5.28 (dd, IH, J = 11.4, 7.2), 5.11 (q, IH, J = 6.9), 4.75 (s, 2H), 3.82 (dd, IH, J = 17.1, 11.4), 3.71 (dd, IH, J = 17.1, 6.9), 2.58 (t, 2H, J = 7.5) 1.66-1.55 (m, 2H), 1.50 (d, 3H, J = 6.9), 1.40-1.24 (m, 4H), 0.89 (t, 3H, J = 6.6). LC/MS: LC: retention time 2.78 and 3.00 minutes (micelle aggregation); MS (APcI): 727.4 (100, [M+H]); calcd C43H42N4θ7 [M+H] 727.8.
Example 36 3-(4-{4-f4-Carboxymethoxy-ρhenvU-5-r4-((E)-2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 225
Figure imgf000142_0001
Compound 225 was synthesized according to General Method 8 from imidazole 55b (300 mg, 0.44 mmol) in DMF (2.2 mL), with Pd(OAc)2 (20 mg, 0.09 mmol), TEA (123 μL, 0.88 mmol), (o-Tolyl)3P (54 mg, 0.18 mmol), and *acrylamide 57g (127 mg, 0.53 mmol) to give after purification by flash column chromatography followed by recrystallization, 3-(4-{4-(4-tert- Butoxycarbonylmethoxy-phenyl)-5-[4-((E)-2-dihexylcarbamoyl- vinyl)-phenyl]-lJf-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid tert-butyl ester as a yellow solid (300 mg, 80%). * Acrylamide 57g was synthesized according to General Method 9 from acryloyl chloride and dihexylamine. The desired imidazole was obtained via hydrolyses of the tert-butyl esters according to General Method 11 to give, after recrystallization, 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 225 as a yellow solid (70 mg, 19%).
Data for 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 225: iH-NMR (300 MHz, DMSO-de): 8.18 (d, 2H, J = 8.1), 7.86 (d, 2H, J = 8.1), 7.72 (d, 2H, J = 8.1), 7.58 (d, 2H, J = 8.4), 7.50-7.45 (m, 3H), 7.03 (d, IH, J = 15.6), 7.01 (d, 2H, J = 8.4), 5.22 (dd, IH, J = 11.4, 7.2), 4.74 (s, 2H), 3.84-3.61 (m, 2H), 3.46-3.30 (m, 4H), 1.51 (brs, 4H), 1.27 (s, 12H), 0.86 (d, 6H, J = 6.3). LC/MS: LC: retention time 3.63 minute; MS (APcI): 721.5 (100, [M+H]); calcd C42H48N4θ7 [M+H] 721.9.
Example 37 3-[4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)-2-(2-nonyloxy- ethylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl1- 4,5-dihydro-isoxazole-5-carboxylic acid 226
Figure imgf000143_0001
Compound 226 was synthesized according to General Method 8 from imidazole 55b (300 mg, 0.44 mmol) in DMF (2.2 mL), with Pd(OAc)2 (40 mg, 0.18 mmol), TEA (123 μL, 0.88 mmol), (o-Tolyl)3P (107 mg, 0.35 mmol), and *acrylamide 57h (127 mg, 0.53 mmol) to give after purification by flash column chromatography followed by recrystallization, 3-[4-(4-(4-tert- Butoxycarbonylmethoxy-phenyl)-5-{4-[(E)-2-(2-nonyloxy- ethylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-2 -yl) -phenyl] -4, 5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester as a yellow solid (139 mg, 38%). * Acrylamide 57h was synthesized according to General Method 9 from acryloyl chloride and 2- nonyloxy-ethylamine. The desired imidazole was obtained via hydrolyses of the tert-butyl esters according to General Method 11 to give, after recrystallization, 3-[4-(4-(4-Carboxymethoxy- phenyl)-5-{4-[(E)-2-(2-nonyloxy-ethylcarbamoyl)-vinyl]-phenyl}- lH-imidazol-2-yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 226 as a yellow solid (50 mg, 72%).
Data for 3-[4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)-2-(2- nonyloxy-ethylcarbamoyl)-υinyl]-phenyl} - 1 H-imidazol-2-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 226: iH-NMR (300 MHz, DMSO-de): 8.15 (d, 3H, J = 8.4), 7.79 (d, 2H, J = 7.8), 7.63-7.36 (m, 7H), 7.04-6.88 (m, 2H), 6.73-6.61 (m, IH), 5.19 (dd, IH, J = 10.5, 6.9), 4.75-4.68 (m, 2H), 3.77 (dd, IH, J = 17.4, 11.4), 3.63 (dd, IH, J= 17.7, 7.2), 3.42-3.27 (m, 6H), 1.49 (t, 2H, J = 5.7), 1.23 (s, 12H), 0.83 (t, 3H, J = 5.1). LC/MS: LC: retention time 3.16 minute; MS (APcI): 723.4 (100, [M+H]); calcd C41H46N4O8 [M+H] 722.8.
Example 38 3-(4-{5-(4-tert-Butoxycarbonylmethoxy-phenvU-4-r4-t(EΪ-2- dodecylcarbamoyl-vinyl)-phenyll- 1-methyl- lH-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester
227
Figure imgf000145_0001
To a solution of the imidazole 55b (equivalent to 135 in Scheme 21) (50 mg, 0.074 mmol) in DMF (150 μL) was added NaH (3.6 mg, 0.15 mmol) in one portion and stirred at r.t. for 20 min. Then, 80 μL of a IM solution of methyliodide in DMF was added dropwise to the reaction flask: After 3h, the reaction was diluted with ethyl acetate, then washed with water, sat. sodium bicarbonate, sat. sodium chloride, dried (MgSθ4), filtered and concentrated in vacuo. Purification by flash column chromatography eluting with hexane/ethyl acetate (7:3) afforded imidazole 137a as a white solid (24 mg, 47%).
Figure imgf000146_0001
Data for imidazole 137a: iH-NMR (300 MHz, CDC13): 7.86 (d, 2H, J = 8.1), 7.80 (d, 2H, J= 8.4), 7.43 (d, 2H, J = 8.4), 7.34 (d, 2H, J = 8.4), 7.29 (d, 2H, J = 8.4), 7.01 (d, 2H, J = 8.4), 5.11 (t, IH, J = 9.3), 4.60 (s, 2H), 3.63 (d, 2H, J= 9.3), 3.55 (s, 3H), 1.53 (s, 9H), 1.52 (s, 9H). LC/MS: LC: retention time 3.81 minute; MS (APcI): 688.2 (100, [M+H]); calcd CseHssBrNsOe [M+H] 688.6.
Compound 227 was synthesized according to General Method 8 from imidazole 137a. The Br imidazole 137a (40 mg, 0.058 mmol) was dissolved in DMF (300 μL), followed by addition of Pd(OA (2.6 mg, 0.012 mmol), TEA (16.2 μL, 0.12 mmol), P-(o-tolyl)3 (7.3 mg, 0.024 mmol) and *acrylamide 57i (17 mg, 0.07 mmol). The reaction was heated to 100 °C for 2h. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water, sat. sodium chloride, dried under MgSθ4, filtered and concentrated to give a yellow oil. The oil was purified by flash column chromatography eluting with hexane/ethyl acetate (7:3) to give 3-(4-{5-(4-teti-Butoxycarbonylmethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l -methyl- lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 227 as a light yellow solid (20 mg, 41%). *acrylamide 57i was synthesized according to General Method 9 from acryloyl chloride and dodecylamine.
Data for 3-(4-{5-(4-tert-Butoxycarbonylmethoxy-phenyl)-4-[4-((E)- 2-dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2-yl}- phenyl)-4,5-dϊhydro-isoxazole-5-carboxylic acid tert-butyl ester 227: iH-NMR (300 MHz, CDCls): 7.85 (d, 2H, J = 8.7), 7.81 (d, 2H, J= 8.4), 7.56-7.50 (m, 3H), 7.35-7.31 (m, 4H), 7.02 (d, 2H, J = 8.7), 6.34 (d, IH, J= 15.6), 5.74 (brs, IH), 5.11 (t, IH, J = 9.3), 4.60 (s, 2H), 3.63 (d, 2H, J = 9.3), 3.54 (s, 3H), 3.36 (q, 2H, J = 6.6), 1.53-1.52 (m, 20H), 1.26 (brs, 18H), 0.88 (t, 3H, J = 6.0). LC/MS: LC: retention time 4.67 minute; MS (APcI): 848.0 (100, [M+H]); calcd C51H66N4O7 [M+H] 848.1.
Example 39 3-(4-{5-(4-Carboxymethoxy-phenvU-4-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl - 1-methyl- lJ-T-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228
Figure imgf000147_0001
The t-butyl ester 226 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-(4-{5-(4-Carboxymethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l -methyl- lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228 as a yellow solid (33 mg, 77%). Data for 3-(4-{5-(4-Carboxymethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 228: iH-NMR (300 MHz, DMSO-de): 8.07 (t, IH, J = 5.1), 7.96 (s, 4H), 7.54 (d, 2H, J = 8.7), 7.47 (d, 2H, J = 8.4), 7.44 (d, 2H, J = 8.4) 7.36 (d, IH, J = 15.6), 7.13 (d, 2H, J = 8.4), 6.60 (d, IH, J = 15.6), 5.26 (dd, IH, J = 11.7, 6.9), 4.79 (s, 2H), 3.82 (dd, IH, J = 16.8, 12.0), 3.71 (dd, IH, J= 17 A, 7.2), 3.56 (s, 3H), 3.12 (q, 2H, J = 6.3), 1.43 (t, 2H, J = 5.4), 1.24 (s, 18H), 0.84 (t, 3H, J = 6.3). LC/MS: LC: retention time 3.69 minute; MS (APcI): 735.4 (100, [M+H]); calcd C43H50N4O7 [M+H] 735.9.
Example 40 3-{4-f5-f4-riE)-2-Dodecylcarbamoyl-vinyl)-phenyn-4-f4- ethoxycarbonylmethoxy-phenyl)- 1-methyl- lH-imidazol-2- yπ-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 229
Figure imgf000149_0001
To a solution of the α-keto bromide 130 (Ri = Et) (207 mg, 0.45 mmol) in 1,4 dioxane (0.5 mL) and DMSO (0.5 mL), was added methylamine hydrochloride (31 mg, 0.45 mmol) and DIEA (117 μL, 0.68 mmol). The reaction was stirred at 0 °C for lh (Scheme 20). After lh, the reaction was removed from the ice bath and stirred at r.t. for 16h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, sat. sodium chloride, dried under MgS04, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography eluting with hexane/ethyl acetate (1 : 1) to afford the desired compound 132a as a light yellow oil (70 mg, 38%).
Figure imgf000150_0001
Data for Compound 132a: iH-NMR (300 MHz, CDC13): 7.92 (d, 2H, J= 8.7), 7.45 (d, 2H, J = 8.1), 7.21 (d, 2H, J = 8.4), 6.89 (d, 2H, J= 8.7), 5.11 (s, IH), 4.65 (s, 2H), 4.27 (q, 2H, J= 7.2), 2.39 (s, 3H), 1.29 (t, 3H, J= 6.9). LC/MS: LC: retention time 4.12 minute; MS (APcI): 377.2 (100, [M+H-CH2CH3]); calcd Cι H20BrNO4 [M+H] 407.3.
The imidazole 134a was prepared from 132a according to General Method 7. Acetic acid (1 mL) was added to a mixture of the α-keto methylamine 132a (65 mg, 0.16 mmol), 3-(4-Formyl- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester (66 mg, 0.24 mmol), and NH4OAc (370 mg, 4.8 mmol) and heated to 100 °C for 2h. The reaction mixture was quenched with ice water, extracted with ethyl acetate (20 mL x 2). The organic layer was washed with water, sat. sodium chloride, dried under MgSθ4, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography eluting with hexane/ethyl acetate (6:4) to afford the desired compound 134a (40 mg, 38%).
Figure imgf000151_0001
Data for Compound 134a: iH-NMR (300 MHz, CDC13): 7.84- 7.77 (m, 4H), 7.61 (d, 2H, J= 8.1), 7.46 (d, 2H, J= 9.0), 7.27 (d, 2H, J = 8.4), 7.80 (d, 2H, J = 8.7), 5.10 (t, IH, J = 9.3), 4.59 (s, 2H), 4.26 (q, 2H, J = 7.2), 3.63 (d, 2H, J = 9.3), 3.54 (s, 3H), 1.52 (s, 9H), 1.29 (t, 3H, J= 6.9).
Compound 229 was prepared as described in General Method 8 from the intermediate 134a. The Br imidazole 134a (260 mg, 0.39 mmol) was dissolved in DMF (0.9 mL), followed by addition of Pd(OA (35 mg, 0.16 mmol), TEA (109 μL, 0.78 mmol), P-(o-tolyl)3 (95 mg, 0.31 mmol) and acrylamide 57i (113 mg, 0.47 mmol). The reaction was heated to 100 C for 2h. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water, sat. sodium chloride, dried under MgSθ4, filtered and concentrated to give a yellow residue. The oil was purified by flash column chromatography eluting with hexane/ethyl acetate /dichloromethane to afford a light yellow solid (200 mg, 63%). Recrystallizing with ethyl acetate/hexane, filtering of the solids and rinsing with ether gave 3-{4-[5-[4-((E)-2-
Dodecylcarbamoyl-vinyl)-phenyl]-4-(4-ethoxycarbonylmethoxy- phenyl)-l-methyl-lH-imidazol-2-yl]-phenyl}-4, 5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 229 as a light yellow solid (167 mg, 84%).
Data for 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)- 1 -methyl- 1 H-imid azo 1-2 -y I] - phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 229: iH-NMR (300 MHz, CDC13): 7.92 (d, 2H, J= 6.9), 7.79 (d, 2H, J = 8.1), 7.66 (d, IH, J = 15.6), 7.57 (d, 2H, J = 7.5), 7.50 (d, 2H, J = 8.7), 7.32 (d, 2H, J = 7.8), 7.80 (d, 2H, J = 8.7), 6.49 (d, IH, J = 15.9), 5.83 (brs, IH), 5.13 (t, IH, J = 9.0), 4.59 (s, 2H), 4.27 (q, 2H, J = 7.2), 3.64 (d, 2H, J = 3.3), 3.60 (s, 3H), 3.41 (q, 2H, J = 6.6), 1.57-1.51 (m, 11H), 1.32-1.27 (m, 21H), 0.89 (t, 3H, J= 6.3).
Example 41 3-{4-r5-r4-((E)-2-Dodecylcarbamoyl-vinyH-ρhenvn-4-(4- ethoxycarbonylmethoxy-phenyl)-l-methyl-lH-imidazol-2- yH-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 230
Figure imgf000152_0001
Compound 230 was prepared according to General Method 11 from 229 (186 mg, 0.24 mmol). Purification via flash column chromatography eluting with 2% methanol/ dicholoromethane with 1% formic acid afforded 3-{4- ]5-]4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)- 1 -methyl- 1 H-imidazol-2-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 230 as a yellow solid (100 mg, 54%). Data for 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)- 1 -methyl- lH-imidazol-2-yl]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 230: iH-NMR (300 MHz, DMSO-de): 8.12 (t, IH, J = 6.0), 7.90 (dd, 2H, J = 8.7), 7.84 (d, 2H, J= 8.7), 7.11 (d, 2H, J= 8.4), 7.49 (d, 3H, J = 8.1), 7.37 (d, 2H, J= 8.7), 6.83 (d, 2H, J = 8.7), 6.70 (d, IH, J = 15.9), 5.22 (dd, IH, J= 11.7, 6.6); 4.73 (s, 2H), 4.14 (q, 2H, J = 6.9), 3.80 (dd, IH, J= 16.8, 11.4), 3.65 (dd, IH, J= 17.4, 7.2), 3.54 (s, 3H), 3.18 (q, 2H, J = 6.6), 1.46 (t, 2H, J = 7.5), 1.24 (brs, 18H), 1.19 (t, 3H, J= 7.2), 0.85 (t, 3H, J= 6.6). LC/MS: LC: retention time 3.95 minute; MS (APcI): 763.5 (100, [M+H]); calcd C45H54N4O7 [M+H] 763.9.
Example 42 3-(4-{4-(4-Carboxymethoxy-ρhenyl)-5-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl - 1-methyl- lH-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 231
Figure imgf000153_0001
Compound 231 was prepared according to General Method 10 from imidazole 230 (40 mg, 0.052 mmol) after workup to obtain 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2-yl}- phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid 231 as a light yellow solid (31 mg, 82%).
Data for 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-l-methyl-lH-imidazol-2-ylj- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 231: iH-NMR (300 MHz, DMSO-de): 8.13 (t, IH, J = 5.7), 7.90 (d, 2H, J = 8.7), 7.85 (d, 2H, J = 8.4), 7.70 (d, 2H, J = 8.1), 7.49 (d, 2H, J = 8.7) 7.48 (d, IH, J = 14.7), 7.36 (d, 2H, J = 8.4), 6.81 (d, 2H, J = 8.4), 6.70 (d, IH, J = 15.9), 5.22 (dd, IH, J = 11.7, 6.9), 4.63 (s, 2H), 3.80 (dd, IH, J = 17.1, 11.7), 3.65 (dd, IH, J = 17.1, 7.2), 3.55 (s, 3H), 3.18 (q, 2H, J= 6.3), 1.46 (t, 2H, J = 5.7), 1.24 (s, 18H), 0.85 (t, 3H, J = 6.3). LC/MS: LC: retention time 3.63 minute; MS (APcI): 734.9 (100, [M+H]); calcd C43H50N4O7 [M+H] 734.9.
Example 43 f5- 4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl -4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol- l-yl]-acetic acid tert-butyl ester 232
Figure imgf000154_0001
α-keto bromide 130 (Ri = Et) (4.1 g, 8.99 mmol) (synthesized according to General Method .23) was dissolved in 1,4-Dioxane (10 mL) and DMSO (10 mL). Glycine tert-butyl ester(1.6 g, 13.48 mmol) was added. After the mixture was stirred at RT for 2h, water (50 mL) was introduced. The reaction was extracted with ethyl acetate (3 x 50 mL) and the combined organic portions were washed by water, brine, dried under magnesium sulfate, filtered, and concentrated to dryness in vacuo. Purification via flash column chromatography afforded the desired product 132b (1.86 g, 40.8%).
Figure imgf000155_0001
Data for 132b: iH-NMR (300 MHz, CDCls): 7.95 (d, IH, J= 8.4), 7.45 (d, 2H, J= 8.4), 7.25 (d, 2H, J = 8.4), 6.90 (d, 2H, J = 8.4), 5.40 (s, IH), 4.65 (s, 2H), 4.30 (q, 2H, J =7.2), 3.30 (s, 2H), 3.00 (brs, IH), 1.50 (s, 9H), 1.31 (t, 3H, J = 7.2). Compound 132b (1.86 g, 3.67 mmol), hexamethylenetetramine (2.57 g, 18.4 mmol), and NH4OAc (8.49 g, 110.2 mmol) were dissolved in acetic acid (15 mL). The mixture was stirred at 100 C for lh, then poured into ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (3 x 100 mL), brine (2 x 100 mL) and dried under magnesium sulfate. After filtration, the clear solution was dried under vacuum. The crude product was purified by silica gel chromatography. The imidazole 134b was obtained
(0.54 g, 28%).
Figure imgf000155_0002
Data for 134b: iH-NMR (300 MHz, CDCI3): 7.62 (s, IH), 7.57 (d, 2H, J = 8.7), 7.40 (d, 2H, J = 9.3), 7.19 (d, 2H, J = 8.1), 6.78 (d, 2H, J = 9.0), 4.59 (s, 2H), 4.40 (s, 2H), 4.26 (q, 2H, J = 7.2), 1.40 (s, 9H), 1.28 (t, 3H, J = 7.2). Compound 134b (0.54 g, 1.05 mmol) was dissolved in DMF (10 mL), followed by addition of Pd(OAφ (0.024 g, 0.1 mmol), TEA (0.44 mL, 3.14 mmol), P-(o-tolyl)3 (0.032 g, 0.1 mmol) and acrylamide 57i (0.3 g, 1.26 mmol). The reaction mixture was heated for 100 °C for 2h. The reaction was quenched via addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic portions were washed with IN HCI (aq.), water, dried under magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography to give the desired product [5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol-l - I] -acetic acid tert- butyl ester 232 (0.34 g, 48%). Data for [5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol-l-yl]-acetic acid tert- butyl ester 232: iH-NMR (300 MHz, CDC13): 7.63 (d, IH, J = 15.3), 7.60 (s, IH), 7.50 (d, 2H, J= 8.1), 7.38 (d, 2H, J = 8.7), 7.26 (d, 2H, J = 8.4), 6.74 (d, 2H, J =8.7), 6.44 (d, IH, J = 15.3), 5.97 (t, IH, J= 5.5), 4.55 (s, 2H), 4.40 (s, 2H), 4.22 (q, 2H, J = 7.2), 3.40-3.34 (m, 2H), 1.60-1.51 (br, m, 2H), 1.35 (s, 9H), 1.30-1.22 (br, m, 21H), 0.86 (t, 3H, J = 6.7).
Example 44 r5-f4-((E1-2-Dodecylcarbamoyl-vinyl)-phenvn-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol- l-yll-acetic acid 233
Figure imgf000157_0001
Hydrolysis of imidazole 232 according to General Method 11 gave, after recrystallization [5-[4-((E)-2-Dodecylcarbamoyl- vinyl)-phenyl]-4-(4-ethoxycarbonylmethoxy-phenyl)-imidazol-l-yl]- acetic acid 233 as a white solid (0.24 g, 70%). Data for [5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol-l-yl]-acetic acid 233: iH-NMR (300 MHz, DMSO-de): 8.83 (br s, IH), 8.14 (t, IH, J = 5.4), 7.69 (d, 2H, J= 8.4), 7.46 (d, IH, J= 15.9), 7.38 (d, 2H, J = 8.1), 7.29 (d, 2H, J = 8.7), 6.91 (d, 2H, J =8.4), 6.70 (d, IH, J =15.6), 4.86 (br s, 2H), 4.77 (s, 2H), 4.14 (q, 2H, J = 7.2), 3.20- 3.13 (m, 2H), 1.50-1.40 (br, m, 2H), 1.24 (br s, 18H), 1.19 (t, . 3H, J= 7.2), 0.85 (t, 3H, J= 6.3). MS (APcI): 618.4 (100, [M+H]); calcd C36H48N3O6 [M+H] 618.4.
Example 45 {4-(4-Carboxymethoxy-phenyl)-5-(4-((E)-2-dodecylcarbamoyl- vinyl)-phenyn-imidazol-l-yl}-acetic acid 234
Figure imgf000157_0002
Imidazole 233 (0.067 g, 0.1 mmol) was dissolved in 1,4- Dioxane (1 mL) and IN LiOH (1 mL, 1 mmol) was added. The reaction was stirred at RT for 2h, acidified with IN HCI (2 mL) and extracted with chloroform. After recrystallization, the desired product {4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-imidazol-l-yl}-acetic acid 234 was obtained (0.035 g, 52%).
Data for {4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-imidazol-l-yl}-acetic acid 234: iH-NMR (300 MHz, DMSO-de): 8.14 (s, IH), 8.13 (t, IH, J = 6.6), 7.65 (d, 2H, J = 7.8), 7.45 (d, IH, J = 15.6), 7.33 (d, 2H, J = 7.8), 7.29 (d, 2H, J = 8.7), 6.81 (d, 2H, J =8.7), 6.68 (d, IH, J = 15.6), 4.73 (br s, 2H), 4.62 (s, 2H), 3.20-3.13 (m, 2H), 1.50- 1.40 (br, m, 2H), 1.24 (br s, 18H), 0.84 (t, 3H, J = 6.3). MS (APcI): 590.4 (100, [M+H]); calcd for C34H44N3O6 [M+H] 590.3.
Example 46 3-(4-{4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1-lff-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 235
Figure imgf000158_0001
Compound 235 was synthesized according to General Method 7 from dione 59a (Ri' = t-butyl, R2' = C12H25) (0.3 g, 0.52 mmol) in acetic acid (3 mL), 3-(4-Formyl-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester (0.17 g, 0.62 mmol) and NH4OAC (1.2 g, 15.6 mmol), which gives, after purification via column chromatography eluting with methanol/ DCM, 3-(4- {4-(4-tert-Bu toxycarbonylmethoxy-phenyl)-5-]4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 235 (0.22 g,
50.7%).
Data for 3-(4-{4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-[4-((E)- 2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 235: iH-NMR (300 MHz, CDCI3): 8.12 (d, 2H, J = 8.1), 7.65 (d, 2H, J= 8.4), 7.50-7.38 (m, 5H), 7.25 (d, 2H, J = 8.1), 6.79 (d, 2H, J = 8.7), 6.31 (d, IH, J = 15.9), 5.08 (t, IH, J = 8.7), 4.49 (s, 2H), 3.57 (d, 2H, J =8.7), 3.38-3.28 (m, 2H), 1.52 (s, 9H), 1.52-1.44 (br, s, 11H), 1.25 (br, s, 18H), 0.88 (t, 3H, J = 6.6).
Example 47 3-(4-{4-(4-Carboxymethoxy-phenvU-5-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl1-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 236
Figure imgf000159_0001
The t-butyl ester of imidazole 235 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 236 as a yellow solid (0.12 g, 50%). Data for 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2~ dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 236: iH-NMR (300 MHz, DMSO-de): 8.20 (d, 2H, J = 8.7), 8.11 (t, IH, J= 5.7), 7.93 (d, 2H, J = 8.1), 7.63 (d, 2H, J = 8.7), 7.58 (d, 2H, J = 8.4), 7.48 (d, 2H, J =8.4), 7.42 (d, IH, J = 15.6), 7.05 (d, 2H, J =9.0), 6.66 (d, IH, J = 15.9), 5.24 (dd, IH, J = 11.7, 6.9), 4.76 (s, 2H), 3.85-3.62 (m, 2H), 3.22-3.11 (m, 2H), 1.50-1.40 (br, m, 2H), 1.24 (br s, 18H), 0.85 (t, 3H, J= 6.6). MS (APcI): 721.4 (100, [M+H]), 649.5 (60), 633.3 (60); calcd C42H49N4θ7 [M+H] 721.4. Example 48
(4-{5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl|-2-pyridin-3- yl-lff-imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester 237
Figure imgf000160_0001
Compound 237 was synthesized according to General
Method 7 from dione 59a (Rr = t-butyl, R2' = Cι2H25) (0.3 g, 0.52 mmol) in acetic acid (3 mL), 4-pyridinecarboxaldehyde (0.06 mL, 0.62 mmol) and NH4OAc (1.2 g, 15.6 mmol), which gives (4- {5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-pyridin-3-yl-lH- imidazol-4-ylj -phenoxy )-acetic acid tert-butyl ester 237 (0.2 g, 57.8%).
Data for (4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2- pyridin-3-yl-lH-imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester 237: iH-NMR (300 MHz, CDCls): 9.20 (br s, IH), 8.58 (br, d, IH, J = 4.8), 8.37 (br, d, IH, J = 7.8), 7.62-7.33 (m, 8H), 6.86 (d, 2H, J =9.0), 6.31 (d, IH, J = 15.3), 5.81 (br s, IH), 4.53 (s, 2H), 3.38-3.31 (m, 2H), 1.59-1.46 (br, m, 11H), 1.26 (br s, 18H), 0.88 (t, 3H, J = 6.7). Example 49
(4-{5- 4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-pyridin-3- yl- lff-imidazol-4-yl}-phenoxy)-acetic acid 238
Figure imgf000161_0001
Compound 237 was hydrolyzed according to General Method 11 to give, after recrystallization from ethyl acetate/methanol, the desired imidazole (4-{5-[4-((E)-2- Dodecylcarbamoyl-vinyl)-phenyl]-2-pyridin-3-yl-lH-imidazol-4- yl}-phenoxy)~acetic acid 238 as a yellow solid (0.06 g, 30%). Data for (4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2- pyridin-3-yl-lH-imidazol-4-ylj-phenoxy)-acetic acid 238: iH-NMR (300 MHz, DMSO-de): 9.31 (br s, IH), 8.68 (br s, IH), 8.52 (br, d, IH, J= 7.8), 8.11 (t, IH, J= 7.5), 7.68-7.56 (m, 5H), 7.48 (d, 2H, J =8.4), 7.41 (d, IH, J = 15.9), 7.02 (d, 2H, J =8.7), 6.63 (d, IH, J = 15.9), 4.74 (s, 2H), 3.20-3.15 (m, 2H), 1.50-1.40 (br, m, 2H), 1.24 (br s, 18H), 0.84 (t, 3H, J = 6.6). MS (APcI): 609.2 (100, [M+H]); calcd C37H45N4O4 [M+H] 609.3
Example 50 3-(4-f2-(4-Diethylamino-ρhenyl)-5-r4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 239
Figure imgf000162_0001
Compound 239 was synthesized according to General Method 7 from dione 46j (0.054 g, 0.095 mmol) in acetic acid (1 mL) with 4-diethylaminobenzaldehyde (0.020 g, 0.105 mmol) and NH4OAC (0.22 g, 2.85 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate (3: 1). The desired precursor imidazole 3- (4-{2-(4-Diethylamino-phenyl)-5-[4-((E)-2-dodecylcarbamoyl-vinyl)- phenyl]-lH-imidazol-4-yl}-phenyl)-4, 5-dihydro-isoxazole-5- carboxylic acid methyl ester was obtained as a yellow solid (0.032 g, 44%). The methyl ester was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-(4-{2-(4-Diethylamino-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 239 as a yellow solid (0.02 g, 62%).
Data for 3-(4-{2-(4-Diethylamino-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-4, 5- dihydro-isoxazole-5-carboxylic acid 239: iH-NMR (300 MHz, CD3OD): 8.30-7.60 (m, 11H), 7.01 (d, 2H, J= 7.0), 6.82 (d, IH, J = 15.9), 5.30-5.20 (m, IH), 4.00-3.40 (m, 8H), 1.85-1.70 (m, 2H), 1.65-1.30 (m, 24H), 1.25-1.00 (m, 3H). Example 51
3-{4-r5-r4-((El-2-Dodecylcarbamoyl-vinylϊ-ρhenvn-2-(4- pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl|-ph.enyl}-4,5- dihydro-isoxazole-5-carboxylic acid tert-butyl ester 240
Figure imgf000163_0001
Compound 240 was synthesized according to General
Method 7 from dione 46b (1.2 g, 1.95 mmol) in acetic acid (15 mL), with 4-pyrrolidin-l-yl-benzaldehyde (0.38 g, 2.14 mmol) and NH4OAC (4.5 g, 58.5 mmol), which gives, after purification via column chromatography eluting with Methanol/ DCM, 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-2-(4-pyrrolidin-l-yl-phenyl)-lH-imidazol-4-yl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 240. Data for 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(4- pyτrolidin-l-yl-phenyl)-lH-imidazol-4-yl]-phenyl}-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 240: iH-NMR (400 MHz, CDCI3: 7.88 (d, 2H, J = 8.4), 7.60-7.50 (br, m, 4H), 7.46- 7.36 (br, m, 3H), 7.31 (d, 2H, J = 8.4), 6.58 (d, 2H, J = 8.4), 6.28 (d, IH, J = 15.6), 6.05 (br,s IH), 5.06-5.01 (m, IH), 3.58- 3.51 (m, 2H), 3.45 (m, 2H, 2.05 (br, s, 4H), 1.50 (br s, 11H), 1.30 (br, s, 18H), 0.85 (t, 3H, = 7.5).
Example 52 3-{4-r5-r4-f(E)-2-Dodecylcarbamoyl-vinyl>-ρhenyn-2-(4- pyrrolidin- 1-yl-phenyl)- lJET-imidazol-4-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid 241
Figure imgf000164_0001
The tert-butyl ester of 240 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-2-(4-pyrrolidin- 1-yl-phenyl)- lH-imidazol-4-yl]-phenyl}- 4,5-dihydro-isoxazole-5-carboxylic acid 241 as a yellow solid (0.4 g, 29%).
Data for Dodecylcarbamoyl-vinyl)-phenyl]-2-(4- pyrrolidin-1 -yl-phenyl)-lH-imidazol-4-yl] -phenyl} -4, 5-dihydro- isoxazole-5-carboxylic acid 241: iH-NMR (300 MHz, DMSO- de): 8.07 (t, IH, J= 5.7), 7.90 (d, 2H, J= 9.0), 7.69 (d, 2H, J = 8.1), 7.62-7.56 (m, 6H), 7.41 (d, IH, J= 15.6), 6.65-6.60 (m, 3H), 5.20-5.14 (m, IH), 3.79-3.54 (m, 2H), 3.30 (br, s, 4H), 3.19-3.13 (m, 2H), 1.98 (br, s, 4H), 1.50-1.40 (br, m, 2H), 1.24 (br, s, 18H), 0.85 (t, 3H, J= 7.5). MS (ESI): 716.8 (100, [M+H]); calcd for C44H53N5O4 [M+H] 716.4. Example 53
(4-{5-r4-»El-2-Dodecylcarbamoyl-vinyl)-phenvIl-2-r4-((E1-
2-tert-butoxycarbonyl-vinyl)-phenyll-lH-imidazol-4-yl}- phenoxy)-acetic acid tert-butyl ester 242
Figure imgf000165_0001
Compound 242 was synthesized according to General Method 7 from dione 59a (Ri' = '"Bu, R2' = Cι2H25) (0.100 g, 0.17 mmol) in acetic acid (2 mL), 4-formylcinnamic acid tert-butyl ester (0.044 g, 0.19 mmol) and NH4OAc (0.400 g, 5.2 mmol). The resulting imidazole was purified by flash column chromatography eluting with 2%methanol in DCM. The desired imidazole (4-{5-[4~((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-[4- ((E)-2-tert-butoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenoxy)-acetic acid tert-butyl ester 242 was obtained as a yellow solid (27 mg, 20%).
Data for (4~{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2- ]4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenoxy)-acetic acid 242: iH-NMR (300 MHz, CDC13): 8.07 (d, 2H, J = 7.5), 7.67-7.36 (m, 8H), 7.29 (d, 2H, J = 7.8), 6.82 (d, 2H, J= 7.5), 6.35 (d, IH, J= 17.1), 6.30 (d, IH, J= 16.8), 6.11 (br s, IH), 4.51 (s, 2H), 3.38-3.24 (m, 2H), 1.65-1.45 (m, 2H), 1.55 (s, 9H), 1.50 (s, 9H), 1.25 (br s, 18H), 0.89 (t, 3H, J = 6.6); MS (APcI): 789.9 (100, [M]), 791.6 (63, [M+H]); calcd C4ιH48N3θ6
([M]) 790.0.
Example 54
(4-{2-r4-(fE)-2-Carboxy-vinyl)-phenyll-5-r4-rtE)-2- dodecylcarbamoyl-vinyl)-phenyl|-li-r-imidazol-4-yl}- phenoxy)-acetic acid 243
Figure imgf000166_0001
The tert-butyl esters of imidazole 242 were hydrolyzed according to General Method 11 to give imidazole 243. After recrystallization from methanol/ ethyl acetate, (4-{2-[4-((E)-2-
Carboxy-vinyl)-phenyl]-5-[4-((E)-2-dodecylcarbamoyl-vinyl)~ phenyl]-lH-imidazol-4-yl}-phenoxy)-acetic acid 243 55 mg,
(80%), was obtained as a yellow solid.
Data for (4-{2-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenoxy)- acetic acid 243: iH-NMR (300 MHz, DMSO-de): 8.12 (d, 2H, J =
8.4), 8.07 (t, IH, J= 5.1), 7.85 (d, 2H, J = 7.8), 7.62 (d, IH, J =
15.9), 7.57 (s, 4H), 7.46 (d, 2H, J = 8.7), 7:40 (d, IH, J= 15.6), • 7.00 (d, 2H, J = 8.4), 6.62 (br d, 2H, J = 16.2), 4.73 (s, 2H), 3.22-3.08 (m, 2H), 1.52-1.38 (m, 2H), 1.23 (br s, 18H), 0.92-
0.78 (m, 3H); MS (APcI): 678.7 (100, [M+H]), 677.9 (85, [M]); calcd C41H48N3O6 ([M+H]) 678.9. Example 55 3-f4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-{4- (E)- 2-(hexadecyl-methyl-carbamoyl)-vinyl1-phenyl}-lH- imidazol-2-yl)-phenyn-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 244
Figure imgf000167_0001
Compound 244 was synthesized according to General Method 8 from imidazole 60a (R1' = tert-butyl, R4 = 4- phenyl-(4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester))(150 mg, 0.22 mmol) in DMF (1.5 mL), with Pd(OAc)2 (10 mg, 0.045 mmol), TEA (62 μL, 0.44 mmol), (o-Tolyl)3P (27 mg, 0.09 mmol), and *acrylamide 61a (70mg, 0.28 mmol) to give after purification by flash column chromatography and recrystallization 3-[4-(4-(4-tert- butoxycarbonylmethoxy-phenyl)-5-{4-[(E)-2-(hexadecyl- methyl-carbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]- 4,5-dϊhydro-isoxazole-5-carboxylic acid tert-butyl ester 244 as a yellow solid (80 mg, 50%). *Acrylamide 61a was synthesized according to General Method 9 from acryloyl chloride and dodecylamine. This precursor acrylamide 57k (4 mmol) was then treated with methyl iodide (6mmol, 1.5 equiv.), and sodium hydride (8 mmol) in DMF (5 mL), for ~ 1 hour. The reaction was worked up, (diluted with ethyl acetate and washed with water, dried (MgS04) and concentrated in vacuo) and the desired acrylamide 61a was used without further purification for the Heck reaction. Data for 3-[4-(4-(4-tert-butoxycarbonylmethoxy-phenyl)-5-{4-[(E)- 2-(hexadecyl-methyl-carbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)- phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 244: iH-NMR (300 MHz, CDC13): 8.40-8.15 (m, IH), 7.85 (d, 2H, J = 7.3), 7.90-7.05 (m, 9H), 7.00 (d, 2H, J = 7.3), 5.35 (t, IH, J = 9.5), 4.69 (s, 2H), 3.77 (d, 2H, J = 9.5), 3.70-3.40 (m, 2H), 3.30 (s, 1.5H), 3.15 (s, 1.5H), 1.85-1.60 (m, 20H), 1.60-1.30 (m, 18H), 1.15-1.00 (m, 3H).
Example 56 3-r4-(4-(4-Carboxymethoxy-ρhenyU-5-{4-r(EΪ-2-(dodecyl- methyl-carbamoyl)-vinyl -phenyl)-lH-imidazol-2-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 245
Figure imgf000168_0001
Compound 245 was synthesized according to General Method 11 from imidazole 244 to give after recrystallization from methanol/ ethyl acetate, 3-[4-(4-(4-Carboxymethoxy- phenyl)-5-{4~[(E)-2-(hexadecyl-methyl-carbamoyl)-vinyl]-phenyl}- 1 H-imidazol-2-yl)-phenyl]-4, 5-dihydro-isoxazole-5-carboxylic acid 245 as a yellow solid (30 mg, 60%). Data for 3-[4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)~2- (hexadecyl-methyl-carbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 245: iH-NMR (300 MHz, DMSO-de): 8.40-8.25 (m, 2H), 7.96 (d, 2H, J= 9.6), 7.90-7.50 (m, 6H), 7.63 (d, 2H, J= 8.7), 7.32 (br d, IH, J = 14.7), 7.16 (br s, 2H), 5.29 (dd, IH, J= 11.1, 6.9), 4.84 (s, 2H), 4.00-3.46 (m, 6H), 3.30 (s, 1.5H), 3.08 (s, 1.5H), 1.80-1.60 (m, 2H), 1.60-1.20 (m, 18H), 1.15-0.90 (m, 3H). MS (APcI): 735.0 (100, [M]), 735.8 (75, [M+H]); calcd C43H51N4O7 ([M+H]) 735.9. Example 57
3-(4-{4-(4-tert-butoxycarbonylmethoxy-phenyl)-5-|4-(2- hexadecylcarbamoyl-cyclopropyl)-phenylH-lH-imidazol- 2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 246
Figure imgf000169_0001
Imidazole 246 was synthesized from imidazole 235 (Example 46) (40 mg, 0.05 mmol) via treatment with bis(benzonitrile)dichloropalladium (II) (1.5 mg, 0.04 mmol) and diazomethane (excess, ~0.332 mmol). The reaction was stirred for 15 minutes, filtered through celite and concentrated in vacuo. Purfication via flash column chromatography eluting with 1% methanol in DCM gave the desired imidazole 3-(4-{4-(4~tert-butoxycarbonylmethoxy- phenyl)-5-[4-(2-hexadecylcarbamoyl-cyclopropyl)-phenyl]-lH- imidazol-2-yl}-phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 246, 22mg (52%). Data for 3-(4-{4-(4-tert-butoxycarbonylmethoxy- phenyl)-5-[4-(2-hexadecylcarbamoyl-cyclopropyl)~phenyl]-lH- imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 246: iH-NMR (300 MHz, CDC13 + 5% CD3OD): 8.18-8.10 (m, 2H), 7.98-7.80 (m, 3H), 7.60-7.48 (m, 4H), 7.18-7.10 (m, 2H), 7.03-6.95 (m, 2H), 5.28-5.15 (m, IH), 4.70-4.62 (m, 2H), 3.85-3.55 (m, 4H), 3.40-3.28 (m, 2H), 2.60-2.48 (m, IH), 1.88-1.75 (m, IH), 1.75-1.53 (m, 20H), 1.52-1.25 (br s, 18H), 0.83 (m, 3H).
Example 58 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-r4-(2- hexadecylcarbamoyl-cyclopropyl)-phenyl]-lff-imidazol-
2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid
247
Figure imgf000170_0001
Compound 247 was synthesized according to General
Method 11 from imidazole 246 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-(4-Carboxymethoxy- phenyl)-5-[4-(2-hexadecylcarbamoyl-cyclopropyl)-phenyl]-lH- imidazol-2-yl}-phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid 247 as a yellow solid (15 mg, 78%).
Data for 3-(4-{4-(4-Carboxymethoxy-phenyl)-5-[4-(2- hexadecylcarbamoyl-cyclopropyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 247: iH-NMR (300 MHz, DMSO-de): 8.12 (d, 2H, J = 6.3), 8.06 (t, IH, J = 2.5),
7.79 (d, 2H, J = 6.0), 7.41 (d, 4H, J = 6.6), 7.10 (br d, 2H, J = 4.1), 6.94 (br d, 2H, J= 4.1), 5.18 (dd, IH, J= 9.0, 5.1), 4.70 (s, 2H), 3.75 (dd, IH, J= 12.6, 8.7), 3.61 (dd, IH, J= 12.6, 4.8), 3.40-3.30 (m, 2H), 3.10-2.98 (m, 2H), 2.25-2.15 (m, IH), 1.90-
1.80 (m, IH), 1.45-1.30 (m, 2H), 1.30-1.10 (br s, 18H), 0.83 (t, 3H, J= 5.1). MS (APcI): 735.3 (100, [M+H]), 647.2 (58); calcd C43H51N4O7 ([M+H]) 735.9. Example 59
(E)-3-{4-r4-r4-((El-2-Carboxy-vinyli-phenyr|-5-(4- dodecyIcarbamoyl-phenyl)-l.ff-imidazol-2-ylϊ-phenyl}- acrylic acid 111
Figure imgf000171_0001
4-iodobenzoic acid tert-butyl ester 83 (Scheme 15, R = t_
Bu, 12.618 g; 41.4 mmol) was charged to a round-bottomed flask along with DMF (110 mL), trimethylsilyl- acetylene (30 mL; 207 mmol), dichlorobis(triphenylphosphine) palladium(II) (610 mg; 0.83 mmol), copper(I) iodide (95 mg; 0.41 mmol), and triethylamine (17 mL; 124 mmol). The resultant mixture was stirred at rt under N2 for 12 h. After cooling to rt the organics were added to NH4CI (200 mL) and extracted with pentane (2 X 200 mL). The organics were then washed with water (200 mL), brine (200 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude material was dried in vacuo to provide 84 (11.4 g).
Figure imgf000172_0001
84 Data for compound 84: iH-NMR (300 MHz, CDC13): 7.92 (d, 2H, J = 8.1), 7.52 (d, 2H, J = 8.1), 1.61 (s, 9H), 0.23 (s, 9H).
Alkyne 84 (Scheme 15, R = t_Bu, 11.4 g) was charged to a round-bottomed flask along with THF (54 mL) . To this was added TBAF (1.0 M in THF, 46 mL, 45.7 mmol) and the reaction was stirred under N2 for 1.5 h. The crude mixture was added to water (200 mL) and extracted with pentane (2 X 200 mL). Organics were then washed with brine (200 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was then taken up in pentanes (200 mL) and filtered through a short pad of silica gel, concentrated, and dried in vacuo to provide 85 (6.7 g).
Figure imgf000172_0002
Data for compound 85: iH-NMR (300 MHz, CDC13): 7.94 (d, 2H, J= 8.1), 7.52 (d, 2H, J= 8.1), 3.2 (s, IH), 1.6 (s, 9H).
Alkyne 85 (Scheme 15, R = t-Bu, 6.7 g) was charged to a round-bottomed flask along with DMF (50 mL), 4-bromo-l- iodobenzene 86 (11.3 g, 40 mmol), copper iodide (63 mg, 0.33 mmol), dichlorobis (triphenyl- phosphine) palladium(II) (470 mg, 0.66 mmol) and triethylamine (14 mL, 100 mmol). The reaction mixture was stirred at rt under an atmosphere of nitrogen for 8 h. The crude reaction mixture was added to a mixture of hexanes/ethyl acetate (4: 1, 200 mL), and washed with NH4C1 (200 mL) and brine (200 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude material was dried in vacuo to provide a dark orange solid 87 (15.3 g). This crude was a mixture of 87 and 86, which was not purified further.
Figure imgf000173_0001
Data for compound 87: iH-NMR (300 MHz, CDCI3): 7.98 (d, 2H, J = 8.0), 7.55 (d, 2H, J = 8.1), 7.51 (d, 2H, J = 8.1), 7.4 (d, 2H, J = 8.0), 1.61 (s, 9H).
Alkyne 87 (Scheme 15, R = t_Bu, 12.0 g) was charged to a round-bottomed flask along with CCU (90 mL), CH3CN (90 mL), H20 (135 mL), and sodium periodate (28.7 g, 134.4 mmol). After stirring for 5 min, ruthenium dioxide (100 mg, 0.74 mmol) was added and the mixture stirred at rt for 6 h. The crude was added to CH2C12 (500 mL), washed with H20 (2 X 250 mL) and brine (250 mL), dried over MgS04, filtered, and concentrated to dryness. The crude was flashed using 10: 1 hexanes/ethyl acetate to provide 88 as a white solid (10.8 g).
Figure imgf000174_0001
88
Data for compound 88: iH-NMR (300 MHz, CDC1 ): 8.13 (d, 2H, J = 8.0), 8.05 (d, 2H, J = 8.1), 7.82 (d, 2H, J = 8.0), 7.64 (d, 2H, J= 8.1), 1.61 (s, 9H).
Dione 88 (Scheme 17, R = t-Bu, 1.4 g) was charged to a round- bottomed flask along with 20% TFA in CH2C12 (20 mL) and the reaction mixture was stirred for 1.5h. The crude material was concentrated and dried in vacuo to provide 106 (1.1 g).
Figure imgf000174_0002
106
Data for compound 106: iH-NMR (300 MHz, DMSO-de): 8.15 (d, 2H, J = 8.1), 8.06 (d, 2H, J = 8.1), 7.87 (m, 4H), 1.61 (s, 9H). Dione 106 (Scheme 17, 300 mg) was charged to a round - bottomed flask along with dodecylamine (200 mg, 1.08 mmol), DMF (10 mL), CH2C12 (10 mL), EDCI (207 mg, 1.08 mmol), and DMAP (110 mg, 0.9 mmol), and the reaction mixture was stirred at rt for 12 h. The crude mixture was added to EtOAc (100 mL) and washed with H20 (100 mL), and brine (100 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was then chromatographed by flash chromatography using 3: 1 Hexanes/EtOAc to provide 108 (280 mg).
Figure imgf000175_0001
108
Data for Compound 108: iH-NMR (300 MHz, CDC13): 8.02 (d, 2H, J = 8.1), 7.93 (m, 4H,), 7.87 (d, 2H, J = 8.2), 6.02 (m, IH), 3.32 (m, 2H), 1.54 (m, 2H), 1.23 (m, 18H), 0.92 (m, 3H). Dione 108 (Scheme 17, 200 mg) was charged to a round- bottomed flask along with t-butyl acrylate (88 μL, 60 mmol), palladium (II) acetate (2 mg, 0.01 mmol), tri-o-tolylphosphine (15 mg, 0.05 mmol), triethylamine (170 μL, 1.2 mmol), and DMF (10 mL), and the reaction was stirred at 100 °C under N for 2h. After cooling to rt the crude was added to CH C12 (50 mL) and washed with H20 (50 mL), brine (50 mL), dried over
MgSθ4, filtered, and concentrated to dryness. The compound was purified using flash chromatography with 3: 1 hexanes/ EtOAc as eluent to provide 109 (142 mg).
Figure imgf000175_0002
109
Data for compound 109: iH-NMR (300 MHz, CDCI3): 8.15 (d, 2H, J= 8.1), 7.95 (m, 4H,), 7.87 (d, 2H, J = 8.2), 7.62 (d, IH, J = 15.4), 6.61 (d, IH, J = 15.5), 5.91 (m, IH), 3.22 (m, 2H), 1.62 (s, 9H), 1.54 (m, 2H), 1.23 (m, 18H), 0.93 (m, 3H). Dione 109 (Scheme 17, 130 mg) was added to a round- bottomed flask along with 34a (55 mg, 0.24 mmol), NH4OAC (0.55 g, 7.2 mmol), and HO Ac (3 mL), and the reaction was stirred at 100 °C under N2 for 1.5 h. After cooling to rt, the mixture was added to CH2C12 (100 mL), washed with H20 (75 mL) and brine (75 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was purified by preparative TLC (1.0 mm) using 15: 1 CH2Cl2/MeOH to provide 110 (62 mg).
Figure imgf000176_0001
Data for imidazole 110: iH-NMR (300 MHz, DMSO-de): 8.53 (m, IH), 8.18 (d, 2H, J= 8.1), 7.95 (m, 4H,), 7.87 (d, 2H, J = 8.2), 7.61 (m, 6H), 6.65 (d, IH, J = 15.5), 6.60 (d, IH, J = 15.6), 3.22 (m, 2H), 1.62 (s, 9H), 1.61 (s, 9H), 1.54 (m, 2H), 1.23 (m, 18H), 0.93 (m, 3H).
Imidazole 110 (Scheme 17, 60 mg) was added to a round- bottomed flask followed by 20% TFA in CH2C12 (3.0 mL). The reaction was stirred at rt for 2.5 h. The crude mixture was concentrated to dryness and purified by preparative chromatography (1.0 mm) using (2X) 10: 1 CH2Cl2/MeOH to provide (E)-3-{4-[4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-(4- dodecylcarbamoyl-phenyl)-lH-imidazol-2-yl]-phenyl}-acrylic acid 111 (24 mg). Data for provide (E)-3-{4-[4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-(4- dodecylcarbamoyl-phenyl)-lH-imidazol-2-yl]-phenyl}-acrylic acid 111: iH-NMR (300 MHz, DMSO-de): 8.53 (m, IH), 8.18 (d, 2H, J = 8.1), 7.95 (m, 4H,), 7.87 (d, 2H, J= 8.2), 7.61 (m, 6H), 6.65 (d, IH, J = 15.5), 6.60 (d, IH, J = 15.6), 3.22 (m, 2H), 1.54 (m, 2H), 1.23 (m, 18H), 0.93 (m, 3H). MS (ESI): 648.5 (100, [M+H]); calcd C41H45N3O5 ([M+H]) 648.4.
Example 60 3-{4-r5-r4-f(E)-2-Dodecylcarbamoyl-vinyl)-ρhenvn-2- (2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yl -phenyl}- acrylic acid 248
Figure imgf000177_0001
Compound 248 was synthesized according to General
Method 7 from dione 123a (200 mg, 0.35 mmol) in acetic acid (1.5 mL), 2,3,4-trimethoxyfbenzaldehyde (100 mg, 0.52 mmol) and NH4OAC (809 mg, 10.5 mmol), which gives after purification by column chromatography eluting with 1-2 % methanol in DCM, 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-2-(2,3,4-trimethoxy-phenyl)-lH-imidazol-4-yl]-phenyl}- acrylic acid tert-butyl ester. The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization 3- {4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2, 3, 4- trimethoxy -phenyl)- lH-imidazol-4-yl] -phenyl} -acrylic acid 248 as a yellow solid (204 mg, 92%). Data for 3-{4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-
(2, 3, 4-trimethoxy-phenyl)-lH-imidazol-4-yl]-phenyl}-4, 5-dihydro- isoxazole-5-carboxylic acid 248: iH-NMR (300 MHz, DMSO-de): 8.14 (t, IH, J = 5.7), 7.81 (d, 2H, J = 8.7) 7.68-7.55 (m, 8H), 7.45 (d, IH J= 15.6), 7.10 (d, IH, J= 9.3), 6.68 (d, IH, J = 15.9), 6.61 (d, IH, J= 15.9), 3.94 (s ,3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.16 (q, 2H, J = 6.6), 1.45 (t, 2H, J = 6.0), 1.24 (brs, 18H), 0.85 (t, 3H, J= 6.3). LC/MS: LC: retention time 3.86 minute; MS (APcI): 694.6 (100, [M+H]), calcd
Figure imgf000178_0001
[M+H] 694.9. Example 61
(E)-3-(4-{5-f4-((E)-2-Hexadecylcarbamoyl-vinyl)-ρhenyl1- lff-imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 249
Figure imgf000178_0002
The starting dione 123b for compound 249 was synthesized according to General Method 15. Imidazole 249 was synthesized from dione 123b (1.5 g, 2.38 mmol, 1.0 eq) in acetic acid (14 mL), DMSO (4 mL), hexamethylenetetramine (1.67 g, 11.9 mmol, 5 eq) and 5.50 g, 71.4 mmol, 30 eq). The resulting imidazole was purified by flash column chromatography eluting with a gradient of 2% - 8% Methanol in DCM. The imidazole (E)-3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 249 was obtained as a yellow solid (1.4 g, 92%). Data for (E)-3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)~phenyl]~ lH-imidazol-4-yl}-phenyl)~acrylic acid tert-butyl ester 249: XH NMR (400 MHz, CDC13); 7.59 (s, IH), 7.50-7.22 (m, 10H), 6.64 (br, s, IH), 6.38 (d, IH, J = 15.2), 6.28 (d, IH, J = 16.0), 3.36- 3.29 (m, 2H), 1.52-1.46 (m, 2H), 1.51 (s, 9H), 1.23 (br, s, 26H), 0.86 (t, 3H, J = 6.6).
Example 62 (E)-3- -{5-f4-((E)-2-Hexadecylcarbamoyl-vinyl)-ρhenyll- 1 J?-imidazol-4-yl}-phenyl)-acrylic acid 250
Figure imgf000179_0001
Imidazole 250 was prepared according to General Method 11, form imidazole 249, to give after recrystallization from methanol/ ethyl acetate, (E)~3-(4~{5-[4 (E)-2- Hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)- acrylic acid 250 as a pale yellow solid (0.77g, 60%). Data for (E)-3-(4-{5-]4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]~ lH-imidazol-4-yl}-phenyl)-acrylic acid 250: iH NMR (300 MHz, DMSO-de); 8.49 (s, IH), 8.11 (t, IH, J = 5.6), 7.73 (d, 2H, J = 8.1), 7.60 (d, 2H, J = 8.4), 7.59 (d, IH, J = 15.9), 7.52 (d, 2H, J = 8.4), 7.51 (d, 2H, J = 8.1), 7.42 (d, IH, J = 15.6), 6.62 (d, IH, J = 15.9), 6.56 (d, IH, J = 16.2), 3.20-3.13 (m, 2H), 1.50-1.40 (m, 2H), 1.22 (br, s, 26H), 0.84 (t, 3H, J = 6.3).
Example 63 3-(4-{5-r4-(2-Hexadecylcarbamoyl-ethy»-ρhenyn-lH- imidazol-4-yll-phenyll-propionic acid 251
Figure imgf000179_0002
Imidazole 251 was obtained via reduction of the double bonds of imidazole 250 according to General Method 14. 3-(4-{5- [4-(2-Hexadecylcarbamoyl-ethyl)-phenyl]~lH-imidazol-4-yl}- phenyl)-propionic acid 251 was obtained 15 mg (80%) after recrystallization as a white solid.
Data for 3-(4-{5-[4-(2-Hexadecylcarbamoyl-ethyl)-phenyl]-lH- imidazol-4-yl}-phenyl)-propionic acid 251: iH-NMR (400 MHz, CD3OD): 8.97 (s, IH), 8.02-7.84 (m, IH), 7.50-7.25 (m, 8H), 3.10 (t, 2H, J= 6.2), 3.08-2.90 (m, 4H), 2.63 (t, 2H, J= 7.6), 2.51 (t, 2H, J = 7.8), 1.48-1.32 (m, 2H), 1.32-1.10 (m, 26H), 0.89 (t, 3H, J = 6.6); MS (APcI): 588.1 (100,[M]), 588.9 (96, [M+H]); calcd C37H53N3O3 ([M]) 587.8. Example 64
3-(4-{4-r4-((E)-2-tert-Butoxycarbonyl-vinvH-ρhenvn-5-r4- (2-hexadecylcarbamoyl-vinyl)-phenyl1-lff-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 252
Figure imgf000180_0001
Compound 252 was synthesized according to General
Method 7 from dione 123b (0.5 g, 0.79 mmol) in acetic acid
(5.5 mL), 4-formylphenyl-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester (0.26 g, 0.95 mmol) and NH4OAc (1.8 g, 23.8 mmol). The resulting imidazole was purified by flash column chromatography eluting with hexane/ethyl acetate
(3: 1). The desired 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)- phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)-phenyl]-lH- imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 252 was obtained as a yellow solid (0.5 g, 72 %).
Data for 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5- [4-(2-hexadecylcarbamoyl-vinyl)-phenyl]-lH~imidazol-2-yl}~ phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 252: iH-NMR (300 MHz, CDCls): 8.01 (br, m, 2H), 7.70-7.20 (br, m, 10H), 6.40-6.10 (br, m, 3H), 5.10 (t, IH, J = 9.3), 3.60 (d, 2H, J = 9.3), 3.30 (br, s, 2H), 1.58 (s, 9H), 1.56 (s, 9H), 1.57 (br, s, 2H), 1.30 (br, s, 26H), 0.85 (t, 3H, J = 7.5).
Example 65 3-(4-{4-r4-(tE)-2-Carboxy-vinyl)-phenyq-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 253 Imidazole 253 was prepared according to General Method 11, from imidazole 252, to give after recrystallization from methanol/ ethyl acetate, 3~(4-{4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)-phenyl]- 1 H- imidazol-2-yl}-phenyl)-4, 5-dihydro-isoxazole-5-carboxylic acid 253 as a pale yellow solid (0.3 g, 69%). Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4,5- dihydro-isoxazole-5-carboxylic acid 253: iH-NMR (300 MHz, DMSO-de): 8.19 (d, 2H, J= 8.7), 8.10 (t, IH, J= 5.4), 7.86 (d, 2H, J= 8.1), 7.75 (d, 2H, J= 8.4), 7.64-7.58 (m, 7H), 7.43 (d, IH, J = 15.6), 6.65 (d, IH, J = 15.9), 6.57 (d, IH, J = 15.9), 5.25-5.19 (m, IH), 3.84-3.61 (m, 2H), 3.19-3.13 (m, 2H), 1.50- 1.40 (br, m, 2H), 1.22 (br, s, 25H), 0.84 (t, 3H, J = 6.60). MS (ESI): 773.8 (30, [M+H]); calcd for C47H56N4O6 [M+H] 773.4. Example 66 (E)-3-(4-{2-r4-((E)-2-Ethoxycarbonyl-vinyl)-ρhenyn-5-f4- (2-hexadecylcarbamoyl-vinyl)-phenyll-lH-imidazol-4-yl}- phenyl)-acrylic acid tert-butyl ester 254
Figure imgf000182_0001
Compound 254 was synthesized according to General Method 7 from dione 461 (1.1 g, 1.75 mmol) in acetic acid (20 mL), 4-formylcinnamic acid ethyl ester (0.53 g, 2.62 mmol) and NH4OAc (4 g, 52 mmol). The resulting imidazole was purified by flash column chromatography eluting with DCM/methanol (95:5).
The desired imidazole (E)-3-(4-{2-[4-((E)-2-Ethoxycarbonyl- vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)-phenyl]- 1 H- imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 254 was obtained as a yellow solid (1.1 g, 77 %).
Data for (E)-3-(4-{2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5- [4-(2-hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}~ phenyl)-acrylic acid tert-butyl ester 254: iH-NMR (300 MHz, CDCls): 8.16 (d, 2H, J=7.2), 7.66 (d, IH, J =6.4), 7.60-7.44 (br, m, 8H), 7.38 (d, 2H, = 8.1), 7.28 (d, 2H, J=8.1), 6.41 (d, IH, J = 15.9), 6.29 (br, d, 2H, J = 15.9), 6.15 (br, s, IH), 4.27 (q, 2H, J=7.2), 3.26 (br, s, 2H), 1.53 (s, 9H), 1.46 (br, s, 2H), 1.34 (t, 3H, J= 7.2), 1.23 (br, s, 26H), 0.87 (t, 3H, J = 6.4).
Example 67 (E)-3-r4-{2-r4-((E)-2-Ethoxycarbonyl-vinvn-phenvn-5-r4- (2-hexadecylcarbamoyl-vinyl)-ρhenyn-lJEf-imidazol-4-yl}- phenyl)-acrylic acid 255
Figure imgf000183_0001
The tert-butyl ester of imidazole 254 was hydrolyzed according to General Method 11 to give, after recrystallization, the desired imidazole (E)-3-(4-{2-[4-((E)-2- Ethoxycarbonyl-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-acrylic acid 255 as a yellow solid (0.4 g, 39 %). Data for (E)-3-(4-{2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyl]-5- [4-(2-hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-acrylic acid 255: iH-NMR (400 MHz, DMSO-de): 7.91 (d, 2H, J =8.0), 7.58-7.49 (m, 4H), 7.43-7.35 (m, 9H), 7.15 (t, IH, J=6.4), 6.37 (d, IH, J = 15.6), 6.36 (d, IH, J = 16.0), 6.29 (d, IH, J = 16.0), 4.14 (d, 2H, J =7.0), 3.23-3.16 (m, 2H), 1.48-1.38 (br, m, 2H), 1.22 (t, 3H, J= 7.0), 1.12 (br, s, 26H), 0.74 (t, 3H, J = 6.2). MS (APcI): 758.7 (100, [M+H]); calcd for C48H60N3O5 [M+H] 758.5.
Example 68 (E)-3-(4-{2-r4-((El-2-Carboχy-vinv»-phenyn-5-r4-f2- hexadecylcarbamoyl-vinyl)-ρhenyl]-lH-imidazol-4-yl}- phenyl)-acrylic acid 256
Figure imgf000184_0001
The ethyl ester of imidazole 255 was hydrolyzed according to General Method 10 to give, after recrystallization, the desired imidazole 3-{4-[5-{4-[(E)-2-(3-Phenyl- propylcarbamoyl)-vinyl]-phenyl}-2-(4-pyrrolidin l-yl-phenyl)- 1 H-imidazol-4-yl]-phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid 256 as a yellow solid (0.23 g, 60%).
Data for 3-{4-[5-{4-[(E)-2-(3-Phenyl-propylcarbamoyl)- vinyl]-phenyl}-2-(4-pyτrolidin- 1-yl-phenyl)- lH-imidazol-4-y l]- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid 256: iH- NMR (300 MHz, DMSO-de): 8.15 (d, 2H, J=8.4), 8.12 (t, IH, J=6.0), 7.87 (d, 2H, J= 8.1), 7.75 (d, 2H, J= 8.1), 7.67- 7.58 (m, 8H), 7.43 (d, IH, J = 15.6), 6.66 (d, IH, J = 15.9), 6.64 (d, IH, J = 15.9), 6.57 (d, IH, J = 16.2), 3.45-3.20 (m, 2H), 1.50-1.40 (br, m, 2H), 1.23 (br, s, 26H), 0.84 (t, 3H, J = 6.0). MS (APcI): 730.7 (100, [M+H]); calcd for C46H56N3O5 [M+H] 730.4.
Example 69 3-(4-{4- 4-((E)-2-Carboxy-vinv»-phenvn-5-r4-(2- dodecylcarbamoyl-vinyl)-phenyl1-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 257
Figure imgf000185_0001
Imidazole 257 was synthesized according to General Method 7 (Scheme 19) from dione 123a (see General Method 15){1.3 g, 2.3 mmol) in acetic acid (4.6 mL), with 3-(4-Formyl- phenyl)-4,5-dihydro-isoxazole-5~carboxylic acid tert-butyl ester (936 mg, 3.4 mmol) and NH4OAc (5.3 g, 69 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4-[4-((E)-2-tert- Butoxycarbonyl-vinyl)-phenyl]-5-[4-(2-dodecylcarbamoyl- vinyl) -phenyl] - 1 ff-imidazol-2-yl}-phenyl) -4 , 5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester (1 g, 53%). The tert-butyl esters were hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol- 2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 257 200 mg (36%) as a yellow solid.
Data for 3-(4-{4-]4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- dodecylcarbarnoyl-vinyl)-phenyl]-lH-irnidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 257: iH-NMR (300 MHz, DMSO-de): 8.20 (d, 2H, J = 8.7), 8.11 (t, IH, J = 5.1), 7.87 (d, 2H, J= 8.4), 7.76 (d, 2H, J = 8.4), 7.64-7.59 (m, 7H), 7.44 (d, IH, J= 15.9), 6.66 (d, IH, J = 16.2), 6.57 (d, IH, J = 15.9), 5.22 (dd, IH, J = 12.0, 6.9), 3.79 (dd, IH, J = 17.1, 11.7), 3.65 (dd, IH, J = 17.4, 7.2), 3.17 (q, 2H, J = 6.6), 1.45 (t, 2H, J = 6.3), 1.24 (s, 18H), 0.85 (t, 3H, J = 6.6). LC/MS: LC: retention time 3.60 minute; MS (APcI): 717.7 (50, [M+H]), 645.6 (100, [M+H-CH2CHC02H]), calcd C43H48N4O6 [M+H] 717.9. Example 70
3-(4-{4-r4-((E)-2-Carboxy-vinyl)-phenvn-5-r4-(2- dodecylcarbamoyl-vinyl)-phenyl1-lff-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid 258
Figure imgf000186_0001
Imidazole 258 was synthesized according to General Method 7 (Scheme 19) from dione 123a (see General Method 15) (300 mg, 0.52 mmol) in acetic acid (2 mL), with 3-(4- Formyl-phenyl)-isoxazole-5-carboxylic acid ethyl ester 37 (synthesized according to General Method 1 using the appropriate alkyne) (192 mg, 0.78 mmol) and NH4OAC (1.2 g, 15.6 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4- [4-((E)-2- tert-Butoxycarbonyl -vinyl)-phenyl]-5-[4-(2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- isoxazole-5-carboxylic acid ethyl ester (200 mg, 48%) . The tert-butyl and ethyl esters are hydrolyzed according to General Method 10 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-((E)-2-Carboxy-vinyl)- phenyl]-5-[4-(2-dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-
2-yl}-phenyl)-isoxazole-5-carboxylic acid 258
35 mg (55%) as a yellow solid.
Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- dodecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- isoxazole-5-carboxylic acid 258: iH-NMR (300 MHz, DMSO- de): 8.24 (d, 2H, J = 8.4), 8.14 (t, IH, J = 4.5), 8.08 (d, 2H, J = 8.4), 7.83 (s, IH), 7.72 (d, 2H, J = 8.1), 7.63-7.59 (m, 7H), 7.42 (d, IH, J = 15.6), 6.64 (d, IH, J= 15.6), 6.54 (d, IH, J = 15.9), 3.15 (t, 2H, J = 4.5), 1.44 (t, 2H, J = 5.7), 1.23 (s, 18H), 0.83 (t, 3H, J = 6.3). LC/MS: LC: retention time 3.72 minute; MS (APcI): 715.1 (100, [M+H]), calcd C43H46N4O6 [M+H] 715.9.
Example 71 3-(4-{4-r4-((E)-2-Carboxy-vinyl)-phenvn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl -lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester 259
Figure imgf000188_0001
Imidazole 259 was synthesized according to General Method 7 (Scheme 19) from dione 123b (520 mg, 0.83 mmol) in acetic acid (2 mL), with 3-(4-formyl-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid ethyl ester (306 mg, 1.2 mmol) and NH4OAC (1.9 g, 25 mmol), which gives, after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl- vinyl) -phenyl] -5- [4-(2-hexadecylcarbamoyl-vinyl) -phenyl]- lH-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid ethyl ester (300 mg). The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4- [4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)-4, 5-dihydro- isoxazole-5-carboxylic acid ethyl ester 259, 200 mg (72%) as a yellow solid.
Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester 259: iH- NMR (300 MHz, DMSO-de): 8.19 (d, 2H, J = 8.4), 8.10 (t, IH, J = 5.1), 7.85 (d, 2H, J = 8.4), 7.74 (d, 2H, J = 8.1), 7.63-7.60 (m, 7H), 7.43 (d, IH, J = 15.6), 6.65 (d, IH, J = 15.9), 6.56 (d, IH, J= 16.2), 5.31(dd, IH, J= 11.7, 6.9), 4.19 (q, 2H, J= 7.2), 3.80 (dd, IH, J = 17.7, 12.0), 3.68 (dd, IH, J= 17.1, 6.6), 3.17 (q, 2H, J= 5.4), 1.45 (t, 2H, J = 5.7), 1.27-1.23 (m, 29H), 0.85 (t, 3H, J = 5.4). LC/MS: LC: retention time 4.33 minute; MS (APcI): 801.1 (100, [M+H]), calcd C49H60N4O6 [M+H] 801.0.
Example 72 3-(4-{4-r4-((E)-2-Carboxy-vinvD-phenyl1-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lff-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid ethyl ester 260
Figure imgf000189_0001
Imidazole 260 was synthesized according to General Method 7 (Scheme 19) from dione 123b (see General Method 15) (500 mg, 0.79 mmol) in acetic acid (4 mL), with 3-(4- Formyl-phenyl) -isoxazole- 5-carboxy lie acid ethyl ester (292 mg, 1.2 mmol) and NH4OAC (1.8 g, 24 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl -vinyl) -phenyl] -5- [4- (2-hexadecylcarbamoyl-vinyl) -phenyl] - lH-imidazol-2-yl}-phenyl)-isoxazole-5-carboxylic acid ethyl ester (377 mg, 56%). The tert-butyl ester was hydrolyzed according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)- phenyl]-lH-imidazol-2-yl}-phenyl)-isoxazole-5-carboxylic acid ethyl ester 260, 403 mg (100%) as a yellow solid.
Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)~ isoxazole-5-carboxylic acid ethyl ester 260: iH-NMR (300 MHz, DMSO-de): 8.29 (d, 2H, J = 8.4), 8.20 (d, 2H, J = 7.8), 8.12 (t, IH, J = 5.4), 8.03 (s, IH), 7.78 (d, 2H, J = 7.8), 7.66-7.59 (m, 7H), 7.44 (d, IH, J = 15.9), 6.67 (d, IH, J = 15.6), 6.59 (d, IH, J= 16.2), 4.12 (q, 2H, J= 7.2), 3.17 (q, 2H, J = 6.0), 1.45 (t, 2H, J = 6.0), 1.36 (t, 3H, J = 7.2), 1.23 (s, 26H), 0.84 (t, 3H, J= 6.6). LC/MS: LC: retention time 4.44 minute; MS (APcI): 799 (100, [M+H]), calcd C49H58N4O6 [M+H] 800. Example 73
3-(4.{4-r4-((E)-2-Carboxy-vinyl)-phenvn-5-r4-(2- hexadecylcarbamoyl-vinyl)-phenyn-lH-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid 261
Figure imgf000190_0001
Imidazole 261 was synthesized from imidazole 260 according to General Method 10 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)~ phenyl]- lH-imidazol-2-yl}-phenyl)-isoxazole-5-carboxylic acid 261, 217 mg (75%) as a yellow solid.
Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- isoxazole-5-carboxylic acid 261: iH-NMR (300 MHz, DMSO- de): 8.31 (d, 2H, J = 8.1), 8.19 (d, 2H, J= 8.4), 8.12 (t, IH, J = 5.1), 7.92 (s, IH), 7.78 (d, 2H, J= 8.1), 7.66-7.59 (m, 7H), 7.44 (d, IH, J = 15.9), 6.67 (d, IH, J = 15.6), 6.59 (d, IH, J = 15.9), 3.16 (q, 2H, J = 6.0), 1.45 (t, 2H, J = 6.0), 1.23 (s, 26H), 0.84 (t, 3H, J = 5.7). LC/MS: LC: retention time 4.18 minute; MS (APcI): 771 (100, [M+H]), calcd C47H54N4O6 [M+H] 772.
Example 74 3-r4-(4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyn-5-{4- [2-(4-heptyl-phenylcarbamoyl)-vinyn-phenyl}-l.Hr- imidazol-2-yl)-phenyl]-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester 262 5
Figure imgf000191_0001
Imidazole 262 was synthesized according to General Method 7 (Scheme 19) from dione 123c (see General Method 15) (285 mg, 0.49 mmol) in acetic acid (3 mL), with 3-(4- Formyl-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester (162 mg, 0.59 mmol) and NH4OAc (758 mg, 9.9 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-[4-(4- [4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5-{4-[2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl} - 1 H-imidazol-2-yl)-phenyl]- 4,5-dϊhydro-isoxazole-5-carboxylic acid tert-butyl ester 262 (400 mg, 98%).
Data for 3-[4-(4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5-{4- ]2-(4-heptyl-phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 262: iH-NMR (300 MHz, CDCls): 8.00 (d, 2H, J = 6.3), 7.64- 7.42 (m, 8H), 7.42-7.28 (m, 4H), 7.28-7.15 (brs, 2H), 7.09 (d, 2H, J= 7.8), 6.84 (d, IH, J = 15.6), 6.56 (d, IH, J = 16.2), 5.06 (t, IH, J = 10.7), 3.60-3.45 (m, 2H), 2.55 (t, 2H, J=7.4), 1.65- 1.40 (m, 20H), 1.40-1.15 (m, 8H), 0.88 (t, 3H, J=5.9).
Example 75 3-r4-(4-r4-(fE)-2-Carboxy-vinyl)-phenvn-5-{4-r2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yU- phenyl -4,5-dihydro-isoxazole-5-carboxylic acid 263
Figure imgf000193_0001
Imidazole 263 was synthesized from imidazole 262 according to General Method 11 to give, after recrystallization from methanol/ ethyl .acetate, 3-[4-(4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-{4-]2-(4-heptyl-phenylcarbamoyl)- vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]-4, 5-dihydro- isoxazole-5-carboxylic acid 263, 200 mg (64%) as a yellow solid.
Data for 3-[4-(4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-{4-[2-(4-heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]-4,5- dihydro-isoxazole-5-carboxylic acid 263: iH-NMR (300 MHz, DMSO-de): 10.16 (s, IH), 8.19 (d, 2H, J = 8.4), 7.87 (d, 2H, J = 8.4), 7.76 (d, 2H, J= 7.8), 7.65-7.52 (m, 10H), 7.14 (d, 2H, J = 8.7), 6.84 (d, IH, J= 15.6), 6.56 (d, IH, J = 15.9), 5.22 (dd, IH, J= 11.7, 6.9), 3.90-3.55 (m, 2H), 2.4-2.6 (m, 2H) 1.6-1.45 (m, 2H), 1.65-1.10 (m, 8H), 0.85 (t, 3H, J= 6.6). MS (APcI): 723.6 (48, [M+H]), 651.8 (82), 635.6 (100); calcd C44H43N4O6 ([M+H]) 723.4.
Example 76 3-(4-{4-r4-»EΪ-2-tert-Butoxycarbonyl-vinylϊ-ρhenyπ-5-f4- (2-dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl)- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 264
Figure imgf000194_0001
Imidazole 264 was synthesized according to General Method 7 (Scheme 19) from dione 123d (see General Method 15) (731 mg, 1.28 mmol) in acetic acid (4 mL), with 3-(4- Formyl-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester (422 mg, 1.54 mmol) and NH4OAc (1.97 g, 26 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4- [4-((E)-2-tert-Butoxycarbonyl-vinyl)-phenyl]-5-[4-(2- dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester 264 (526 mg, 53%).
Data for 3-(4-{4-[4-((E)-2-tert-Butoxycarbonyl-vinyl)- phenyl]-5-[4-(2-dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol- 2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester 264: iH-NMR (300 MHz, CDC13): 8.23 (d, 2H, J = 8.7), 7.69 (d, 2H, J= 8.7), 7.60-7.36 (m, 8H), 7.32 (d, 2H, J = 8.4), 6.71 (d, IH, J= 15.3), 6.29 (d, IH, J = 15.9), 5.08 (t, IH, J = 9.3), 3.56 (d, IH, J= 10.2), 3.45-3.30 (m, 4H), 1.60- 1.40 (m, 22H), 1.40-1.17 (m, 12H), 0.96-0.80 (m, 6H).
Example 77 3-(4-{4-r4-((E)-2-Carboxy-vinv»-phenyll-5-r4-(2- dihexylcarbamoyl-vinyH-ρhenyl^-lH-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid 265
Figure imgf000195_0001
Imidazole 265 was synthesized from imidazole 264 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-((E)- 2-Carboxy-vinyl)-phenyl]-5-[4-(2-dihexylcarbamoyl-vinyl)- phenyl]-lH-imidazol-2-yl}~phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid 265, 300 mg (62%) as a yellow solid. Data for 3-(4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- dϊhexylcarbamoyl-vinyl)-phenyl]- 1 H-imidazol-2-yl}-phenyl)- 4,5-dihydro-isoxazole-5-carboxylic acid 265: iH-NMR (300 MHz, DMSO-de): 8.19 (d, 2H, J = 8.7), 7.85 (d, 2H, J = 8.4), 7.76 (d, 2H, J= 8.7), 7.74 (d, 2H, J = 8.1), 7.68-7.55 (m, 5H), 7.50 (d, IH, J = 15.0), 7.14 (d, IH, J= 15.6), 6.56 (d, IH, J = 16.2), 5.21 (dd, IH, J= 11.4, 6.9), 3.78 (dd, IH, J = 17.1, 11.7), 3.64 (dd, IH, J= 17.4, 6.9), 3.46 (t, 2H, J = 6.4), 3.23 (t, 2H, J= 7.4), 1.6-1.4 (m, 4H), 1.4-1.15 (m, 12H), 0.95-0.75 (m, 6H). MS (APcI): 717.2 (55, [M+H]), 215.3 (100); calcd C43H49N4O6 ([M+H]) 717.5.
Example 78 (E)-3-r4-r5-(4-r(E)-2-(4-Heptyl-phenylcarbamoyl)-vinyl]- phenyl}- lH-imidazol-4-yl)-phenyl]-acrylic acid tert-butyl ester 266
Figure imgf000196_0001
Imidazole 266 was synthesized according to General Method 7 (Scheme 19) from dione 123c (see General Method 15) (300 mg, 0.52 mmol) in acetic acid (6 mL), with hexamethylene tetramine (360 mg, 2.58 mmol) and NH4OAC (1.19 g, 15.5 mmol), which gives after purification via column chromatography eluting with DCM: methanol (95:5), (E)-3-[4-(5-{4-[(E)-2-(4-Heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]- acrylic acid tert-butyl ester 266 (110 mg, 36%).
Data for (E)-3-[4-(5-{4-[(E)-2-(4-Heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]- acrylic acid tert-butyl ester 266: iH-NMR (300 MHz, CDCI3): 8.96 (br, s, IH), 7.77 (br, s, IH), 7.61 (d, 2H, J = 7.8), 7.61- 7.20 (m, 10H), 7.09 (d, 2H, J = 8.0), 6.67 (d, IH, J = 15.3), 6.27 (d, IH, J = 15.9), 2.54 (br, t, 2H, J= 7.2), 1.60- 1.48 (m, 2H), 1.51 (s, 9H), 1.34-1.20 (m, 8H), 0.87 (t, 3H, J = 6.6). Example 79
(E)-3-f4-(5-{4-(fE1-2-f4-Heρtyl-phenylcarbamovH-vinyll- phenyl}- lH-imidazol-4-yl)-phenyl]-acrylic acid 267
Figure imgf000197_0001
Imidazole 267 was synthesized from imidazole 266 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, (E)-3-[4-(5-{4- ](E)-2-(4-Heptyl-phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol- 4-yl)-phenyl]-acrylic acid 267, 31 mg (28%) as a yellow solid.
Data for (E)-3-[4-(5-{4-[(E)-2-(4-Heptyl- phenylcarbamoyl)-vinyl]-phenyl}-lH-imidazol-4-yl)-phenyl]~ acrylic acid 267: iH-NMR (400 MHz, DMSO-de): 12.40 (br, s, IH), 10.12 (s, IH), 7.95 (s, IH), 7.69 (d, 2H, J= 8.0), 7.63-7.51 (m, 10H), 7.14 (d, 2H, J = 8.4), 6.82 (d, IH, J = 16.0), 6.53 (d, IH, J = 16.0), 2.52 (t, 2H, J =8.0), 1.58-1.50 (br, m, 2H), 1.30-1.22 (br, m, 8H), 0.85 (t, 3H, J =6.8). MS (APcI): 534.4 (100, [M+H]); calcd for C34H36N3O3 [M+H] 534.3.
Example 80
(E)-3-(4-{5-r4-((E)-2-Dihexylcarbamoyl-vinyl)-phenvn-lH- imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 268
Figure imgf000197_0002
Imidazole 268 was synthesized according to General
Method 7 (Scheme 19) from dione 123d (see General Method 15) (410 mg, 0.71 mmol) in acetic acid (5 mL), with hexamethylenetetramine (1.05 g, 21.4 mmol) and NH4OAC (1.97 g, 26 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), (E)-3-(4- {5-[4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4- yl}-phenyl)-acrylic acid tert-butyl ester 2 (280 mg, 68%). Data for (E)-3-(4-{5-[4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenyl)-acrylic acid tert-butyl ester 268: iH-NMR (400 MHz, CDC ): 8.06 (s, IH), 7.56-7.50 (m, 6H), 7.45 (d, 2H, J= 8.0), 7.42 (d, 2H, J= 8.0), 6.82 (d, IH, J= 16.0), 6.34 (d, IH, J = 16), 3.34-3.36 (m, 4H), 1.66-1.56 (m, 4H), 1.62 (s, 9H), 1.32 (br, s, 12H), 0.87 (t, 6H, J= 6.8).
Example 81 (E)-3-(4-{5-r4-((E)-2-Dihexylcarbamoyl-vinyl)-phenvn-lH- imidazol-4-yl}-phenyl)-acrylic acid 269
Figure imgf000198_0001
Imidazole 269 was synthesized from imidazole 268 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, (E)-3-(4-{5-[4-((E)-2-Dihexylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-acrylic acid 269, 50 mg (18 %) as a yellow solid. Data for (E)-3-(4-{5-[4-((E)-2-Dihexylcarbamoyl-vinyl)-phenyl]-lH- imidazol-4-yl}-phenyl)-acrylic acid 269: iH-NMR (300 MHz, DMSO-de): 7.86 (s, IH), 7.68 (br, d, 4H, J= 6.3), 7.61-7.44 (m, 6H), 7.11 (d, IH, J= 15.0), 6.52 (d, IH, J = 15.9), 3.45 (t, 4H, J = 7.2), 1.51 (br, m, 4H), 1.27 (br, s, 12H), 0.86 (t, 6H, J=7.5). MS (APcI): 528.5 (100, [M+H]); mass calcd for C33H4-2N3O3 [M+H] 528.3.
Example 82 3-r3-(4-{5-f4-((E)-2-Hexadecylcarbamoyl-vinvH-ρhenyl]- lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid 160a
Figure imgf000199_0001
Compound 160a was synthesized according to
General Method 6, from imidazole 250 (0.41 g, 0.7 mmol) in CHC13 (5 mL) and DMF (5 mL), EDCI (0.16 g, 0.84 mmol), DMAP (0.086 g, 0.7 mmol), H-β-ALA-O'Bu .HCI (0.15 g, 0.84 mmol) . After purification via column chromatography eluting with ethyl acetate: hexane the imidazole precursor 3-[3-(4-{5-[4- ((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]-lH-imidazol-4-yl}- phenyl)-allanoylamino]-propionic acid tert-butyl ester 160a (0.2 g, 40%). (Scheme 25) Data for 3-[3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]- lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid tert-butyl ester 160a: iH-NMR (400 MHz, CDCI3): 8.06 (s, IH), 7.56-7.50 (m, 6H), 7.45 (d, 2H, J = 8.0), 7.42 (d, 2H, J= 8.0), 6.82 (d, IH, J= 16.0), 6.34 (d, IH, J = 16), 3.34-3.36 (m, 4H), 1.66-1.56 (m, 4H), 1.62 (s, 9H), 1.32 (br, s, 12H), 0.87 (t, 6H, J = 6.8). Example 83
3-f3-(4-{5-r4-((E)-2-Hexadecylcarbamoyl-vinyl)-ρhenyn- lJ-f-imidazol-4-yl}-phenyl)-allanoylamino1-propionic acid 270
Figure imgf000200_0001
Imidazole 270 was synthesized from imidazole 160a according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-[3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl- vinyl)-phenyl]-lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid 270, 62 mg (30%) as a yellow solid.
Data for 3-[3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)- phenyl]-lH-imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid 270: iH-NMR (300 MHz, DMSO-de): 12.22 (br, s, IH), 8.18 (t, IH, J = 6.5), 8.06 (t, IH, J= 6.6), 7.91 (s, IH), 7.56-7.49 (m,
8H), 7.41 (d, IH, J = 15.9), 7.39 (d, IH, J = 15.3), 6.63 (d, IH, J = 16.0), 6.60 (d, IH, J = 15.9), 3.44-3.24 (m, 2H), 3.19-3.12 (br, m, 2H), 2.45 (t, 2H, J =6.3), 1.48-1.40 (m, 2H), 1.23 (br, s, 26H), 0.84 (t, 3H, J= 7.5). MS (APcI): 655.7 (100, [M+H]); calcd C40H55N4O4 [M+H] 655.4.
Example 84 3-f4-(5-Benzylcarbamoyl- l-hexadecyl-4-phenyl- 1 H- imidazol-2-yl)-phenyr|-4,5-dihydro-isoxazole-5- carboxylic acid 147
Figure imgf000200_0002
Carboxylic acid 142 (300 mg, 1.03 mmol), amine 143 (248 mg, 1.03 mmol), isocyanide 144 (120 mg, 1.03 mmol), and phenylglyoxal 145 (138 mg, 1.03 mmol) were added to a round- bottomed flask along with a 1 : 1 mixture of THF/ MeOH (10 mL) and the mixture was stirred at rt for 4 days. The reaction mixture was concentrated and dried in vacuo to provide crude Ugi product 146 which was added to AcOH (10 mL) and NH4OAc (2.3 g , 30.9 mmol) and heated to 100 °C for 1.5 h. After cooling the reaction mixture was added to CH2C12 (100 mL) and washed with H20 (100 mL) and brine (100 mL), dried over MgS04, filtered and concentrated to dryness. Purification by flash column chromatography using 2: 1 Hexanes/ EtOAc provided the precursor ester 146a (322 mg).
The ester of 146a (320 mg, 0.43 mmol) was then added to a round-bottomed flask along with 20% TFA in CH2C12 (5 mL) and stirred at rt for 1.5 h. The reaction was concentrated and dried in vacuo to provide 3-[4-(5-Benzylcarbamoyl-l-hexadecyl- 4-phenyl-lH-imidazol-2-yl)-phenyl]-4,5-dihydro-isoxazole-5- carboxylic acid 147 (288 mg). Data for 3-[4-(5-Benzylcarbamoyl-l-hexadecyl-4-phenyl-lH- imidazol-2-yl)-phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid 147;iH-NMR (300 MHz, CDCI3): 7.65 (m, 4H), 7.59 (m, 2H), 7.32 (m, 6H), 7.18 (m, 2H), 6.20 (m, IH), 5.08 (m, IH), 4.44 (m, 2H), 4.38 (m, 2H), 3.54 (m, IH), 3.21 (m, IH), 1.62 (m, 2H), 1.20 (m, 26H), 0.82 (m, 3H). MS (ESI): 691.6 (100, [M+H]); calcd C43H55N4O4 ([M+H]) 691.45. Example 85 3-(4-{4-f4-(tert-Butoxycarbonylmethyl-carbamoyl)- phenyl]-5-decyl-lH-imidazol-2-yl}-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 81
Figure imgf000202_0001
4-Iodo-benzoic acid 74 (4.77 mmol), was dissolved in DCM (30mL) and the mixture cooled to 0 °C. Oxalyl chloride (9.54 mmol) was added followed by 1 drop of DMF. The mixture was stirred for 30 mins at 0 °C then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was resuspended in DCM (30 mL). Glycine tert-butyl ester 76 (5.72 mol) was added, and the reaction mixture allowed to stir overnight. The reaction mixture was then washed with IN HCI aq. (2 x 10 mL), sat. sodium bicarbonate aq. (2 x 10 mL), brine (10 mL), dried (MgSθ4) and concentrated in vacuo. The crude residue 77 was used for the next step. Iodide 77 (6.6 mmol), was dissolved in dry THF (26 mL), 1- dodecyne (1.48 mL, 6.9mmol), PdCl2(PPh3)2 (230 mg), Cul (16mg), and triphenyl phosphine (43 mg), and triethylamine (1.85 mL) was added. The reaction mixture was stirred for 3 hours at room temperature. Then diluted with sat. ammonium chloride aq. and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with IN HCI aq. (2 10 mL), sat. sodium bicarbonate aq. (2 x 10 mL), brine (10 mL), dried (MgSθ4) and concentrated in vacuo. Alkyne 79, 2g (72 %) was obtained after purification via column chromatography eluting with ethyl acetate: hexane (20:80). This alkyne was then oxidized. Alkyne 79 (1.2g, 3 mmol) was dissolved in CHC13:CH3CN:H20 (18mL: 18mL:27mL). Ru02 (8 mg, 0.06 mmol) was added followed by sodium periodate (2.56g, 12 mmol). The reaction mixture was allowed to stir for 18 hours. Dione 80 675mg (52 %) was obtained after purification via column chromatography eluting with ethyl acetate: hexane (1:9), as a white foam (Scheme 14).
Figure imgf000203_0001
Data for Dione 80: iH-NMR (300 MHz, CDC13): 8.05 (d, 2H, J= 8.7), 7.91 (d, 2H, J = 8.7), 6.80 (br s, IH), 4.15 (d, 2H, J = 4.8), 2.89 (t, 2H, J= 7.4), 1.78-1.60 (m, 2H), 1.51 (br s, 9H), 1.42-1.10 (m, 14H), 0.88 (t, 3H, J = 6.5); MS (APcI): 417.3 (100, [M-CH3+H]), 432.3 (8, [M+H]), 376.3 (48); calcd C25H37N05 ([M+H]) 432.6.
Imidazole 81 was synthesized according to General Method 7 (Scheme 19) from dione 80 (336 mg, 0.78 mmol) in acetic acid (5 mL), with 3-(4-formyl-phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid tert-butyl ester (214 mg, 0.78 mmol) and NH4OAC (1.8 g, 23 mmol), which gives after purification via column chromatography eluting with DCM:methanol (95:5), 3-(4-{4-[4-(tert-Butoxycarbonylmethyl-carbamoyl)-phenyl]-5- decyl-lH-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5~ carboxylic acid tert-butyl ester 81, 180 mg (34%). Date for 3-(4-{4-[4-(tert-Butoxycarbonylmethyl-carbamoyl)- phenyl]-5-decyl-lH-imidazol-2-yl}-phenyl)-4,5-dihydro- isoxazole-5-carboxylic acid tert-butyl ester 81: iH-NMR (300 MHz, CDCls): 7.96 (d, 2H, J= 8.1), 7.75 (d, 2H, J = 8.1), 7.63 (d, 2H, J = 7.2), 7.57 (d, 2H, J = 8.1), 6.98-6.86 (m, IH), 5.03 (dd, IH, J = 9.9, 8.1), 4.11 (d, 2H, J = 5.1), 3.65- 3.45 (m, 2H), 2.75 (t, 2H, J= 7.5), 1.72-1.60 (m, 2H), 1.49 (br s, 18H), 1.40-1.05 (m, 14H), 0.84 (t, 3H, J = 6.6); MS (APcI): 687.3 (100, [M+H]); calcd C40H54N4O6 ([M+H]) 687.4.
Example 86 3-(4-{4-[4-(Carboxymethyl-carbamoyl)-phenyn-5-decyl- lff-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5- carboxylic acid 82
Figure imgf000204_0001
Imidazole 82 was synthesized from imidazole 81 according to General Method 11 to give, after recrystallization from methanol/ ethyl acetate, 3-(4-{4-[4-(Carboxymethyl- carbamoyl)-phenyl]-5-decyl-lH-imidazol-2-yl}-phenyl)-4, 5- dihydro-isoxazole-5-carboxylic acid 82, 119 mg (91%) as a pale yellow solid. Data for 3-(4-{4-[4-(Carboxymethyl-carbamoyl)-phenyl]-5-decyl- lH-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid
82: iH-NMR (400 MHz, CD3OD): 7.99 (d, 2H, J= 8.0), 7.98 (d, 2H, J = 7.6), 7.76 (d, 2H, J= 8.4), 7.74 (d, 2H, J= 8.0), 5.16 (dd, IH, J = 12.0, 7.2), 4.12 (s, 2H), 3.72 (dd, IH, J = 17.2, 12.0), 3.59 (dd, IH, J = 17.2, 6.8), 2.88 (t, 2H, J = 7.6), 1.80-1.68 (m, 2H), 1.42-1.15 (m, 14H), 0.87 (t, 3H, J = 6.8); MS (APcI):, 575.3 (100, [M+H]), 487.4 (95); calcd C32H39N4θ6 ([M+H]) 575.7. Example 87
Compound 104
Figure imgf000205_0001
4-Iodophenol 96 (Scheme 16, 3.38 g; 15.4 mmol) was charged to a round-bottomed flask along with D-mannose pentaacetate (5.0 g, 12.8 mmol), and CH2C12 (20 mL) followed by slow addition of BF3.OEt2 (8mL, 64.0 mmol). After the addition was complete the reaction stirred at rt under N2 for 8 h. The crude reaction mixture was added to CH2C12 (200 mL) and washed with H20 (200 mL) and brine (200 mL), dried over MgSθ4, filtered, and concentrated to dryness. Purification by flash column chromatography using 4: 1 hexanes/ EtOAc provided 97 (4.7 g). .«.# n.iy iy per.Ac-Man- w //
97
Data for Compound 97: iH-NMR (300 MHz, CDC13): 7.60 (d, 2H, J = 9.3), 6.88 (d, 2H, J = 9.3), 5.53 (m, 2H), 5.43 (m, IH), 5.36 (t, IH, J= 10.2), 4.27 (m, IH), 4.06 (m, 2H), 2.21 (s, 3H),
5 2.06 (s, 3H), 2.05 (s, 6H).
Glycoside 97 (Scheme 16, 4.0 g, 7.27 mmol) was added to a round-bottomed flask along with TMSalkyne (63) (5.14 mL, 36.3 mmol), bistriphenylphosphine palladium (II) dichloride (102 mg, 0.15 mmol), copper (I) iodide (14 mg, 0.073 mmol), *0 triethylamine (3.0 mL, 21.8 mmol), and DMF (30 mL). The mixture was stirred at rt under N2 for 10 h. The crude was then added to EtOAc (200 mL) and washed with H20 (150 mL), NH4CI (150 mL), and brine (150 mL), dried over MgS04, filtered, and concentrated to dryness. Purification by flash 5 chromatography using 4: 1 hexanes/EtOAc provided 98 (2.5 g). per.Ac-Man— <\ > — — TMS 98
Data for Compound 98: iH-NMR (300 MHz, CDCI3): 7.42 (d, 2H, J = 9.2), 7.02 (d, 2H, J = 9.3), 5.54 (m, 2H), 5.44 (m, IH), 5.36 (t, IH, J = 9.9), 4.28 (m, IH), 4.06 (m, 2H), 2.21 (s, 3H), 0 2.06 (s, 3H), 2.05 (s, 6H), 0.25 (s, 9H).
Alkyne 98 (Scheme 16, 2.49g, 4.78 mmol) was charged to a round-bottomed flask along with THF (10 mL). To this was added TBAF (1.0 M in THF, 5.7 mL, 5.7 mmol) and the reaction was stirred under N2 for 1.5 h. The crude mixture was added 5 to water (50 mL) and extracted with CH2C12 (2 X 100 mL). Organics were then washed with brine (200 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was dried in vacuo to provide 99 (2.0 g). per.Ac-Man— <\ — =— H 99
Data for 99: iH-NMR (300 MHz, CDCls): 7.44 (d, 2H, J = 8.7), 7.04 (d, 2H, J= 8.7), '5.55 (m, 2H), 5.44 (m, IH), 5.37 (t, IH, J = 10.2), 5.28 (m, IH), 4.06 (m, 2H), 3.04 (s, IH), 2.21 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H).
Alkyne 99 (Scheme 16, 2.0 g, 4.46 mmol) was charged to a round-bottomed flask along with DMF (20 mL), 4-bromo-l- iodobenzene 86 (1.5 g, 5.35 mmol), copper iodide (9.0 mg, 0.045 mmol), dichlorobis (triphenyl- phosphine) palladium(II) (63 mg, 0.09 mmol) and triethylamine (2.0 mL, 13.4 mmol). The reaction mixture was stirred at rt under an atmosphere of nitrogen for 8 h. The crude reaction mixture was added to a mixture of ethyl acetate (100 mL), and washed with NH4C1 (100 mL) and brine (100 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was purified by flash column chromatography using 4: 1 to 2: 1 hexane s/ EtOAc providing 100 (420 mg). per.Ac-Man— ^ > — ≡ — ^ >— Br
100
Data for compound 100: iH-NMR (300 MHz, CDCI3): 7.54 (d, 2H, J = 8.4), 7.47 (d, 2H, J= 8.1), 7.23 (d, 2H, J = 8.7), 7.05 (d,
2H, J= 8.6), 5.54 (m, 2H), 5.44 (m, IH), 5.36 (m, IH), 4.27 (m,
IH), 4.06 (m, 2H), 2.21 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03
(s, 3H).
Alkyne 100 (Scheme 16, 430 mg, 0.7 mmol) was charged to a round-bottomed flask along with CC14 (4.0 mL), CH3CN (4.0 mL), H20 (6.0 mL), and sodium periodate (610 mg, 2.85 mmol).
After stirring for 5 min, ruthenium dioxide (2.0 mg, 0.016 mmol) was added and the mixture stirred at rt for 6 h. The crude was added to CH2C12 (100 mL), washed with H20 (2 X 55 mL) and brine (50 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude was flashed using 1 : 1 hexanes/ethyl acetate to provide 101 as a white solid (425 mg).
Figure imgf000208_0001
Data for Compound 101: iH-NMR (300 MHz, CDC13): 7.98 (d, 2H, J = 8.5), 7.85 (d, 2H, J = 8.6), 7.68 (d, 2H, J = 8.4), 7.21 (d, 2H, J = 8.5), 5.62 (m, IH), 5.57 (m, IH), 5.48 (m, IH), 5.39 (m, IH), 4.24 (m, IH), 4.02 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H).
Dione 101 (Scheme 16, 0.4 g) was added to a round- bottomed flask along with 57i (226 mg, 0.95 mmol), DMF (10 mL), palladium (II) acetate (5.0 mg, 0.02 mmol), tri-o- tolylphosphine (23 mg, 0.08 mmol), and triethylamine (26 μL). The resultant reaction mixture was heated to 100 °C for 1.5 h. The crude was added to CH2C12 (75 mL), washed with H20 (50 mL) and brine (50 mL), dried over MgSθ4, filtered, and concentrated to dryness. Flash Chromatography using 1: 1 hexanes to ethylacetate provided 102 (302 mg) as a yellow solid.
Figure imgf000208_0002
Data for Compound 102: iH-NMR (300 MHz, CDCI3): 7.98 (d, 2H, J= 8.6), 7.61 (m, 4H), 7.21 (m, 3H), 6.48 (d, IH, J= 15.4), 5.62 (m, IH), 5.57 (m, IH), 5.47 (m, IH), 5.40 (m, IH), 4.28 (m, IH), 4.05 (m, 2H), 3.20 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.59 (m, 2H), 1.22 (m, 18H), 0.82 (m, 3H). Dione 102 (Scheme 16, 250 mg, 0.32 mmol) was added to a round-bottomed flask along with 34a (81 mg, 0.35 mmol), NH4OAc (0.74 g, 9.6 mmol), and HO Ac (5 mL), and the mixture was heated to 100 °C under N2 for 1.2 h. The crude material was added to ethyl acetate (50 mL), washed with H20 (50 mL) and brine (50 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude material was eluted on a preparative TLC plate (1.0 mm) using 10: 1 CH2Cl2/MeOH to provide 103 (178 mg) as a yellow solid.
Figure imgf000209_0001
Data for compound 103;iH-NMR (300 MHz, CDCls): 8.1 (d, 2H, J= 8.4), 7.98 (m, IH), 7.78 (d, 2H, J= 8.6), 7.45 (m, 5H), 7.40 (d, 2H, J = 8.2), 7.06 (d, 2H, J= 8.5), 6.38 (d, IH, J = 15.2), 5.58 (m, 2H), 5.40 (m, 2H), 5.10 (t, IH, J= 11.2), 4.29 (m, IH), 4.08 (m, 2H), 3.60 (m, 2H), 3.38 (m, 2H), 2.21 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.57 (s, 9H), 1.23 (m, 21H), 0.87 (m, 3H).
Imidazole 103 (Scheme 16, 150 mg) was added to a round-bottomed flask along with 20% TFA in CH2C12 (2 mL) and stirred at rt under N2 for 1.5 h. The crude, which was a mixture of 104 and 105 (see example 88) was concentrated to dryness and chromatographed by preperative TLC (1.0 mm) using 10: 1 CH2Cl2/MeOH to provide 104 (12 mg) and 105 (52 mg). Data for compound 104: iH-NMR (300 MHz,
CDCI3/CD3OD): 8.08 (d, 2H, J = 8.4), 7.98 (m, IH), 7.76 (d, 2H, J = 8.6), 7.45 (m, 5H), 7.40 (d, 2H, J = 8.2), 7.06 (d, 2H, J = 8.5), 6.36 (d, IH, J = 15.2), 5.54 (m, IH), 5.10 (t, IH, J= 11.2), 4.32-3.95 (m, 6H), 3.60 (m, 2H), 3.38 (m, 2H), 1.57 (s, 9H), 1.23 (m, 21H), 0.87 (m, 3H). MS (ESI): 881.2 (100, [M+H]); calcd C5oH65N4Oιo ([M+H]) 881.52.
Example 88 Compound 105
Figure imgf000210_0001
Data for Compound 105: iH-NMR (300 MHz, CD3OD):
8.12 (d, 2H, J = 8.4), 7.98 (m, IH), 7.76 (d, 2H, J= 8.6), 7.48 (m, 5H), 7.40 (d, 2H, J = 8.2), 7.06 (d, 2H, J= 8.5), 6.36 (d, IH, J = 15.2), 5.52 (m, IH), 5.10 (t, IH, J = 11.2), 4.35-3.99 (m, 6H), 3.60 (m, 2H), 3.38 (m, 2H), 1.23 (m, 21H), 0.87 (m, 3H). MS (ESI): 825.7 (100, [M+H]); calcd C46H57N4O10 ([M+H]) 824.39. Example 89 (E)-3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyl1-4- |4-(2-hydroxy-l-hydroxymethyl-ethylcarbamoyl)- phenyl]-lH-imidazol-2-yU-phenyl)-acrylic acid tert-butyl ester 94
Figure imgf000211_0001
Dione 88 (Scheme 15, R = t-Bu, 0.5 g - see Example 59) was added to a round-bottomed flask along with acrylamide 57i (305 mg, 2.6 mmol), DMF (10 mL), palladium (II) acetate (11 mg, 0.08 mmol), tri-o-tolylphosphine (52 mg, 0.31 mmol), and triethylamine (0.5 mL). The resultant reaction mixture was heated to 100 °C for 1 ,5 h. The crude was added to CH2C12 (75 mL), washed with H20 (50 mL) and brine (50 mL), dried over MgSθ4, filtered, and concentrated to dryness. Flash
Chromatography using 3: 1 hexanes to ethyl acetate provided Dione 90 (428 mg) as a yellow solid.
Data for dione 90: iH-NMR (300 MHz, CDCls): 8.19 (d, 2H, J= 8.2), 8.0 (d, 2H, J = 8.1), 7.81 (d, IH, J= 15.7), 7.79 (d, 2H, J = 8.0), 7.07 (d, 2H, J = 8.1), 6.50 (d, IH, J = 15.8), 5.95 (m, IH), 3.22 (m, 2H), 1.61 (s, 9H), 1.46 (m, 2H), 1.24 (m; 18H), 0.835 (m, 3H). Dione 90 (Scheme 15, R = "Bu, 405 mg) was charged to a round-bottomed flask and 20% TFA in CH2C12 (7 mL) was added followed by stirring at rt for 1.5 h. The crude material was concentrated to dryness and dried in vacuo to provide carboxylic acid 91 (360 mg) as a light yellow powder.
Data for carboxylic acid 91: iH-NMR (300 MHz, DMSO- de): 8.18 (d, 2H, J= 8.0), 8.08 (d, 2H, J= 8.0), 7.9 (m, 4H), 7.8 (d, IH, J = 15.7), 6.52 (d, IH, J = 15.7), 5.92 (m, H), 3.22 (m, 2H), 1.47 (m, 2H), 1.24 (m, 18H), 0.84 (m, 3H). Carboxylic acid 91 (Scheme 15, R = t-Bu, 350 mg) was added to a round-bottomed flask followed by DMF (5 mL), EDCI (137 mg, 0.7 mmol), and serinol (92) (130 mg, 1.4 mmol), and the mixture was stirred at rt for 36 h. The crude was added to ethyl acetate (100 mL) and washed with H20 (50 mL) and brine (50 mL), dried over MgS04, filtered, and concentrated to dryness. Flash chromatography using 10: 1 CH Cl2/MeOH as eluent provided 93 as a yellow oil (248 mg) .
Data for Dione 93;iH-NMR (300 MHz, CDC13): 8.09 (d, 2H, J = 8.2), 7.89 (m, 4H), 7.78 (m, 3H), 6.53 (d, IH, J = 15.5), 5.95 (m, IH), 3.65-3.5 (m, 4H), 3.2-3.14 (m, 5H), 1.45 (m, 2H), 1.25 (m, 18H), 0.91 (m, 3H).
Dione 93 (Scheme 15, R = t_Bu, 240 mg) was added to a round-bottomed flask along with 34a (99 mg, 0.43 mmol), NH4OAC (0.98 g, 13.1 mmol), and HOAc (6 mL), and the mixture was heated to 100 °C under N2 for 1.2 h. The crude material was added to ethyl acetate (50 mL), washed with H20 (50 mL) and brine (50 mL), dried over MgSθ4, filtered, and concentrated to dryness. The crude material was eluted on a preparative TLC plate (1.0 mm) using 10: 1 CH2Cl2/MeOH to provide (E)-3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-[4- (2-hydroxy-l-hydroxymethyl-ethylcarbamoyl)-phenyl]-lH- imidazol-2-yl}-phenyl)-acrylic acid tert-butyl ester 94 (132 mg) as a yellow solid.
Data for (E)-3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-4-[4-(2-hydroxy- 1 -hydroxymethyl-ethylcarbamoyl)- phenyl]-lH-imidazol-2-yl}-phenyl)-acrylic acid tert-butyl ester 94: iH-NMR (300 MHz, CDC13): 8.19 (d, 2H, J = 8.1), 7.91 (m, 4H), 7.79(d, 2H, J = 8.0), 7.62 (m, 6H), 6.63 (m, 2H), 5.93 (m, IH), 3.64-3.52 (m, 4H), 3.21-3. l l(m, 5H), 1.61 (s, 9H), 1.45 (m, 2H), 1.22 (m, 18H), 0.82 (m, 3H). MS (ESI): 777.3 (100, [M+H]); calcd C47H60N4O6 ([M+H]) 777.5.
Example 90 (E)-3-(4-{5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenvπ-4- [4-(2-hydroxy-l-hydroxymethyl-ethylcarbamoyl)- phenyl]- lH-imidazol-2-yl}-phenyl)-acrylic acid 95 Example 89
Figure imgf000213_0002
Figure imgf000213_0001
Imidazole 94 (Scheme 15, R = t-Bu, 100 mg) was added to a round-bottomed flask along with 20% TFA in CH2C12 (2 mL) and stirred at rt under N2 for 1.5 h. The crude material was concentrated to dryness and chromatographed by preperative TLC (1.0 mm) using*8: l CH2Cl2/MeOH to provide (E)-3-(4-{5-[4- ((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-[4-(2-hydroxy-l- hydroxymethyl-ethylcarbamoyl)-phenyl]-lH-imidazol-2-yl}- phenyl)-acrylic acid 95 (43 mg).
Data for (E)-3-(4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)- phenyl]-4-[4-(2-hydroxy-l-hydroxymethyl-ethylcarbamoyl)- phenyl]-lH-imidazol-2-yl}-phenyl)-acrylic acid 95: iH-NMR (300 MHz, DMSO-de): 8.19 (d, 2H, J = 8.1), 7.91 (m, 4H), 7.78 (d, 2H, J = 8.0), 7.60 (m, 6H), 6.63 (m, 2H), 5.93 (m, IH), 3.64- 3.52 (m, 4H), 3.21-3. l l(m, 5H), 1.45 (m, 2H), 1.22 (m, 18H), 0.82 (m, 3H). MS (ESI): 721.6 (100, [M+H]); calcd C43H52N4O6 ([M+H]) 720.43
Biological Assay The biological activity of Formulas 1 , 2 and 3 is determined by the following procedures: Materials and Methods P-selectin ELISA Assay
An ELISA-type assay was used to screen for inhibitors of selectin-ligand interactions. A P-selectin-IgG chimera, constructed as described by Foxall and colleagues (Foxall et al, FASEB 117: 895 (1992)), and sialyl-Lewisx pentaceramide were obtained from Kanebo, Ltd. (Osaka) (Kiyoi et al, Bioorg. Med. Chem. 6: 587 (1998)).
Assays were performed essentially as described (Ohmoto et al, J. Med. Chem. 39: 1339 (1996)). Polystyrene microtiter plates (Falcon Pro-Bind) were coated with the sialyl-Lewisx analog at 40-100 pmol/well. Coated wells were blocked with 5% bovine serum albumin (BSA) in 50 mM imidazole buffer, pH 7.2, for 1 hour at room temperature.
Compounds were diluted from DMSO stock solutions in assay buffer (50 mM imidazole buffer, pH 7.2, containing 1% BSA and 1 mM CaCl2). Compounds were always run in duplicate B W&l W^ or triplicate. A complex consisting of P-selectin IgG chimera, biotinylated goat F(ab')2 anti-human IgG, and streptavidin- alkaline phosphatase conjugate was made in assay buffer. Selectin chimera was omitted from the complex for negative control ("background") wells. The complex and the test compounds (or vehicle controls) were combined in wells of a polypropylene microtiter plate and incubated for 30 minutes at room temperature. The complex-compound mixture was then added to the blocked, sialyl- Lewisx -ceramide coated plate and allowed to incubate for 45 minutes at 37°C. After washing 3-4 times with 50 mM imidazole, the bound complex was detected using the colorimetric phosphatase substrate, p- nitrophenylphosphate, at 1 mg/mL in 1 M diethanolamine containing 0.01% MgCl2. After developing for 1-2 hours at room temperature, the absorbance at 405 nM was measured in a Molecular Devices microplate reader. Percent inhibition was calculated by comparing the test compound result with the vehicle control after subtracting the background from each. IC50 values were calculated by in-house data analysis software (OntoASSAY; Ontogen, Corp.) using standard algorithms. Cell-Selectin Adhesion Assays
The ability of compounds to inhibit the adhesion of HL60 cells to purified selectin proteins was measured using a "cell- selectin" assay. Recombinant soluble P- and E-selectin proteins purchased from R&D Systems (Minneapolis, MN) were diluted to 2.5 μg/mL in Dulbecco's PBS containing calcium and magnesium (PBS+) . Falcon Pro-Bind microtiter plate wells were incubated with 50 μL of the P- or E-selectin protein solution for 1 hr at 37°C or overnight at 4°C. The selectin protein was omitted from negative control ("background") wells. Coated wells were then washed three times with PBS+ and then blocked with 1% BSA in PBS+ for 1 hour at room temperature. After blocking, the plates were washed 3 times with PBS+. Compounds were diluted to 2x final test concentration in PBS+ and added to the blocked, selectin-coated wells in a volume of 50 μL. Samples were always run in duplicate or triplicate. Compounds and vehicle controls were pre-incubated in the wells for -20 minutes at room temperature.
HL60 cells obtained from the ATCC (Manassas, VA) were cultivated in RPMI medium containing 10% heat- inactivated fetal bovine serum (FBS). For the assay, cells were harvested by centrifugation, washed once with PBS+, and resuspended in PBS+ at a concentration of 2 x 106 cells/mL. Cells were added directly to the compound-containing wells in a volume of 50 μL per well, bringing the compound to its final test concentration in a total volume of 100 μL. Cells and compound were incubated on the selectin-coated wells for 45 minutes at 37°C. Unbound cells were removed using a vacuum manifold and a single wash with 200 μL PBS+ (added slowly using a manual multichannel pipettor) . Retained cells were labeled directly on the plate by adding 5 μg/mL of the membrane-permeable fluorescent dye, calcein-AM, and incubating for 30 minutes at 37°C. Signal was quantified in a Wallac Victor fluorescent microplate reader using 485 nM excitation and 535 nM emission. Percent inhibition and IC50 values were calculated as described above for the ELISA assay.
The results which show inhibitory activity of compounds of the current invention against the selectins, are tabulated in Table 3 below: Table 3
Figure imgf000217_0001
Figure imgf000218_0001
Included within the scope of this invention are prodrugs of Formulas 1, 2 and 3. In the case of the -COOH being present, pharmaceutically acceptable esters can be employed. These include, but are not limited to, compounds such as Formulas 4, 5 and 6, where R' can be methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
Figure imgf000219_0001
Formulas 4, 5 and 6
Pharmaceutically acceptable salts of the compounds of Formulas 1, 2 and 3, where a basic or acidic group is present in the structure, are also included within the scope of this invention. 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, methane sulfonate, ethanesul- fonate, picrate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) p.1-19 and incorporated herein by reference, can be used as the dosage form.
In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention. The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or others. The present invention provides a method of administering a compound selected from those defined in Formulas 1 , 2 and 3 above in cases where inhibition or modulating selectin activity in a body is needed. These conditions include but are not limited to the foregoing described diseases.
To administer Formulas 1, 2 and 3, the compounds may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. The tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or 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 mono stearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U.S. Patent Nos. 4,256, 108; 4, 160,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of ethylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylen-oxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned 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 conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
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 can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidyl-cholines.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formulas 1, 2 and 3 are employed.
The compounds of Formulas 1 , 2 and 3 may also be administered directly into the lungs by inhalation or intranasal delivery when formulated in a solvent that is suitable for aerosol formation. Such delivery would be useful for direct delivery to the site of action, as in asthma. However, because administration to the lungs may result in significant blood levels of the compound, this route of administration can be also used in cases where systemic exposure is required. Dosage levels of the compounds of the present invention are of the order of about 0.5 mg to about 100 mg per kilogram body weight, with a preferred dosage range between about 20 mg to about 50 mg per kilogram body weight per day (from about 25 mg to about 5 g's per patient 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 5 mg to 1 g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient.
It will be understood however, that the specific dose 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, gender, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The dosage needs to be individualized by the clinician.

Claims

We claim:
A compound having the structural Formula la:
Where at least one and no more than two of R1, R2, R3, R or R5 =
Figure imgf000225_0001
,Calcium binding moiety
X= N or O
Formula la as defined in Group 1
Case A: When one of R1, R2, R3, or R4 is selected from Group I (templates 1-6):
Group I is defined in Figure 1, Table 1, below:
Group I =
Figure imgf000225_0002
where R equals one of the following in Table 1 :
Figure 1 Table 1
Figure imgf000225_0003
Figure imgf000226_0001
Figure imgf000227_0001
(n", and/or n' and/or n can be 0, 1, 2, 3, 4, 5 or 6) and one of R1, R2, R3, or R4 must be selected from Group II:
Group II is defined as one of the following:
(i) C0-6CO2R11 , Co-βCONHRi 1 , Co-βNHCORi 1 , C0- 6NHC(0)NHRH, Co-eNHSOaR11, wherein R" is C8-i6 alkyl, or C3-8 alkylaiyl, in which the said aryl group is mono- or disubstituted with a member selected from the group consisting of hydrogen, hydroxy, halo, Cι-6 alkyl and Cι-6 alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy; or (ii) substituted or unsubstituted Cs-iβ alkyl or substituted Cs-iβ alkenyl, wherein the substituents are selected from the group consisting of hydrogen, hydroxy, Ci-β alkyloxy, amino, Ci-β alkylamino, or Ci-β dialkylamino, or aryl; or (iii) Unsubstituted, mono-, di-, or tri-substituted aryl- Co- 11 alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of: (a) C0-6CO2R12, Co~6CON(Η)R12, Co-δNHS02R12, trans- CH=CHC02R12, rαns-CH=CHCON(Η)R12, or cyclopropylCON(Η)R12 wherein R12 is Cβ-iβ alkyl, bis-
C4-16 alkyl (* no H), N-(methyl) C8-i6 alkyl (* no H), C8-ιe alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaiyl, C 1-5 alkylaiyl Ci-β alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group is unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Ci-β alkyl and Ci- β alkyloxy, Cι-6 cycloalkyloxy, C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Cι-4 alkyl, or C1-4 alkyloxy; or R10 can be N-Boc- piperidino, or N-carboethoxypiperidino; And one of R1, R2, R3, or R4 must be selected from Group III: Group III is defined as either: (i) Hydrogen; o
(ii) Unsubstituted, mono or disubstituted Ci-iβ alkyl, Co-iβ alkylamino, amino Co-iβ alkyl, Co-6 alkylcarboxyl or Co-6 alkyl carboxyl ester, Co-iβ alkyloxyalkyl or C2-16 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Ci-s alkyl, Ci-s alkyloxyalkyl, Ci-s alkylthioalkyl, phenyl-Ci-s alkylamino, C 1-8 alkoxycarbonyl; or Co-6 carboxyl, triazole, 2,3- (me thylenedioxy) benzyl; or
(iii) substituted or unsubstituted N or C-linked pyrrolidino, piperidino, piperidonyl, morpholino, piperazino, N-Boc- piperazino, N-C1-10 alkylpiperazino, N-C3-6 alkenylpiperazino, N-(Cι-6 aikoxy Ci-β alkyl) piperazino, N- (C1-6 aikoxy C3-6 alkenyl)piperazino, N-(Cι-6 alkylamino Ci-
6 alkyl) piperazino, N-(C 1-6 alkylamino C3-6 alkenyl)piperazino, uracil or other purine or pyrimidine heterocycles, wherein the substituents are N or C-linked, and are independently selected from: (a) substituted Ci-iβ alkyloxy, C3-16 alkenyloxy, substituted C3-16 alkynyloxy; or
(b) substituted C1-6 alkyl-amino, di(substituted Cι-6 alkyl) amino; or
(c) CONHC1-C16 alkyl, COOCι-C16 alkyl, Co-11 alkylC02H, Co-nNHC(0)NHRH, C0-11NHSO2R11, trans- CH=CHCO2Rn, or trans- CH=CHCONHR11 wherein R11 is hydrogen, Cue alkyl, or Ci-iβ alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Cι-6 alkyl and Cι-6 alkyloxy, Cι-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl; or (iv) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) unsubstituted or substituted C0-3 alkyloxy C0-3 alkyl, C3-16 alkenyloxy, substituted C3-16 alkynyloxy, aryl; or (c) mono or di-substituted C1-6 alkyl-amino, di(substituted Ci-β alkyl)amino; or (d) CONHC1-C16 alkyl, COOCi-Cie alkyl, Co-11 alkylC02H, Co-ιιNHC(0)NHR , C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHR wherein R11 is hydrogen, Ci-ie alkyl, or Ci-iβ alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and Ci-β alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl. (e) O- or C-linked hexose or furanose. and one of R1, R2, R3, or R4 must be selected from Group
IV:
Group IV is defined as either: (i) hydrogen; or (ii) substituted or unsubstituted Ci-iβ alkyl or C2-ι2 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, C1-6 alkyloxy, Ci-βalkylthio, C1-6 alkylamino, phenyl-Ci-β alkylamino, C1-6 alkoxycarbonyl; or (iii) mono, di or tri-substituted aryl C0-4 alkyl or substituted C0-4 alkyl aryl, wherein the aryl group is selected from phenyl, imidazolyl, indolyl, furyl, thienyl or pyridyl in which the substituents are selected from: (a) hydrogen; or (b) hydroxy or halo
The remaining R group must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, or R4 are selected from Group I (templates 1-6), one of R1, R2, R3, or R4 must be selected from Group II, and one of R1, R2, R3, or R4 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined above; and the pharmaceutically acceptable salts and esters thereof.
2. We claim a compound having the structural Formula lb:
Where at least one and no more than two of R1, R2, R3, R4 or R5 =
Figure imgf000232_0001
,Calcium binding moiety
X = N or 0
Formula lb as defined in Group 1
Case A: When one of R1, R2, R3, R4, or *R5 (*in General Formula 3) is selected from Group I (template 7):
Group I (template 7) is defined in Figure 2, Table 2, below:
Group I =
Figure imgf000232_0002
where R equals one of the following in Table 2: Figure 2
Table 2
Figure imgf000233_0001
one of R1, R2, R3, or R4 must be selected from Group V: Group V is defined as one of the following: (i) Unsubstituted, mono-, di-, or tri-substituted aryl-
Co-ii alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of: (a) Co-6C02Ri2, Co-eCON(*H)R12, C0-6NHSO2R12, trans- CH=CHC02R12, trcms-CH=CHCON(*H)R12, or cyclopropylCON(*H)R12 wherein R12 is Cβ-iβ alkyl, bis- C4-16 alkyl (* no H), N-(methyl) C8-ι6 alkyl (* no H), C8-i6 alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaiyl, C 1-5 alkylaiyl Cι-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Cι-6 alkyl and Ci- 6 alkyloxy, C1-6 cycloalkyloxy, C1-C4 alkyl. and one of R1, R2, R3, or R4 must be selected from Group VI. Group VI is defined as one of the following: (i) Hydrogen; or
(ii) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) CONHC1-C16 alkyl, CONHCi-2 bis- C2-4 alkyl, COOC1-C16 alkyl, Co-11 alkylC02H, Co- nNHC(0)NHR , C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRH wherein R11 is hydrogen, C1-16 alkyl, or C1-16 alkyl aryl, in which the said aryl groups, or alkyl groups are mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl.
(c) O- or C-linked hexose or furanose.
The remaining R groups must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, or R4 are selected from Group I (template 7), one of R1, R2, R3, or R4 must be selected from Group V. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III, IV, V, and VI are defined above; and the pharmaceutically acceptable salts and esters thereof.
3. A compound having the structural Formula 2a:
Figure imgf000235_0001
Case A: When one of R1, R2, R3, or R4 is selected from Group I (templates 1-6):
Group I is defined in Figure 1, Table 1, below:
Group I =
Figure imgf000235_0002
where R equals one of the following in Table 1 :
Figure 1
Table 1
Figure imgf000235_0003
Figure imgf000236_0001
Figure imgf000237_0001
and one of R1, R2, R3, or R4 must be selected from Group
II:
Group II is defined as one of the following:
(i) C0-6CO2R11, Co-eCONHR11, Co-eNHCOR11, C0- eNHC^JNHRH, C0-6NHSO2R11, wherein R11 is C8-i6 alkyl, or C3-8 alkylaryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy; or (ii) substituted or unsubstituted Cs-iβ alkyl or substituted Cs-iβ alkenyl, wherein the substituents are selected from the group consisting of hydrogen, hydroxy, C1-6 alkyloxy, amino, C1-6 alkylamino, or C1-6 dialkylamino, or aryl; or (iii) Unsubstituted, mono-, di-, or tri-substituted aryl- Co-11 alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of: (a) C0-6CO2R12, Co-6CON(Η)Ri2, Co-6NHS02R12, trans- CH=CHC02R12, trαns-CH=CHCON(*H)Ri2, or cyclopropylCON(*H)R12 wherein R12 is C8-i6 alkyl, bis-
C4-16 alkyl (* no H), N-(methyl) C8-i6 alkyl (* no H), Cβ-ie alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaryl, C 1-5 alkylaryl C 1-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Ci-e alkyl and Ci- 6 alkyloxy, Cι-6 cycloalkyloxy, C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy; or R10 can be N-Boc- piperidino, or N-carboethoxypiperidino; And one of R1, R2, R3, or R4 must be selected from Group III: Group III is defined as either: (i) Hydrogen; or
(ii) Unsubstituted, mono or disubstituted C1-16 alkyl, Co-iβ alkylamino, amino C0-16 alkyl, Co-6 alkylcarboxyl or Co-6 alkyl carboxyl ester, Co-iβ alkyloxyalkyl or C2-16 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Ci-β alkyl, Cι-8 alkyloxyalkyl, C1-8 alkylthioalkyl, phenyl-Cι-8 alkylamino, C1-8 alkoxycarbonyl; or Co-6 carboxyl, triazole, 2,3- (methylenedioxy)benzyl; or
(iii) substituted or unsubstituted N or C-linked pyrrolidino, piperidino, piperidonyl, morpholino, piperazino, N-Boc- piperazino, N-Cι-10 alkylpiperazino, N-C3-6 alkenylpiperazino, N-(Cι-6 aikoxy C1-6 alkyl) piperazino, N- (C1-6 aikoxy C3-6 alkenyl) piperazino, N-(Cι-6 alkylamino Ci-
6 alkyl) piperazino, N-(Cι-6 alkylamino C3-6 alkenyl) piperazino, uracil or other purine or pyrimidine heterocycles, wherein the substituents are N or C-linked, and are independently selected from: (a) substituted Ci-iβ alkyloxy, C3-16 alkenyloxy, substituted C3-16 alkynyloxy; or
(b) substituted C1-6 alkyl-amino, di(substituted C1-6 alkyl) amino; or
(c) CONHC1-C16 alkyl, COOCi-Cie alkyl, Co-11 alkylC02H, Co-nNHC^NHR11, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRn wherein R11 is hydrogen, Cue alkyl, or C1-16 alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Cι-6 alkyl and Cι-6 alkyloxy, Cι-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl; or (iv) either unsubstituted, mono-, di, or tri-substituted aryl, or Co-Cι2 aryl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) unsubstituted or substituted C0-3 alkyloxy C0-3 alkyl, C3-16 alkenyloxy, substituted C3-16 alkynyloxy, aryl; or (c) mono or di-substituted C1-6 alkyl-amino, di(substituted Ci-β alkyl)amino; or (d) CONHC1-C16 alkyl, COOCi-Ciβ alkyl, Co-11 alkylC02H, Co-nNHCfOJNHR11, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRn wherein R11 is hydrogen, Ci-iβ alkyl, or Ci-iβ alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and Ci-β alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl. (e) O- or C-linked hexose or furanose. and one of R1, R2, R3, or R4 must be selected from Group IV:
Group IV is defined as either: (i) hydrogen; or (ii) substituted or unsubstituted Ci-iβ alkyl or C2-12 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, Ci-β alkyloxy, Ci-βalkylthio, C1-6 alkylamino, phenyl-Cι-6 alkylamino, C1-6 alkoxycarbonyl; or (iii) mono, di or tri-substituted aryl C0-4 alkyl or substituted C0-4 alkyl aryl, wherein the aryl group is selected from phenyl, imidazolyl, indolyl, furyl, thienyl or pyridyl in which the substituents are < selected from: (a)hydrogen; or
(b) hydroxy or halo The remaining R group must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, or R4 are selected from Group I (templates 1-6), one of R1, R2, R3, or R4 must be selected from Group II, and one of R1, R2, R3, or R4 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined above; and the pharmaceutically acceptable salts and esters thereof.
4. A compound having the structural Formula 2b: Where at least one and no more than two of R1, R2, R3, R4 or R5 =
,Calcium binding moiety
Figure imgf000242_0001
Formula 2b as defined in Group 1
Case A: When one of R1, R2, R3, or R4, is selected from Group I (template 7):
Group I (template 7) is defined in Figure 2, Table 2, below:
Group I =
Figure imgf000242_0002
where R equals one of the following in Table 2: Figure 2
Table 2
Figure imgf000242_0003
one of R1, R2, R3, or R4 must be selected from Group V: Group V is defined as one of the following:
(i) Unsubstituted, mono-, di-, or tri-substituted aryl- Co-n alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of:
(a) C0-6CO2R12, Co-δCON(*H)R12, C0-6NHSO2R12, trans- CH=CHC02R12, trαns-CH=CHCON(*H)R12, or cycloproρylCON(Η)R12 wherein R12 is Cβ-iβ alkyl, bis- C4-16 alkyl (* no H), N-(methyl) C8-i6 alkyl (* no H), C8-i6 alkyloxyalkyl, C0-3 alkyl C7-ιo perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaryl, C1-5 alkylaryl Cι-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Ci-β alkyl and Ci- 6 alkyloxy, Cιre cycloalkyloxy, C1-C4 alkyl. and one of R1, R2, R3, or R4 must be selected from Group VI. Group VI is defined as one of the following: (i) Hydrogen; or (ii) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) CONHC1-C16 alkyl, CONHCι-2 bis- C2-4 alkyl, COOC1-C16 alkyl, Co-11 alkylC02H, Co- nNHC(0)NHRn, C0-11NHSO2R11, trans- CH=CHC0 Rn, or trans- CH=CHCONHR wherein R11 is hydrogen, Ci-iβ alkyl, or Ci-iβ alkyl aryl, in which the said aryl groups, or alkyl groups are mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Cι-6 alkyl and Cι-6 alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either * unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl. (c) O- or C-linked hexose or furanose. The remaining R groups must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, or R4 are selected from Group I (template 7), one of R1, R2, R3, or R4 must be selected from Group V. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III, IV, V, and VI are defined above; and the pharmaceutically acceptable salts and esters thereof.
A compound having the structural Formula 3a:
Figure imgf000244_0001
Case A: When one of R1, R2, R3, R4 or R5 is selected from
Group I (templates 1-6):
Group I is defined in Figure 1, Table 1, below:
Group I =
Figure imgf000244_0002
where R6 equals one of the following in Table 1 :
Figure 1 Table 1
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
and one of R1, R2, R3, R4 or R5 must be selected from Group II:
Group II is defined as one of the following: (i) C0-6CO2R11, Co-eCONHR11, Co-eNHCORH, Co-
6NHC(0)NHRH, C0-6NHSO2R11, wherein R11 is C8-i6 alkyl, or C3-8 alkylaryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, C1-6 cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy; or (ii) substituted or unsubstituted Cs-i6 alkyl or substituted Cs- 16 alkenyl, wherein the substituents are selected from the group consisting of hydrogen, hydroxy, C1-6 alkyloxy, amino, C1-6 alkylamino, or C1-6 dialkylamino, or aryl; or (iii) Unsubstituted, mono-, di-, or tri-substituted aryl-Co-11 alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of:
(a) C0-6CO2R12, Co-6CON(*H)R12, C0-6NHSO2R12, trans- CH=CHC02R12, trαns-CH=CHCON(*H)Ri2, or cyclopropylCON(*H)R12 wherein R12 is Cs-iβ alkyl, bis- C4-16 alkyl (* no H), N-(methyl) Cβ-ie alkyl (* no H), Cβ-ie alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaryl, C 1-5 alkylaryl C1-8 alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, C1-6 alkyl and Ci- 6 alkyloxy, Ci-β cycloalkyloxy, C1-C4 alkyl aryl or C1-C4 aikoxy aryl, in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo,
C1-4 alkyl, or C1-4 alkyloxy; or R10 can be N-Boc- piperidino, or N-carboethoxypiperidino; And one of R1, R2, R3, R4 or R5 must be selected from Group III: Group III is defined as either: (i) Hydrogen; or (ii) Unsubstituted, mono or disubstituted Ci-iβ alkyl, C0-16 alkylamino, amino Co-iβ alkyl, Co-6 alkylcarboxyl or Co-6 alkyl carboxyl ester, Co-iβ alkyloxyalkyl or C2-16 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, C1-8 alkyl, Cι-8 alkyloxyalkyl, C1-8 alkylthioalkyl, phenyl-Cι-8 alkylamino, C 1-8 alkoxycarbonyl; or Co-6 carboxyl, triazole, 2,3- (methylenedioxy) benzyl; or (iii) substituted or unsubstituted N or C-linked pyrrolidino, piperidino, piperidonyl, morpholino, piperazino, N-Boc- piperazino, N-Ci-10 alkylpiperazino, N-C3-6 alkenylpiperazino, N-(Cι-6 aikoxy Cι-6 alkyl)piperazino, N- (C1-6 aikoxy C3-6 alkenyl) piperazino, N-(Cι-6 alkylamino Ci- 6 alkyl) piperazino, N-(Cι-β alkylamino C3-6 alkenyl) piperazino, uracil or other purine or pyrimidine heterocycles, wherein the substituents are N or C-linked, and are independently selected from:
(a) substituted C1-16 alkyloxy, C3-16 alkenyloxy, substituted C3-16 alkynyloxy; or (b) substituted C1-6 alkyl-amino, di(substituted C1-6 alkyl) amino; or (c) CONHC1-C16 alkyl, COOCi-Cie alkyl, Co-11 alkylC02H, C0-nNHC(O)NHRH, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRn wherein R11 is hydrogen, Ci-ie alkyl, or Ci-iβ alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, Ci-6 alkyl and C1-6 alkyloxy, Ci-e cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl; or
(i) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl, wherein the substituents are independently selected from; (a) hydroxy, halo; or (b) unsubstituted or substituted C0-3 alkyloxy C0-3 alkyl, C3-16 alkenyloxy, substituted C3-16 alkynyloxy, aryl; or (c) mono or di- substituted C1-6 alkyl-amino, di(substituted Ci-e alkyl)amino; or (d) CONHC1-C16 alkyl, COOC1-C16 alkyl, Co-11 alkylC02H, C0-ιιNHC(O)NHR , C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHRn wherein R11 is hydrogen, Cue alkyl, or C1-16 alkyl aryl, in which the said aryl group, is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and Ci-β alkyloxy, Ci-β cycloalkyloxy, or C1-C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, C1-4 alkyloxy, and aryl. (e) O- or C-linked hexose or furanose. and one of R1, R2, R3, R4 or R5 must be selected from Group IV: Group IV is defined as either: (i)hydrogen; or
(ii) substituted or unsubstituted Ci-iβ alkyl or C2-12 alkenyl wherein the substituents are independently selected from the group consisting of hydroxy, C1-6 alkyloxy,
Ci-βalkylthio, Ci-β alkylamino, phenyl-Cι-6 alkylamino, C1-6 alkoxycarbonyl; or (iii) mono, di or tri-substituted aryl C0-4 alkyl or substituted C0-4 alkyl aryl, wherein the aryl group is selected from phenyl, imidazolyl, indolyl, furyl, thienyl or pyridyl in which the substituents are selected from: (a)hydrogen; or (b) hydroxy or halo The remaining R group must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, or R4 are selected from Group I (templates 1-6), one of R1, R2, R3, or R4 must be selected from Group II, and one of R1, R2, R3, or R4 must be selected from Group IV. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III and IV are defined above; and the pharmaceutically acceptable salts and esters thereof.
A compound having the structural Formula 3b:
Figure imgf000251_0001
Case A: When one of R1, R2, R3, R4, or *R5 (*in General Formula 3) is selected from Group I (template 7) :
Group I (template 7) is defined in Figure 2, Table 2, below:
Group I =
Figure imgf000252_0001
where R equals one of the following in Table 2: Figure 2 Table 2
Figure imgf000252_0002
one of R1, R2, R3, R4 or *R5 must be selected from Group V: Group V is defined as one of the following:
(i) Unsubstituted, mono-, di-, or tri-substituted aryl- Co-ii alkyl wherein aryl is selected from the group consisting of phenyl, or pyridino, wherein the substituents are selected from the group consisting of: (a) Co-6C02R12, Co-eCON(*H)R12, Co-6NHS02R12, trans-
CH=CHC02R12, irαns-CH=CHCON(Η)R12, or cyclopropylCON(*H)R12 wherein R12 is Cs-iβ alkyl, bis- C4-16 alkyl (* no H), N-(methyl) Cβ-iβ alkyl (* no H), C8-i6 alkyloxyalkyl, C0-3 alkyl C7-10 perfluoroalkyl, C5-8 cycloalkyl, C2-11 alkylaryl, C 1-5 alkylaiyl Ci-s alkyl, aminoaryl, C0-4 alkyltetrahydrofurfuryl, C0-4 alkyldiphenylmethyl which the said alkyl group or said aryl group, are unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, carboxy, halo, Cι-6 alkyl and Ci- 6 alkyloxy, Cι-6 cycloalkyloxy, C1-C4 alkyl. and one of R1, R2, R3, R4 or *R5 must be selected from Group VI.
Group VI is defined as one of the following: (i) Hydrogen; or
(ii) either unsubstituted, mono-, di, or tri-substituted aryl, or C0-C12 aryl, wherein the substituents are independently selected from;
(a) hydroxy, halo; or
(b) CONHC1-C16 alkyl, CONHC1-2 bis- C2-4 alkyl, COOC1-C16 alkyl, Co-11 alkylC02H, Co- nNHC(0)NHRi i, C0-11NHSO2R11, trans- CH=CHC02Rn, or trans- CH=CHCONHR wherein R11 is hydrogen, C1-16 alkyl, or Ci-iβ alkyl aryl, in which the said aryl groups are mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-6 alkyl and C1-6 alkyloxy, Ci-β cycloalkyloxy, or Ci-
C4 alkyl aryl or C1-C4 aikoxy aryl in which said aryl group is either unsubstituted, mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C1-4 alkyl, Ci- 4 alkyloxy, and aryl.
(c) O- or C-linked hexose or furanose.
The remaining R groups must be either unsubstituted or be equal to Hydrogen.
Case B: When two of R1, R2, R3, R4, or *R5 (*in General Formula 3) are selected from Group I (template 7), one of R1, R2, R3, R4 or *R5 must be selected from Group V. The remaining R groups must be either unsubstituted or be equal to Hydrogen; where Groups I, II, III, IV, V, and VI are defined above.
7. A compound according to claim 1, by the name of 3- [4-(2-(4-Diethylamino-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl)-vinyl1-phenyl}-lH-imidazol-4-yl)- phenyl]-4,5-dihvdro-isoxazole-5-carboxylic acid methyl ester having the following structural formula:
Figure imgf000254_0001
And the corresponding pharmaceutically acceptable salts thereof.
8. A compound according to claim 1, by the name of 3- [4-(2-(4-Diethylamino-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-4-yl) -phenyl] - 4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000255_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
9. A compound according to claim 1, by the name of 3- {4-[5-(4-[(E)-2-(3-Phenyl-propylcarbamoyl)-vinyl]-phenyl}-2- (2 ,4 ,6-trimethyl-phenyl) - 1 H-imidazol-4-yl]-phenyl}-4 , 5- dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000255_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
10. A compound according to claim 1, by the name of 3^ {4- [5-{4- [ f E) -2- (3-Phenyl-propylcarbamoyl) -vinyl] -phenylj-2 - (4-pyrrolidin- 1-yl-phenyl)- lff-imidazol-4-yl]-phenyl}-4, 5- dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000256_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
11. A compound according to claim 1 , by the name of 3- r4-(2-(4-Carboxy-phenyl)-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl) -vinyl] -phenylj- 1 H-imidazol-4-yl) -phenyl] - 4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000256_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
12. A compound according to claim 1, by the name of 3- [4-(2-(4-Diethylamino-2-hydroxy-phenyl)-5-[4-[(E)-2-(3- phenyl-propylcarbamoyl)-vinyl]-phenyl|-lH-imidazol-4-yl)- phenyl]-4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000257_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
13. A compound according to claim 1, by the name of 3- {4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(2- hydroxy-phenyl) - 1 H-imidazol-4-yl] -phenylj-4 , 5-dihydro- isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000257_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
14. A compound according to claim 1, by the name of 3- (4-|5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl1- lH- imidazol-4-yl|-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000258_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
15. A compound according to claim 1, by the name 3-(4- {5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl1-2-[4-((E)-2- ethoxycarbonyl- vinyl) -phenyl] - 1 H- imidazol-4-yl}-phenyl) - 4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester having the following structural formula:
Figure imgf000258_0002
And the corresponding pharmaceutically acceptable salts thereof.
16. A compound according to claim 1, by the name of 3- (4-{5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyl1-2-[4-((E)-2- ethoxycarbonyl-vinyl) -phenyl] - 1 ff-imidazol-4-yl|-phenyl) - 4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000259_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
17. A compound according to claim 1, by the name of 3- (4-(2-(2,4-Dioxo-l ,2,3,4-tetrahvdro-pyrimidin-5-yl)-5-[4- ( (E) -2 -dodecylcarbamoyl-vinyl) -phenyl] - 1 fjr-imidazol-4-yl|- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000259_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
18. A compound according to claim 1, by the name of 3^ {4-f2-(4-Diethylamino-phenyl)-5-(4-{(E)-2-[2-(lH-indol-3-yl)- ethylcarbamoyl] -vinyl}-phenyl) - 1 H-imidazol-4-yl] -phenyl}- 4,5-dibydro-isoxazole-5-carboxylic acid methyl ester having the following structural formula:
Figure imgf000260_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
19. A compound according to claim 1, by the name of 3- (4-[2-(4-Diethylamino-phenyl)-5-(4-{(E)-2-f2-(lH-indol-3-yl)- ethylcarbamoyl] -vinyl}-phenyl) - 1 H"-imidazol-4-yl] -phenyl}- 4 ,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000261_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
20. A compound according to claim 1, by the name of 3^ [4-(2-(4-Diethylamino-2-hvdroxy-phenyl)-5-{4-[(E)-2-(N- phenyl-hydrazinocarbonyl)-vinyl]-phenyl}- li:jr-imidazol-4-yl)- phenyl]-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000261_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
21. A compound according to claim 1 , by the name of 3^ {4- 2-(4-Diethylamino-2-hydroxy-phenyl)-5-(4-{(E)-2-[2-(4- fluoro-phenyl)-ethylcarbamoyl]-vinyl}-phenyl)-lH"-imidazol- 4-yl1-phenyl}-4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000262_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
22. A compound according to claim 1, by the name of 3^ {4-[5-(4-{(E)-2-[2-(4-Fluoro-phenyl)-ethylcarbamoyl]-vinyl}- phenyl) -2- (4-pyrrolidin- 1 -yl-phenyl) - 1 H-imidazol-4-yl] - phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester having the following structural formula:
Figure imgf000262_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
23. A compound according to claim 1, by the name of 3- {4-f5-f4-{(E)-2-r2-(4-Fluoro-ρhenyl)-ethylcarbamoyll-vinyl}- phenyl)-2-(4-pyrrolidin- 1 -yl-phenyl)- 1 Jf~imidazol-4-yl]- phenyl}-4, 5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000263_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
24. A compound according to claim 1, by the name of 3- {4-[2-(4-Hexadecylcarbamoyl-ρhenyl)-5-(4-((E)-2- [(tetrahydro-furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)- lH-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid tert-butyl ester having the following structural formula:
Figure imgf000263_0002
And the corresponding pharmaceutically acceptable salts thereof.
25. A compound according to claim 1, by the name of 3-
|4-f2-(4-Hexadecylcarbamoyl-ρhenyl)-5-(4-{(E)-2-
[(tetrahydro-furan-2-ylmethyl) -carbamoyl] -vinyl}-phenyl) - lJ-r-imidazol-4-yl]-phenyl}-4,5-dihydro-isoxazole-5- carboxylic acid having the following structural formula:
Figure imgf000264_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
26. A compound according to claim 1, by the name of 3- {4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4-{(E)-2-[(tetrahvdro- furan-2-ylmethyl)-carbamoyl]-vinyl}-phenyl)-l.H"-imidazol-4- yl1-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester having the following structural formula:
Figure imgf000265_0001
And the corresponding pharmaceutically acceptable salts thereof.
27. A compound according to claim 1, by the name of 3^ |4-[2-(4-Dodecylcarbamoyl-phenyl)-5-(4-|(E)-2-f(tetrahvdro- furan-2-ylmethyl) -carbamoyl] -vinyl}-phenyl) - 1 Jjr-imidazol-4- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000265_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
28. A compound according to claim 1, by the name of [4- (2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-{4- (E)-2-(l- methyl-dodecylcarbamoyl)-vinyl]~phenyl}-lff-imidazol-4-yl)- phenoxy] -acetic acid having the following structural formula:
Figure imgf000266_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
29. A compound according to claim 1, by the name of (4- (5-(4- [(E) -2- (3 ,3-Diphenyl-propylcarbamoyl) -vinyl] -phenyl}- 2 - [4- ((E) -2 -ethoxycarbonyl-vinyl) -phenyl] - 1.Ff-imidazol-4-yl phenoxy) -acetic acid tert-butyl ester having the following structural formula:
Figure imgf000266_0002
And the corresponding pharmaceutically acceptable salts thereof.
30. A compound according to claim 1, by the name of (4- {5-{4-[(E)-2-(3,3-Diphenyl-propylcarbamoyl)-vinvn-phenyl}- 2-[4-((E)-2-ethoxycarbonyl-vinyl)-phenyl]-lJ[ -imidazol-4-yl}- phenoxy) -acetic acid having the following structural formula:
Figure imgf000267_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
31. A compound according to claim 1, by the name of (4- 15-14- [(E) -2- (3H-Benzotriazol-5-ylcarbamoyl) -vinyl] -phenyl}- 2 - [4- ( (E) -2-ethoxycarbonyl-vinyl) -phenyl] - 1 ff-imidazol-4-yl}- phenoxy) -acetic acid having the following structural formula:
Figure imgf000268_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
32. A compound according to claim 1, by the name of 4_ [2-f4-f(E)-2-Ethoxycarbonyl-vinyl)-phenyn-5-(4-{(E)-2-[l-(4- pentyl-phenyl) -ethylcarbamoyl] -vinyl}-phenyl) - 1 J-f-imidazol 4-yl]-phenoxy}-acetic acid having the following structural formula:
Figure imgf000268_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
33. A compound according to claim 1, by the name of [4- (2- 4-((E)-2-Ethoxycarbonyl-vinyl)-ρhenyll-5-{4-[(E)-2-(2- methoxy-ethylcarbamoyl) -vinyl] -phenyl}- 1 J-imidazol-4-yl) - phenoxyl-acetic acid having the following structural formula:
Figure imgf000269_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
34. A compound according to claim 1, by the name of [4- (2-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenyll-5-(4-[(E)-2- (2.2,3, 3,4,4, 5, 5,6.6,7,7,8, 8,8-pentadecafluoro- octylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-4-yl) -phenoxy] - acetic acid having the following structural formula:
Figure imgf000269_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
35. A compound according to claim 1, by the name of (E)- 3-(4-(4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dihexylcarbamoyl-vinyl) -phenyl] - 1 H-imidazol-2-yl}-phenyl) - acrylic acid ethyl ester having the following structural formula:
Figure imgf000270_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
36. A compound according to claim 1, by the name of 3^ [4-(4-(4-tert-Butoxycarbonylmethoxy-phenyl)-5-(4-[(E)-2-(l- methyl-dodecylcarbamovD-vinyl] -phenyl}- 1 H-imidazol-2-yl) - phenyl] -4, 5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester having the following structural formula:
Figure imgf000270_0002
And the corresponding pharmaceutically acceptable salts thereof.
37. A compound according to claim 1, by the name of 3- [4-(4-(4-Carboxymethoxy-phenyl)-5-(4-[(E)-2-(l-methyl- dodecylcarbamoyl)-vinyl]-phenyl}-lff-imidazol-2-yl)-phenyn- 4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000271_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
38. A compound according to claim 1, by the name of 3- 14- [4- (4- tert-Butoxycarbonylmethoxy-phenyl) -5-(4-{(E) -2- [ 1 - (4-pentyl- phenyl) -ethylcarbamoyl] -vinyl}-phenyl) - 1 H- imidazol-2-yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert-butyl ester having the following structural formula:
Figure imgf000272_0001
And the corresponding pharmaceutically acceptable salts thereof.
39. A compound according to claim 1, by the name of 3^ {4-[4-(4-Carboxymethoxy-phenyl)-5-(4-{(E)-2-[l-(4-ρentyl- phenyl)-ethylcarbamoyn-vinyl}-phenyl)-lJf-imidazol-2-yn- phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000272_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
40. A compound according to claim 1, by the name of 3^
(4-(4-(4-carboxymethoxy-phenyl)-5-[4-((E)-2- dihexylcarbamoyl-vinyl) -phenyl] - 1 Jf-imidazol-2 -vU-phenyl) -
4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000273_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
41. A compound according to claim 1 , by the name of 3- [4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)-2-(2-nonyloxy- ethylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-2 -yl) -phenyl] - 4 ,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000274_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
42. A compound according to claim 1, by the name of 3^ (4-{5-(4-tert-Butoxycarbonylmethoxy-phenyl)-4-[4-((E)-2- dodecylcarbamoyl- vinyl) -phenyl] - 1 -methyl- 1 ff-imidazol-2 - yl}-phenyl)-4,5-dihvdro-isoxazole-5-carboxylic acid tert- butyl ester having the following structural formula:
Figure imgf000274_0002
And the corresponding pharmaceutically acceptable salts thereof.
43. A compound according to claim 1, by the name of 3- (4-{5-(4-Carboxymethoxy-ρhenyl)-4-[4-((E)-2- dodecylcarbamoyl- vinyl) -phenyl]- 1-methyl- lff-imidazol-2- yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000275_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
44. A compound according to claim 1, by the name of 3; (4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-ρhenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)- 1-methyl- lH-imidazol-2- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid tert- butyl ester having the following structural formula:
Figure imgf000276_0001
And the corresponding pharmaceutically acceptable salts thereof.
45. A compound according to claim 1, by the name of 3^ {4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyll-4-(4- ethoxycarbonylmethoxy- phenyl)- 1-methyl- lH-imidazol-2- yl]-phenyl}-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000276_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
46. A compound according to claim 1, by the name of 3^ (4-{4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl-vinyl)-phenyl]- 1-methyl- lH-imidazol-2- yl}-phenyl) -4 , 5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000277_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
47. A compound according to claim 1, by the name of [5- [4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-(4- ethoxycarbonylmethoxy-phenyl)-imidazol- l-yl]-acetic acid tert-butyl ester having the following structural formula:
Figure imgf000277_0002
And the corresponding pharmaceutically acceptable salts thereof.
48. A compound according to claim 1, by the name of |5 [4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-f4- ethoxycarbonylmethoxy-phenyl) -imidazol- 1 -yl] -acetic acid having the following structural formula:
Figure imgf000278_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
49. A compound according to claim 1, by the name of {4- (4-Carboxymethoxy-phenyl)-5-[4-((E)-2-dodecylcarbamoyl- vinyl) -phenyl] -imidazol- 1 -yl}- acetic acid having the following structural formula:
Figure imgf000278_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
50. A compound according to claim 1, by the name of 3^ (4-(4-(4-Carboxymethoxy-phenyl)-5-[4-((E)-2- dodecylcarbamoyl -vinyl) -phenyl] - 1 H-imidazol-2 -yl}- phenyl) - 4 ,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000279_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
51. A compound according to claim 1 , by the name of (4- {5- [4- ((E) -2-Dodecylcarbamoyl-vinyl) -phenyl] -2-pyridin-3-yl- lH-imidazol-4-yl}-phenoxy)-acetic acid tert-butyl ester having the following structural formula:
Figure imgf000279_0002
And the corresponding pharmaceutically acceptable salts thereof.
52. A compound according to claim 1, by the name of (4- {5- 4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-pyridin-3-yl- lj J"-imidazol-4-yl}-phenoxy) -acetic acid having the following structural formula:
Figure imgf000280_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
53. A compound according to claim 1, by the name of 3^ (4-{2-(4-Diethylamino-phenyl)-5-[4-((E)-2-dodecylcarbamoyl- vinyl) -phenyl] - 1 H-imidazol-4-yl}-phenyl) -4 , 5-dihydro- isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000280_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
54. A compound according to claim 1, by the name of 3; {4-[5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-2-(4- pyrrolidin- 1-yl-phenyl)- lff-imidazol-4-yl]-phenyl}-4,5- dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000281_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
55. A compound according to claim 1, by the name of 3- [4-(2-[4-((E)-2-Carboxy-vinyl)-phenvn-5-{4-[(E)-2-(3-phenyl- propylcarbamoyl) -vinyl] -phenyl}- 1 H-imidazol-4-yl) -phenyl] - 4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000281_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
56. A compound according to claim 1, by the name of (4- {2-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-f4-((E)-2- dodecylcarbamoyl- vinyl) -phenyl] - 1 H-imidazol-4-yl}- phenoxy) -acetic acid having the following structural formula:
Figure imgf000282_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
57. A compound according to claim 1, by the name of (4_ (5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]-2-[4-((E)-2- ethoxycarbonyl-vinyl) -phenyl] - 1. f-imidazol-4-yl}-phenoxy) - acetic acid having the following structural formula:
Figure imgf000283_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
58. A compound according to claim 1, by the name of 3^ [4-(4-(4-Carboxymethoxy-phenyl)-5-{4-[(E)-2-(hexadecyl- methyl-carbamoyl)-vinyl]-phenyl}-lH-imidazol-2-yl)-phenyl]- 4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
And the corresponding pharmaceutically acceptable salts and esters thereof.
59. A compound according to claim 1, by the name of 3- (4-|4-(4-Carboxymethoxy-phenyl)-5-[4-(2- hexadecylcarbamoyl-cyclopropyl)-phenyl]-l-cJ-imidazol-2-yl}- phenyl)-4 ,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000284_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
60. A compound according to claim 2, by the name of (E)- 3-(4-f4-f4-((E)-2-Carboxy-vinyl)-phenyl]-5-(4- dodecylcarbamoyl-phenyl)-lj J'-imidazol-2-yl1-phenyl}-acrylic acid having the following structural formula:
Figure imgf000284_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
61 i A compound according to claim 1, by the name of 3- (4-[5-f4-((E)-2-Dodecylcarbamoyl-vinyl)-phenvn-2-(2,3,4- trimethoxy-phenyl)- 1 fJ"-imidazol-4-yl] -phenyl}-4 , 5-dihydro- isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000285_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
62. A compound according to claim 2, by the name of (E)- 3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]-li:f- imidazol-4-yl}-phenyl)-acrylic acid having the following structural formula:
Figure imgf000285_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
63. A compound according to claim 1, by the name of 3^ (4-(5- [4-(2-Hexadecylcarbamoyl-ethyl) -phenyl] - 1 H-imidazol- 4-yl}-phenyl)-propionic acid having the following structural formula:
Figure imgf000286_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
64. A compound according to claim 2, by the name of (E)- 3-(4-|5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl1-lH- imidazol-4-yl}-phenyl) -acrylic acid having the following structural formula:
Figure imgf000286_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
65. A compound according to claim 1, by the name of 3- (4-{4-[4-((E)-2-Carboxy-vinyl)~phenyl]-5-[4-(2- hexadecylcarbamoyl-vinyl)-phenyl]- 1 iϊ-imidazol-2-yl}- phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000287_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
66. A compound according to claim 2, by the name of (E)- 3-(4-(2-[4-((E)-2-Carboxy-vinyl)-phenyl]-5- 4-(2- hexadecylcarbamoyl-vinyl) -phenyl] - 1 H-imidazol-4-yl}- phenyl) -acrylic acid having the following structural formula:
Figure imgf000287_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
67. A compound according to claim 2, by the name of (E)- 3-(4-{2-r4-((E)-2-Ethoxycarbonyl-vinyl -phenyll-5-[4-(2- hexadecylcarbamoyl- vinyl) -phenyl] - 1 fJ-imidazol-4-yl}- phenyl) -acrylic acid having the following structural formula:
Figure imgf000288_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
68. A compound according to claim 1, by the name of 3- (4-{4~[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- dodecylcarbamoyl-vinyl) -phenyl]- 1 H-imidazol-2-yl}-phenyl) - 4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000288_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
69. A compound according to claim 1, by the name of 3- (4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-r4-(2- dodecylcarbamoyl-vinyl) -phenyl] - 1 H"-imidazol-2-yl}-phenyl) - isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000289_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
70. A compound according to claim 1, by the name of 3 (4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-f4-(2- hexadecylcarbamoyl-vinyl)-phenyl]~ lH-imidazol-2-yl}~ phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester having the following structural formula:
Figure imgf000289_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
71. A compound according to claim 1 , by the name of 3^ (4-{4-[4-((E)-2-Carboxy-vinyl)-ρhenyll-5-[4-(2- hexadecylcarbamoyl-vinyl) -phenyl] - 1 JJ-imidazol-2-yl}- phenyl)-isoxazole-5-carboxylic acid ethyl ester having the following structural formula:
Figure imgf000290_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
72. A compound according to claim 1, by the name of 3^ (4-{4-[4-((E)-2-Carboxy-vinyl)-phenyl]-5-[4-(2- hexadecylcarbamoyl -vinyl) -phenyl] - 1 if-imidazol-2 -yl}- phenyl) -isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000291_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
73. A compound according to claim 1, by the name of 3-
[4-f4-[4-((E)-2-Carboxy-vinyl)-phenyll-5-{4-[2-(4-heptyl- phenylcarbamoyl) -vinyl] -phenyl}- 1 H-imiάazol-2 -yl) -phenyl] -
4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000291_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
74. A compound according to claim 1, by the name of 3- (4-{4-[4-((E)-2-Carboxy-vinyl)-phenvπ-5-[4-(2- dihexylcarbamoyl- vinyl) -phenyl] - 1 H-imidazol-2-yl}-phenyl) - 4,5-dihydro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000292_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
75. A compound according to claim 2, by the name of (E)- 3-[4-(5-(4-[(E)-2-(4-Heptyl-phenylcarbamoyl)-vinyll-phenyl}- lfJ-imidazol-4-yl)-phenyl]-acrylic acid having the following structural formula:
Figure imgf000292_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
76. A compound according to claim 2, by the name of (E)- 3-(4-{5-[4-((E)-2-Dihexylcarbamoyl-vinyl)-ρhenyl1-lH- imidazol-4-yl}-phenyl)-acrylic acid having the following structural formula:
Figure imgf000293_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
77. A compound according to claim 1, by the name of 3- [3-(4-{5-[4-((E)-2-Hexadecylcarbamoyl-vinyl)-phenyl]-lff- imidazol-4-yl}-phenyl)-allanoylamino]-propionic acid having the following structural formula:
Figure imgf000294_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
78. A compound according to claim 1, by the name of 3- [4-(5-Benzylcarbamoyl- l-hexadecyl-4-phenyl- lH-imidazol- 2-yl)-phenyl]-4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula: .;•
Figure imgf000294_0002
And the corresponding pharmaceutically acceptable salts and esters thereof.
79. A compound according to claim 1, by the name of 3- (4-{4-[4-(Carboxymethyl-carbamoyl)-phenyl]-5-decyl-li:f- imidazol-2-yl}-phenyl)-4,5-dihvdro-isoxazole-5-carboxylic acid having the following structural formula:
Figure imgf000295_0001
And the corresponding pharmaceutically acceptable salts thereof.
80. A compound according to claim 1, having the following structural formula:
Figure imgf000295_0002
And the corresponding pharmaceutically acceptable salts thereof.
81. A compound according to claim 1, having the following structural formula:
Figure imgf000296_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
82. A compound according to claim 2, by the name of (E)- 3-(4-j5-[4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl1-4-[4-(2- hydroxy- 1 -hydroxymethyl-ethylcarbamoyl) -phenyl] -1H- imidazol-2-yl}-phenyl)-acrylic acid tert-butyl ester having the following structural formula:
Figure imgf000296_0002
And the corresponding pharmaceutically acceptable salts thereof.
83. A compound according to claim 2, by the name of (E)- 3-(4-(5-r4-((E)-2-Dodecylcarbamoyl-vinyl)-phenyl]-4-[4-(2- hydroxy- 1 -hydroxymethyl-ethylcarbamoyl) -phenyl] - 1 H- imidazol-2-yl}-phenyl)~acrylic acid having the following structural formula:
Figure imgf000297_0001
And the corresponding pharmaceutically acceptable salts and esters thereof.
84. A method for treating human diseases involving P-, L- and E-selectin in a subject, which comprises the administration of an effective therapeutic amount of a compound selected from those defined in Claims 1-6, 43, 45, 50, 62, 65, 69-77 or the pharmaceutically acceptable salts and esters thereof.
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US7282500B2 (en) 2001-05-19 2007-10-16 Smithkline Beecham P.L.C. Imidazole-2-carboxamide derivatives as Raf kinase inhibitors

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