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WO2017134146A1 - Gpbp inhibitors and uses and scaleable synthesis thereof - Google Patents

Gpbp inhibitors and uses and scaleable synthesis thereof Download PDF

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Publication number
WO2017134146A1
WO2017134146A1 PCT/EP2017/052220 EP2017052220W WO2017134146A1 WO 2017134146 A1 WO2017134146 A1 WO 2017134146A1 EP 2017052220 W EP2017052220 W EP 2017052220W WO 2017134146 A1 WO2017134146 A1 WO 2017134146A1
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alkyl
alkoxy
compound
halo
hydroxy
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WO2017134146A9 (en
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Juan Saus
Raul Blasco
Francisco Revert-Ros
Fernando Revert
Nuria Roda
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FibroStatin SL
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FibroStatin SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/74—Unsaturated compounds containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

Definitions

  • the present disclosure relates to GPBP inhibitors, uses thereof, and a scaleable synthesis thereof.
  • NCI non-collagenous domain of the a3 chain of the basement membrane collagen IV
  • GPBP Goodpasture antigen-binding protein
  • GPBP is a non-conventional protein kinase that catalyzes the conformational isomerization of the a3NC 1 domain during its supramolecular assembly, resulting in the production and stabilization of multiple a3NCl conformers in basement membranes. Elevated levels of GPBP have been associated with the production of non-tolerized a3NCl conformers, which conduct the autoimmune response mediating Goodpasture (GP) disease.
  • autoantibodies against the a3NCl also known as GP antigen
  • GN rapidly progressive glomerulonephritis
  • lung hemorrhage the two cardinal clinical manifestations of the GP disease.
  • GPBP regulates inflammation, apoptosis and protein folding, and that increased GPBP expression induces antibody-mediated glomerulonephritis (IgA nephropathy, systemic lupus erythematosus and Goodpasture autoimmune syndrome) and resistance of cancer cells to a number of chemotherapeutic agents including those inducing protein misfolding- mediated endoplasmic reticulum (ER) stress (e.g. paclitaxel).
  • ER endoplasmic reticulum
  • inhibitors of GPBP are useful for the treatment of antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis.
  • GPBP inhibitors have also been shown to be effective in treating and/or limiting the development of type 2 diabetes (WO 2015/044352).
  • GPBP also known as GPBP-1 or 77 kD GPBP
  • GPBP-2 also known as GPBPA26 or CERT
  • GPBP-3 also known as 91 kD GPBP
  • Elevated GPBP expression and secretion have been also associated with collagen IV expansion in immune complex-mediated glomerulonephritis (Revert et al. 2007, Am J Path. 171, 1419-30.).
  • GPBP yields trimeric and multimeric aggregates, the latter displaying increased specific activity (WO 00/50607).
  • EMT epithelial-mesenchymal transition
  • E-cadherin expression supports cell-cell attachment in epithelial phenotype and vimentin expression renders cells prone to cell-cell detachment and migration in mesenchymal phenotype.
  • Collagen IV is a primary component of the extracellular matrix that interacts with cancer stem cells (CSCs) forming a protective shield against conventional antitumor therapies (Ye J et al, 2014, Tumour Biol. 35, 3945-51; Su C et al. ,2007, Cancer Invest. 2, 542-9).
  • the invention provides a compound of Formula I: rmaceutically acceptable salt thereof, wherein
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C 6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6 alkyl)sulfanyl(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)NH 2 , (aryl)C 2 -C
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
  • R 2 is cyano, hydroxyl(Ci-C6 alkyl), or formyl
  • R 3 is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C 6 alkyl), -C(0)OH, -(CH 2 )i-5-C(0)OH, -C(0)(G-C 6 alkoxy),
  • R 4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
  • -CH CH-C(0)(Ci-C 6 alkoxy), -0(CH 2 )i- 5 -C(0)OH, -0(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), (aryl)Ci C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
  • the compounds of the invention have the formula:
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C 6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6
  • alkyl sulfanyl(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), and -(CH 2 )i-5-C(0)NH 2 ;
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
  • R 3 is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C 6 alkyl), -C(0)OH, -(CH 2 )i-5-C(0)OH, -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)(Ci-C 6 alkoxy), -C(0)NH 2 , -(CH 2 )i-5-C(0)NH 2 , -C(0)NH(Ci-C 6 alkyl), -(CH 2 )i-5-C(0)NH(Ci-C 6
  • R 4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
  • the compound of the invention may have the formula
  • R 1 , R 3 , R 4 , and R 5 are as defined above.
  • the compounds of the invention may be coupled to a detectable label.
  • compositions comprising the compounds of the invention and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
  • the invention comprises the compounds or the pharmaceutical compositions of the invention for use as a medicament.
  • Further embodiments include the compounds or pharmaceutical compositions of the invention for use in the treatment of various diseases and disorders, including antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis and type 2 diabetes, as well as methods of treating the aforementioned diseases and disorders by administration of the compounds or the pharmaceutical compositions of the invention.
  • diseases and disorders including antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated
  • the invention provides for the compounds or the pharmaceutical compositions of the invention for use in inhibiting mesenchymal phenotype after epithelial-to- mesenchymal transition (EMT), as well as methods for inhibiting mesenchymal phenotype after EMT, by administration of the compounds or the pharmaceutical compositions of the invention.
  • EMT epithelial-to- mesenchymal transition
  • the inhibition of mesenchymal phenotype after EMT may comprise treating a subject with chronic kidney disease, immune-complex mediated glomerulonephritis, organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, type 2 diabetes, or an invasive tumor.
  • the subject has an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition.
  • the cell markers include but are not limited to one or more of vimentin, E-cadherin, collagens I and IV, matrix metalloproteinase 9 (MMP-9), chemokine (C-C motif) ligand 2 (CCL2), also referred to as monocyte chemotactic protein 1 (MCP-1), ⁇ 5 (IV) chain, (a5 (IV) ) 3 protomer, and Goodpasture antigen binding protein (GPBP).
  • MMP-9 matrix metalloproteinase 9
  • CCL2 chemokine (C-C motif) ligand 2
  • MCP-1 monocyte chemotactic protein 1
  • GPBP Goodpasture antigen binding protein
  • the subject has an increase in vimentin expression and a decrease in E-cadherin expression in a relevant tissue
  • the subject has an increased expression of ⁇ 5( ⁇ ) chain, and/or (a5 (IV)) 3 protomer in a relevant tissue sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
  • the subject has an increased expression of ( ⁇ 1) 2 2 (IV) protomer and/or an increased expression ⁇ 1, ⁇ 2 (IV) chains in a relevant tissu sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
  • the invasive tumor is a invasive carcinoma, including but not limited to invasive breast tumors and invasive lung tumors.
  • treating the invasive tumor reduces tumor metastases in the subject.
  • the compounds or the pharmaceutical compositions ol the invention are used as a mono-therapeutic. In other embodiments, they are administered in combination with one or more other therapeutics.
  • the compounds or the pharmaceutical compositions of the invention may be administered to a mammal or a bird.
  • the invention provides methods for detecting EMT in a tissue, comprising contacting tissue from a subject with an amount effective to label the tissue with a detectably labeled compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical compositioi comprising a detectably labeled compound of the invention, for a time and under conditions suitable to promote binding of the detectably labeled compound to the tissue, and then detecting the detectably labeled compound bound to the tissue, thereby detecting EMT in the tissue.
  • the tissue may be selected from the group consisting of a tumor, a joint, and tissue from any organ.
  • the tissue is a kidney, and detecting EMT in the kidney indicates that the subject has chronic kidney disease or immune-complex mediated glomerulonephritis.
  • the tissue is tissue from any organ, and detecting EMT indicates that the subject has organ fibrosis.
  • the tissue is a lung, and detecting EMT in the lung indicates that the subject has pulmonary fibrosis.
  • the tissue is a joint, and detecting EMT indicates that the subject has rheumatoid arthritis.
  • the tissue is a tumor, and detecting EMT indicates that the subject has an invasive tumor.
  • the tumor may be an invasive carcinoma, including but not limited to invasive breast tumors and invasive lung tumors.
  • the invention comprises a method of preparing a compound of Formula II:
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci- C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6 alkyl) sulfanyl(Ci-C 6 alkyl) sulfanyl(Ci-C 6
  • R is hydrogen, halogen, cyano, hydroxy, Ci-C 6 alkyl, halo(Ci-C6 alkyl), C1- 6 alkoxy, halo(Ci-C6
  • R 2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-
  • C 6 alkoxy)Ci-C 6 alkyl formyl(Co-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6 alkyl)sulfanyl(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)OH, -(CH 2 )i_ 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i_
  • R 3 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-
  • C 6 alkoxy)Ci-C 6 alkyl formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6 alkyl)sulfanyl(Ci-C 6 alkyl), -(CH 2 )i_ 5 -C(0)OH, -(CH 2 )i_ 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i_
  • R 4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy),
  • M is a monovalent cation
  • X I is leaving group
  • R 3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl),
  • R is CH
  • R 1 is Ci-C 6 alkyl
  • R 2 is Ci-Ce alkyl.
  • R A -CH CH-C(0)(Ci-C 6 alkoxy)
  • R 4 is Ci-Ce alkoxy
  • X is fluoro
  • M is K +
  • X 1 is bromo.
  • the compound is of one of the following formulas:
  • Figures 1A and IB show the competition of binding of biotinylated T12 to A427 cells with compounds c the disclosure.
  • FIG. 2 shows T12 and T109 reduce tumor growth in BALBc mice inoculated with 4T1 cells.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C 6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6
  • alkyl sulfanyl(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)NH 2 , (aryl)C 2 -C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
  • R 2 is cyano, hydroxyl(Ci-C6 alkyl), or formyl
  • R 3 is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C 6 alkyl), -C(0)OH, -(CH 2 )i-5-C(0)OH, -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)(Ci-C 6 alkoxy), -C(0)NH 2 , -(CH 2 )i-5-C(0)NH 2 , -C(0)NH(Ci-C 6 alkyl), -(CH 2 )i-5-C(0)NH(Ci-C 6
  • R 4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
  • the compounds of the invention are new GPBP inhibitors with improved therapeutic profiles relative to prior GPBP inhibitors (e.g. T12, a terphenyl shown previously to be active against
  • GPBP inhibitors of the invention have improved performance in water solubility, lower epithelial toxicity, and/or synergy with doxorubicin.
  • a "GPBP inhibitor” refers to any compound or molecule that reduces the activity or the expression of all or individual GPBP isoforms.
  • the GPBP inhibitors of the invention compromise cell viability after epithelial-to-mesenchymal transition to a much greater extent than they affect epithelial cell viability, and inhibit growth and metastasis of invasive tumors (i.e.: those having predominant mesenchymal phenotype) to a much greater extent than they effect the growth of tumors having predominant epithelial phenotype.
  • the methods of the invention can be used, for example, to treat invasive tumors as well as disorders mediated by organ fibrosis.
  • GPBP refers to any polypeptide isoform (such as GPBP-1, -2 and -3 a derived polypeptides) expressed from COL4A3BP gene.
  • GPBP-1 inhibitor means any compound that reduces the expression or activity (such as the kinase activity) of GPBP- 1 and which may or may not reduce the expression or activity (such as the kinase activity) of other GPBP isoforms.
  • GPBP-1 is a nonconventional Ser/Thr kinase displaying autophosphorylation activity that bind and phosphorylates the a3NCl domain (Raya et al.1999 and 2000). GPBP-1 forms large multimeric aggregates whose specific kinase activity is much higher than that of aggregates of lower molecular weight (Raya et al. 2000).
  • the compound has the formula
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-
  • C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), amino, (C1-G5 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C 6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C 6 alkyl) sulfanyl(Ci-C 6 alkyl);
  • R 3 is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C 6 alkyl), -C(0)OH, -(CH 2 )i-5-C(0)OH, -C(0)(Ci-C 6 alkoxy),
  • R 4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C 6 alkoxy);
  • R 3 is Ci
  • R is selected fror N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
  • R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy);
  • R 3 is selected fror N and CR 5
  • the compound of Formula I or embodiments thereof has the formula:
  • R is hydrogen
  • R 3 is -(CH 2 )i- 2 -C(0)OH or -(CH 2 )i_ 2 -C(0)(Ci-C 6 alkoxy).
  • R 3 is
  • R 4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
  • R 4 is hydroxy or C1-C6 alkoxy.
  • R 5 if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
  • R 5 if present, is C1-C6 alkyl or halo(Ci-C6 alkyl).
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R 3 is -C(0)OH, -
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R 3 is -(CH 2
  • R 1 is hydrogen;
  • R 3 is -(CH 2 )i_ 2 -C(0)OH, -(CH 2 )i_ 2 -C(0)(Ci-C 6 alkoxy), or -(CH 2 )i_ 2 -C(0)NH 2 ;
  • R 4 is hydroxy or C1-C6 alkoxy;
  • R 5 if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
  • R 1 is hydrogen;
  • R 3 is -(CH 2 )i_ 2 -C(0)OH; and
  • R 4 is Ci-C 6 alkoxy.
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
  • R 1 is hydrogen;
  • R 4 is Ci-C 6 alkoxy.
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy);
  • R 1 is hydrogen;
  • R 4 is Ci-C 6 alkoxy.
  • the compound is:
  • the GPBP inhibitor may be
  • the compounds of the invention include pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, including but not limited to carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limitationc to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
  • esters of the compounds of this invention include C1-C6 alkyl esters, wherein the alkyl group is straight or branched, substituted or unsubstituted, and C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl and triphenylmethyl.
  • C1-C4 alkyl esters are preferred, such as methyl, ethyl, 2,2,2-trichloroethyl, and tert-butyl esters.
  • Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines, wherein the alkyl groups are straight or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • prodrugs are provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
  • the compound of Formula I or any embodiments thereof may be coupled to a detectable label.
  • Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials.
  • suitable enzymes include horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, or acetylcholinesterase.
  • suitable prosthetic-group complexes include streptavidin/biotin and avidin/biotin.
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin.
  • An example of a luminescent material includes luminol.
  • suitable radioactive material include 125 I, 13 35 S or 3 H.
  • the detectable label is biotin or fluorescein.
  • a third aspect of the invention provides pharmaceutical compositions comprising the compounds disclosed herein and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
  • the carrier is biotin.
  • the biotin is D-biotin.
  • compositions are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compositions may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • compositions of this invention may be provided in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and mode: of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delaj material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the compounds of the invention may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • compositions of the invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic
  • parenteral includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the compositions include one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired othei active ingredients.
  • compositions containing compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known in the art foi the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques.
  • such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action ove a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate,
  • dispersing or wetting agents may be a naturally- occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • phosphatide for example, lecithin
  • condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectablt aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable 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
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions of the present invention may also be prepared in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • compositions of the present invention may be administered parenterally in a sterilt medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • a fourth aspect of the invention is directed to compounds of the invention, or pharmaceutical compositions thereof, for use as a medicament.
  • the compounds of the invention, or pharmaceutical compositions thereof may also be used in medical methods, including methods of treating subjects with one or more diseases or disorders in need of treatment for those diseases or disorders. Unless otherwise noted, the methods of administration and/or treatment disclosed herein are to be understood to include both methods of treatment and the corresponding medical uses.
  • the invention provides a method for treating antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis or type 2 diabetes, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.
  • ER endoplasmic reticulum
  • GN immune-complex mediated glomerulonephritis
  • organ fibrosis pulmonary fibrosis
  • rheumatoid arthritis type 2 diabetes
  • the invention provides a method for inhibiting mesenchymal phenotype after epithelial-to-mesenchymal transition (EMT), comprising administering to a subject in need thereof an amount effective to inhibit mesenchymal phenotype after EMT of a compound disclosed herein or a pharmaceutical composition thereof.
  • EMT epithelial-to-mesenchymal transition
  • EMT epithelial cells undergo trans-differentiation towards a phenotype with an enhanced migratory capacity and invasiveness, high resistance to apoptosis and an outstanding capacity t( synthesize extracellular matrix (see for review Kalluri et al. , 2009, J. Clin. Invest. 119: 1420-8).
  • EMTs have been recognized in embryo implantation and development (type 1); tissue repair and organ fibrosis (type 2); or cancer malignancy and metastasis formation (type 3)
  • type 1 embryo implantation and development
  • type 2 tissue repair and organ fibrosis
  • type 3 cancer malignancy and metastasis formation
  • the subject may be one that has or is suspected of having any disorder characterized by EMT, including but not limited to chronic kidney disease, immune-comple: mediated glomerulonephritis, organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor, and type 2 diabetes.
  • EMT chronic kidney disease
  • immune-comple mediated glomerulonephritis
  • organ fibrosis fibrosis
  • pulmonary fibrosis pulmonary fibrosis
  • rheumatoid arthritis an invasive tumor
  • type 2 diabetes type 2 diabetes
  • the invention provides a method for treating an invasive tumor, comprising administering to a subject in need thereof an effective amount of a compound disclosed hereii or a pharmaceutical composition thereof.
  • the invasive tumor is an invasive carcinoma, including but not limited to ai invasive breast tumor or an invasive lung tumor.
  • treating the invasive tumor reduces tumor metastases in the subject.
  • treat or “treating” with regard to tumors means accomplishing one or more of the following: (a) reducing tumor size; (b) reducing tumor growth; (c) reducing or limiting development and/or spreading of metastases; (d) reducing the amount of antitumor drug required to maintain therapeutic objective for subject receiving treatment; (e) reducing circulating cancer cells; and (f) depleting CSC in the tumor.
  • treating the tumor comprises depleting CSC in the tumor.
  • GPBP inhibitors can reduce viability of CSC in tumors.
  • CSC are expected to be responsible for drug resistance because they are not likely to be killed by antimitotic drugs since they divide slowly and they have abundant xenobiotic transporters, among other characteristics.
  • treating the tumor comprises reducing tumor metastasis.
  • "Inhibiting" tumor cell metastasis may comprise any amount of inhibition compared to no treatment.
  • the methods may comprise inhibiting tumor cell metastasis, by 5%, 10%, 25%, 50%; 100%, or more compared to control (such as no treatment).
  • the different active compounds can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition, such as in thi pharmaceutical compositions of the invention.
  • dosage levels of the anti-tumor drugs and compounds can be determined by those of skill in the art in light of the teachings herein as well as other clinical factors.
  • Exemplary dosage levels o the order of from about 0.01 mg to about 50 mg per kilogram of body weight per day, and more preferably between 0.1 mg to about 50 mg per kilogram of body weight per day, are generally useful in the treatment of the above-indicated conditions.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • compositions are administered in an amount sufficient to carry out the methods of the invention.
  • Amounts effective for these uses depend on factors including, but not limited to, the nature of the compound (specific activity, etc.), the route of administration, the stage and severity of the disorder, the weight and general state of health of the subject, and the judgment of the prescribing physician.
  • the active compounds are effective over a wide dosage range. However, it will be understooc that the amount of the compound actually administered will be determined by a physician, in the light of the above relevant circumstances. Therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the invention includes the compounds disclosed herein or pharmaceutical compositions thereof for use in inhibiting mesenchymal phenotype after EMT, wherein EMT has contributed to the pathogenesis of chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor and/or type 2 diabetes.
  • EMT has contributed to the pathogenesis of chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor and/or type 2 diabetes.
  • GN immune-complex mediated glomerulonephritis
  • the method for inhibiting mesenchymal phenotype after EMT comprises administering a compound disclosed herein or a pharmaceutical composition thereof to a subject who has chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor and/or type 2 diabetes.
  • GN immune-complex mediated glomerulonephritis
  • E-cadherin expression supports cell-cell attachment in epithelial phenotype and vimentin expression renders cells prone to cell-cell detachment and migration in mesenchymal phenotype.
  • Collagen IV is a primary component of the extracellular matrix that interacts with cancer stem cells (CSCs) forming a protective shield against conventional anti-tumor therapies (Ye J et ah, 2014, Tumour Biol. 35, 3945-51; Su C et ah, 007, Cancer Invest. 2, 542-9).
  • CSCs cancer stem cells
  • the subject to be treated may have an issu related to EMT based on an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition.
  • the cell markers may include but are not limited to one or more of vimentin, E-cadherin, collagens I and IV, MMP-9, CCL2 / MCP-1, ⁇ 5 (IV) chain, (a5 (IV)) 3 protomer, and Goodpasture antigen binding protein (GPBP). These markers are consistently altered (i.e.: increased (such as vimentin and collagen I and IV, a5 (IV), (a5 (IV)) 3 , MMP-9, CCL2 / MCP-1, and GPBP) or decreased (such as E-cadherin)) after EMT.
  • vimentin such as vimentin and collagen I and IV, a5 (IV), (a5 (IV)) 3 , MMP-9, CCL2 / MCP-1, and GPBP
  • E-cadherin Goodpasture antigen binding protein
  • the subject has an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition.
  • the cell markers include, but are not limited to, one or more of vimentin, E-cadherin, collagens I and IV, MMP-9, CCL2 / MCP-1, ⁇ 5 (IV) chain, (a5 (IV)) 3 protomer, and Goodpasture antigen binding protein (GPBP).
  • the subject has an increase in vimentin expression and a decrease in E- cadherin expression in a relevant tissue sample compared to a control tissue.
  • Mesenchymal phenotype expresses, along with the classical collagen IV made of al 2 chains, a collagen IV made of a5 chain.
  • the GPBP inhibitors of the invention and related compounds reduce the expression of the ⁇ 1 2 ⁇ 5 chains, which provides compelling evidence that collagen IV networks (made up of the 1 2 ⁇ 5 chains) supports mesenchymal phenotype, and is different in composition than the typical collagen IV networks which support epithelial phenotypes ( ⁇ 1 ⁇ 2, ⁇ 3 ⁇ 4 ⁇ ! and ⁇ 5 ⁇ 6).
  • mesenchymal collagen IV made of the a5 chain can be used to identify mesenchymal tumor cells: detecting ⁇ 1 , ⁇ 2, ⁇ 5 chains in a tumor in the absence of significant expression o ⁇ 3, ⁇ 4, ⁇ 6 chains will be indicative of EMT in a carcinoma; detecting a5 and no significant levels of al, a2, a3, a4, and a6 in a tumor will be indicative of sarcoma.
  • Inhibition of the mesenchymal collagen IV made of the ⁇ 1, ⁇ 2, ⁇ 5 chains using GPBP inhibitors such as those of the invention results in either death of mesenchymal or tumor cells, or reversion of the cell phenotype to epithelial (WO 2016/107906).
  • the subject has an increased expression of a5(IV) chain, and/or (a5 (IV)) 3 protomer in a relevant tissue sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
  • the subject may have an increased expression of (al) 2 2 (TV) protomer and/or an increased expression ⁇ 1, ⁇ 2 (IV) chains in a relevant tissue sample compared to ; control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
  • the compound disclosed herein or a pharmaceutical composition thereof is the only therapeutic administered to the subject.
  • the compound disclosed herein or a pharmaceutical composition is administered in combination with another therapeutic, such as an antitumor agent.
  • the GPBP inhibitors of the invention can act synergistically with anti-tumor agents to provide a more effective therapeutic option for treating tumors, and the inhibitors of Formula I provide particularly good activity. While not being bound by a specific mechanism of action, the inventors believe that GPBI inhibitors, such as those of Formula I and embodiments thereof, are synergistic with anti-tumor agents (exemplified by doxorubicin) in treating tumors because both compounds act to inhibit GPBP kinase in a different fashion, and because the GPBP inhibitors reduce viability of cancer stem cells (CSC) in the tumor. CSC are expected to be responsible for drug resistance because they are not likely to be killed by antimitotic drugs since they divide slowly and they have abundant xenobiotic transporters, among other characteristics.
  • CSC cancer stem cells
  • any suitable anti-tumor agent can be used since all tumors possess populations of CSC an ⁇ GPBP inhibitors of the invention reduce CSC viability. Thus, combining the GPBP inhibitors of the invention with any anti-tumor agent is likely to provide an improved therapeutic product.
  • any suitable anti-tumor drug can be used in combination with the compounds of the present invention, including but not limited to anthracyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, ethylenimines, methylmelarmines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs, pyrimidine analogs, enzymes, podophyllotoxins, platinum-containing agents, interferons, and interleukins.
  • alkylating agents e.g., mitomycin C
  • alkyl sulfonates e.g., aziridines, ethylenimines, methylmelarmines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate
  • chemotherapeutic agents to which the cancer may have developed resistance include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, cannustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomiustine, mnitobronitoi, mitolactol, pipobroman, aclacinomycin
  • the antitumor drug is selected from the group consisting of paclitaxel, a topoisomerase II inhibitor, 5-fluorouracil (5-FU), and cisplatin.
  • the antitumor drug is a topoisomerase II inhibitor.
  • the topisomerase II inhibitor comprises an anthracyclin or podophyllotoxin derivative.
  • the anthracyclin drug is doxorubicin and the podophyllotoxin derivative is etoposide.
  • the subject of the disclosed methods is a mammal or a bird.
  • the mammal is a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
  • the compounds of the invention, or pharmaceutical compositions thereof may be used for diagnostic purposes.
  • the compounds of the invention, or pharmaceutical compositions thereof are for use in the detection of EMT in a tissue of a subject, wherein the compound is detectably labeled and capable of binding to the tissue to detect EMT in the tissue.
  • Also included in this aspect of the invention is a method for detecting EMT in a tissue comprising (a) contacting a tissue ir a subject with an effective amount to label the tissue of a detectably labeled compound of the invention oi a pharmaceutical composition thereof under conditions suitable to promote binding of the detectably labeled compound to the tissue; and (b) detecting the detectably labeled compound bound to the tissue, thereby detecting EMT in the tissue.
  • Contacting the tissue may be carried out in vivo (i.e.: administering the detectably labeled compounds to the subject as appropriate) or in vitro (i.e.: contacting a tissue biopsy or other tissue specimen obtained from the subject).
  • Methods for detecting the detectably labeled compound will depent on the detectable substance; such detection techniques are well known to those of skill in the art.
  • the tissue is a tumor, a joint, or a tissue from any organ.
  • detecting EMT in the kidney indicates that the subject has chronic kidney disease and/or immune-complex mediated GN.
  • detecting EMT indicates that the subject has organ fibrosis; where the tissue is lung, detecting EMT in the lung indicates that the subject has pulmonary fibrosis; where the tissue is a joint, detecting EMT in the joint indicates that the subject has rheumatoid arthritis; or where the tissue is a tumor, detecting EMT in the tumor indicates that the subject has an invasive tumor.
  • the invasive tumor may be an invasive carcinoma, including but not limited to an invasive breast tumor or an invasive lung tumor.
  • the diagnostic methods may be used in mammalian or avian subjects.
  • the mammalian subjects include, but are not limited to, a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
  • the compound may be detectably labeled by coupling it to a detectable label selected from the group consisting of an enzyme, a prosthetic group, a fluorescent material, a luminescent material, and a radioactive material, including biotin and fluorescein.
  • the invention provides a scaleable synthetic process for preparing GPBP inhibitors, including those disclosed herein.
  • the present invention is directed to a method o preparing a compound of formula (II):
  • R is selected from N and CR 5 ;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6 alkyl)sulfanyl(Ci-C 6 alkyl), -(CH 2 )i-5-C(0)OH, -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i_ 5 -C
  • R 1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C 6 alkyl), or (Ci-C 6 alkyl) sulfanyl(Ci-C 6 alkyl);
  • R 2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C 6 alkoxy)Ci-C 6 alkyl, formyl(Co-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C 6 alkyl), -(CH 2 )i_ 5 -C(0)OH, -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i- 5 -C(0)NH 2 , (aryl)Ci-C 6 alkyl, or (heteroaryl)Ci-C 6 alkyl;
  • R 3 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C 6 alkyl), -(CH 2 )i_ 5 -C(0)OH, -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)NH 2 , -(CH 2 )i- 5 -C(0)NH(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)N(Ci-C 6 alkyl) 2
  • R 4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy),
  • M is a monovalent cation
  • X I is leaving group
  • R 3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C 6 alkyl), -(CH 2 )i_ 5 -C(0)OH, -(CH 2 )i- 5 -C(0)(Ci-C 6 alkoxy), -(CH 2 )i-5-C(0)NH 2 , -(CH 2 )i- 5 -C(0)NH(Ci-C 6 alkyl), -(CH 2 )i- 5 -C(0)N(Ci-C 6 alkyl)
  • X is fluoro, chloro or bromo. In certain embodiments, X is fluoro.
  • M is Li + , Na + , K + or Cs + ; M is Li + , Na + or K + ; M is Na + or K + ; or M is K + .
  • X 1 is halogen, -OTf or -Oms; X 1 is halogen; X 1 is fluoro, chloro or bromo; or X 1 is bromo.
  • R is CR 5 .
  • R 5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, (Ci-C 6 alkoxy)Ci-C 6 alkyl, -(CH 2 )i- 5 -C(0)OH, -(CH 2 )i- 5 -C(0)(Ci-C 6
  • R 5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy)Ci-C6 alkyl, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl.
  • R 5 is selected from the group consisting of hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)Ci-C6 alkyl, (aryl)Ci-C6 alky] and (heteroaryl)Ci-C6 alkyl.
  • R 5 is selected from the group consisting of hydrogen C1-C6 alkyl and (C1-C6 alkoxy)Ci-C6 alkyl and in other embodiments R 5 is selected from the group consisting of hydrogen and C1-C6 alkyl.
  • R 5 is C1-C6 alkyl, and in an additional embodiment, R 5 is hydrogen.
  • R is N
  • R 1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci-C 6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), or (Ci-C 6 alkyl)sulfanyl(Ci-C6 alkyl).
  • R 1 is hydrogen, halogen, cyano, hydroxy or C1-C6 alkyl, and in a still further embodiment, R 1 is hydrogen, cyano or C1-C6 alkyl. In an additional embodiment, R 1 is hydrogen. In another embodiment, R 1 is C1-C6 alkyl.
  • R 1 may be hydrogen cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), or (Ci-C 6 alkyl)sulfanyl(Ci-C 6 alkyl); R 1 may be C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C 6 alkyl, amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), or (Ci-C 6 alkyl)
  • R 2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C 6 alkyl or formyl(Co-C 6 alkyl);
  • R 2 is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C, alkoxy) or (C1-C6 alkoxy)Ci-C6 alkyl;
  • R is cyano, C1-C6 alkyl, C1-C6 alkoxy or (C1-C6 alkoxy)Ci-C6 alkyl;
  • R 2 is C1-C6 alkyl or C1-C6 alkoxy;
  • R 2 is C1-C6 alkyl;
  • R 2 is C1-C6 al
  • R 3A is
  • R 3A is Ci-C 6 alkyl, halo(Ci-C 6 alkyl), Ci-C 6 alkoxy, halo(Ci-C 6 alkoxy), hydroxy(Ci-C 6 alkyl), (Ci-C 6 alkoxy)Ci-C 6 alkyl, formyl(Ci-C 6 alkyl), amino(Ci-C 6 alkyl), sulfanyl(Ci-C 6 alkyl), (Ci-C 6
  • R 3A is cyano, Ci-C 6 alkyl, halo(Ci-C 6 alkyl) C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl,
  • R 3A is Ci-C 6 alkyl, halo(Ci-C 6 alkyl)
  • R 4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy, (aryl)Ci-C6 alkyl, 01 (heteroaryl)Ci-C6 alkyl; R 4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R 4 is hydroxy, C1-C6 alkoxy, halo(Ci-C6 alkoxy) or benzyloxy; R 4 is hydroxy, cyano, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R 4 is hydroxy, halogen, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R 4 is hydroxy, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R
  • R 4 is cyano, Ci-C 6
  • R 4 is Ci-C 6 alkoxy, -(CH 2 )i_ 5 -C(0)OH or -(CH 2 )i_ 5 -C(0)(Ci-C 6 alkoxy
  • synthetic processes disclosed herein may further comprise
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3,7- dimethylocta-2,6-dienyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the paren molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH 2 -, -CH 2 CH 2 - , -CH 2 CH 2 CHC(CH 3 )-, -CH 2 CH(CH 2 CH 3 )CH 2 -.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from one to six, from one to four, from on to three, from one to two, or from two to three.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • An alkylene chain also may be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3- butynyl, 2-pentynyl, and 1-butynyl.
  • aryl means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system.
  • the bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring.
  • the fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups.
  • bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3- dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-l-yl, inden 2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen- 1-yl, 5,6,7,8-tetrahydronaphthalen- 1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,
  • the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • haloalkyl refers to an alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring.
  • the monocyclic heteroaryl can be a 5 or 6 membered ring.
  • the 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiet ⁇ through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia.
  • bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring
  • the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system.
  • the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring
  • the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system.
  • Representative examples of bicyclic heteroaryl include, but are not limited to,
  • benzimidazolyl benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-l-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7, 8-tetrahydroquinolin-2-yl, 5,6,7,8- tetrahydroquinolin-3-yl, 5,6,7, 8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin- 1-yl,
  • the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic eteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionall; substituted with one or two groups which are independently oxo or thia.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio or which have otherwise been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • Example 1 New compounds to specifically target tumor with mesenchymal phenotype
  • New Goodpasture antigen binding protein (GPBP)-inhibitor compounds with an improved therapeutic profile relative to earlier GPBP inhibitors were sought, e.g. compounds having limited A549 toxicity (IC50 elevated) and synergism with doxorubicin in reducing A549 cell viability (reduction of doxorubicin IC50).
  • IC50 limited A549 toxicity
  • doxorubicin in reducing A549 cell viability
  • a variety of new compounds were synthesized to identify T12 related compounds with improved performance in water solubility, lower epithelial toxicity (higher IC50) or synergy with doxorubicin.
  • T12 derivatives with their chemical structure and quantified selection criteria is displayed in Table 1. Displayed are from left to right columns: the chemical structure of the individual compounds determined by ⁇ ⁇ and 13 C NMR; MW; log S calculated using the Chemdraw Professional 15.0 algorithms. Log S of T12 was -6.49. Asterisks indicate compounds with significant improved solubility with respect to T12; synergy with doxorubicin as fold reduction of doxorubicin IC50 (compound concentration used: 50 uM); normalized synergy as fold with respect to the doxorubicin synergy of T12; the IC50; and the normalized IC50 respect to T12. All ex vivo determinations were done on A549 cell cultures. Table 1
  • terphenyls displaying better performance with doxorubicin were tested for their affinity for the mesenchymal GPBP multimer as determined by competing biotinylated-T12 binding to A427 cultures using In Cell technology. Specifically, A427 cells were seeded in 96 well plates, fixed, permeabilized and stained with 1 ⁇ bioT12 and streptavidin-AF488, in the presence of the indicated competitor (terphenyl) at 50 ⁇ . The fluorescence of individual cells was determined using an IN CELL Analyzer 2000. Results are shown in Figures 1A and IB.
  • T109 was shown to exhibit improved properties over T12.
  • T109 reduced autophosphorylation and doxorubicin IC50 (synergism) more than T12 and more importantly, T109 exhibited higher IC50 for A549 and higher affinity for A427 than T12 (data not shown), revealing its lower inhibitory capacity over epithelial phenotype and higher inhibitory capacity over mesenchymal phenotype.
  • T109 diverged from the original Ti l target sequence only ii a double bond in the propionic chain.
  • This acrylic acid derivative was expected to provide structural rigidity to the substituent representing the side chain of the critical Glu 264 . Indeed, among all compounds synthesized, those significantly changing propionic acid in the third ring were essentially discarded durinj selection mainly because of low doxorubicin synergism, except for T109.
  • T109 displayed a similar anti-tumor effect as T12 in 4T1 and A549 models, however the presence of a hydroxyl group in the second ring improves water solubility and facilitates administration at higher doses in the drinking water than T12.
  • the higher performance of T12 when compared to Tl 1 and the improved performance of T 109 with respect to T12 in vitro and ex vivo suggested that Ti l did not fully mimic interactive a-helix motif stabilizing the GPBP multimer.
  • the evidence suggests that the hydroxyl group in the second ring, by electrostatically disturbing carboxyl group of third ring (i.e.
  • bio-SS-T12 exhibits an enhanced potential to compromise the viability of carcinoma cell lines A549 and A427 exhibiting epithelial and mesenchymal phenotypes, respectively (data not shown).
  • bio-SS-T12 reduced IC50 for T12 between 2.9 (A427) and 2.3 (A549) times, demonstrating that enhanced intracellular delivery of T12 and T12 related compounds is a therapeutic approach to fight cancer.
  • PBS phosphate buffer saline
  • T12 staining solution 1 ⁇ biotinylated T12 (bioT12), streptavidin- AF488 (Molecular Probes, S32354; https://www.thermofisher.com order/catalog/product/S32354, diluted 1:400) and 0.6 ⁇ 4',6-diamidino-2-phenylindole (DAPI; Molecular Probes, D1306;
  • En Vision FLEX Antibody Diluer (Dako, K8006; http://www.agilent.com/en/products/immunohistochemistry/visualization- systems/envision-flex-optional-reagents/antibody-diluent). T12 staining solutions were incubated for 1 h before they were added to cells. DAPI stains nuclei which are used to identify individual cells.
  • the fluorescence emitted by the complex T12-biotin-streptavidin-AF488 was measured in individual cells using an IN CELL Analyzer 2000 device (GE). Briefly, DAPI fluorescence emission was used to identify individual cells and green fluorescence (AF488) was measured in each individual cell. Ai average of 540 cells, and at least 300 cells, were measured in each well. Analysis was done at least in duplicates. Finally, the average of fluorescence of whole cells or their cytoplasm and the 95% CI
  • the first step of this synthesis consisted of the regio selective bromination of commercial 3- hydroxybenzaldehyde in accordance with a known procedure (Kaiser et al. J. Org. Chem. 2002, (57, 9248 9256). The resulting bromoaryl 1 was then transformed in boronate 4 with a good overall yield (Scheme 1).
  • Scheme 3 shows the way the triflate 7 was reacted with different commercial boronic acids or boronates to give the compounds 8-13 with moderate yields.
  • the formyl group of the compound 13 was transformed into a cyano group (14).
  • the last step of the synthesis was the basic hydrolysis of the ethyl ester to give the final products 15-20 with excellent yields.
  • Scheme 7 synthesis of compounds 66 and 68 Further, a new and multi-gram scale synthesis of compound T12 was designed (the first synthesis of this compound is described in US Patent No. 8,586,776). This new synthesis is shown in Scheme 8.
  • the Scheme 11 shows the synthesis of an adduct between T12 and D-biotin with the use of commercial 2,2'-dithiodiethanol as a linker.
  • the position chosen to anchor T12 and D-biotin to the linker was the carboxylic acid (Scheme 11).
  • 5-bromosalicylaldehyde (804 mg), boronate (1.45 g, 1.1 equiv) and palladium tetrakistriphenylphosfine (138 mg, 0.03 equiv) were dissolved in a 10: 1 mixture of dimethoxyethane/ethanol (20 mL). Then, a 2 M aqueous Na 2 C03 solution (848 mg, 2 equiv) was added to this yellow solution and the resulting mixture was refluxed under inert atmosphere until the completion of the reaction. Thereafter, the mixture was concentrated in vacuo and the residue was taken up in water and extracted with AcOEt (3x10 mL). The combined organic fractions were dried over Na 2 S0 4 , filtered and evaporated.
  • Triflate (1 equiv), commercial boronic acid or boronate (1.2 equiv), sodium carbonate (2 equiv) and palladium tetrakistriphenylphosphine (0.01 equiv) were dissolved in a 7:3 mixture of acetonitrile/water (5 mL) and refluxed under inert atmosphere until completion of the reaction. Thereafter, the mixture was neutralized with 1M HC1 solution and was extracted with AcOEt (3x5 mL). The combined organic fractions were dried over Na 2 S0 4 , filtered and evaporated. The crude was purified by FC.
  • the crude reaction was dissolved in AcOEt (1 mL) and washed with water (15 mL) and brine (15 mL). The combined aqueous layers were further extracted with AcOEt (3x10 mL). The combined organics were dried over Na 2 S04, filtered and concentrated.
  • the concentrated crude reaction was taken up in MeOH (25 mL) and cooled with an ice bath. To this cooled mixture was added 3 mL of a 4.5M aqueous KHF 2 solution (1.05 g, 4.5 equiv) and the reaction was stirred for 10 min at 0 °C and for 1 h at room temperature. The resulting mixture was the concentrated and lyophilized overnight to remove any traces of water.
  • the reaction was cooled to room temperature, filtered through a thin pad of Celite (eluting with 3x25 mL of AcOEt) and concentrated.
  • the crude reaction was dissolved in AcOEt (150 mL) and washed with water (100 mL) and brine (50 mL). The combined aqueous layers were further extracted with AcOEt (3x25 mL). The combined organics were dried over Na 2 S0 4 , filtered and concentrated.
  • the concentrated crude reaction was taken up in MeOH (200 mL) and cooled with an ice bath.
  • Oxalyl chloride (16 ⁇ , 0.18 mmol) was added to a solution of T12 (44 mg, 0.12 mmol) in 1,2- dichloroethane (2 mL), followed by the addition of 1-2 drops of DMF. The reaction mixture was refluxed for 1 h. Next, the reaction mixture was warmed at room temperature and cooled in an ice bath. Then, a solution of compound 95 (46 mg, 0.12 mmol) and Et 3 N (50 ⁇ , 0.36 mmol) in DCE (1 mL) was added at 0°C and stirred overnight at room temperature.
  • the reaction was cooled to room temperature, filtered through a thin pad of Celite (eluting with 3x20 mL of AcOEt) and concentrated.
  • the crude reaction was dissolved in AcOEt (100 mL) and washed with water (100 mL) and brine (50 mL). The combined aqueous layers were further extracted with AcOEt (3x20 mL). The combined organics were dried over Na 2 S0 4 , filtered and concentrated.
  • the concentrated crude reaction was taken up in MeOH (150 mL) and cooled with an ice bath. To this cooled mixture was added a 4.5M aqueous KHF 2 solution (15.77 g, 4.5 equiv) and the reaction was stirred for 30 min at 0 °C and for 3 h at room

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Abstract

The present invention provides compounds and compositions thereof that inhibit Goodpasture antigen binding protein. Also disclosed is use of the compounds for the treatment various diseases and disorders, including invasive tumors, for the inhibition of mesenchymal phenotype after epithelial-to-mesenchymal transition (EMT), and for detecting EMT in a tissue. A method of preparing the compounds of the invention and related compounds is also provided.

Description

GPBP INHIBITORS AND USES AND SCALEABLE SYNTHESIS THEREOF BACKGROUND OF THE INVENTION
Cross Reference to Related Applications
This application claims priority to U.S. Provisional Patent Application Serial Nos. 62/290,238, filed February 2, 2016 and 62/310,395, filed March 18, 2016, the contents of which are hereby incorporated by reference in their entirety.
Field of the Invention
The present disclosure relates to GPBP inhibitors, uses thereof, and a scaleable synthesis thereof.
Description of the Related Art
The conformation of the non-collagenous (NCI) domain of the a3 chain of the basement membrane collagen IV (a3NCl) depends in part on phosphorylation. Goodpasture antigen-binding protein (GPBP) (WO 00/50607; WO 02/061430) is a non-conventional protein kinase that catalyzes the conformational isomerization of the a3NC 1 domain during its supramolecular assembly, resulting in the production and stabilization of multiple a3NCl conformers in basement membranes. Elevated levels of GPBP have been associated with the production of non-tolerized a3NCl conformers, which conduct the autoimmune response mediating Goodpasture (GP) disease. In GP patients, autoantibodies against the a3NCl (also known as GP antigen) cause a rapidly progressive glomerulonephritis (GN) and often lung hemorrhage, the two cardinal clinical manifestations of the GP disease.
Furthermore, it has been proposed that GPBP regulates inflammation, apoptosis and protein folding, and that increased GPBP expression induces antibody-mediated glomerulonephritis (IgA nephropathy, systemic lupus erythematosus and Goodpasture autoimmune syndrome) and resistance of cancer cells to a number of chemotherapeutic agents including those inducing protein misfolding- mediated endoplasmic reticulum (ER) stress (e.g. paclitaxel). Thus, inhibitors of GPBP are useful for the treatment of antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis. GPBP inhibitors have also been shown to be effective in treating and/or limiting the development of type 2 diabetes (WO 2015/044352).
GPBP (also known as GPBP-1 or 77 kD GPBP) is the primary product of COL4A3BP which undergoes secretion and can be found circulating or associated with collagen IV. The gene also expresses two alternative isoforms, GPBP-2 (also known as GPBPA26 or CERT) which remains cytosolic and GPBP-3 (also known as 91 kD GPBP) which is associated with cellular membranes and promotes GPBP secretion (WO 00/50607; WO 2010/009856; Revert-Ros et al, 2011, J Biol. Chem 286, 35030-35043).
Elevated GPBP expression and secretion have been also associated with collagen IV expansion in immune complex-mediated glomerulonephritis (Revert et al. 2007, Am J Path. 171, 1419-30.).
GPBP yields trimeric and multimeric aggregates, the latter displaying increased specific activity (WO 00/50607). An isolated peptide (Q2) encompassing a five-residue motif which is critical for GPBP multimer stabilization inhibited GPBP kinase activity and abated collagen accumulation in mouse models of immune complex-mediated glomerulonephritis (WO 2004/070025).
Differentiated epithelial cells have the potential to acquire a mesenchymal phenotype through complex biological processes known as epithelial-mesenchymal transition (EMT). Throughout EMT epithelial cells undergo trans-differentiation towards a phenotype with an enhanced migratory capacity and invasiveness, high resistance to apoptosis and an outstanding capacity to synthesize extracellular matrix (see for review Kalluri et al, 2009, J. Clin. Invest. 119: 1420-8). Whereas different EMTs have been recognized in embryo implantation and development (type 1); tissue repair and organ fibrosis (type 2); or cancer malignancy and metastasis formation (type 3), the general consensus is that common molecular mechanism must exist among them. Accordingly, E-cadherin expression supports cell-cell attachment in epithelial phenotype and vimentin expression renders cells prone to cell-cell detachment and migration in mesenchymal phenotype. Collagen IV is a primary component of the extracellular matrix that interacts with cancer stem cells (CSCs) forming a protective shield against conventional antitumor therapies (Ye J et al, 2014, Tumour Biol. 35, 3945-51; Su C et al. ,2007, Cancer Invest. 2, 542-9).
SUMMARY OF THE INVENTION
In one embodiment, the invention provides a compound of Formula I:
Figure imgf000004_0001
rmaceutically acceptable salt thereof, wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)C2-C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, hydroxyl(Ci-C6 alkyl), or formyl;
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(G-C6 alkoxy),
-(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(G-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH,
-CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i-5-C(0)(Ci-C6 alkoxy), (aryl)Ci C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
In certain embodiments, the compounds of the invention have the formula:
Figure imgf000005_0001
wherein:
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)(Ci-C6 alkoxy), and -(CH2)i-5-C(0)NH2;
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, or -0(CH2)i-5-C(0)(Ci-C6 alkoxy).
In other embodiments, the compound of the invention may have the formula
Figure imgf000005_0002
wherein R1, R3, R4, and R5 are as defined above.
In certain embodiments, the compounds of the invention may be coupled to a detectable label.
Further embodiments of the invention include pharmaceutical compositions comprising the compounds of the invention and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent. In certain embodiments, the invention comprises the compounds or the pharmaceutical compositions of the invention for use as a medicament. Further embodiments include the compounds or pharmaceutical compositions of the invention for use in the treatment of various diseases and disorders, including antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis and type 2 diabetes, as well as methods of treating the aforementioned diseases and disorders by administration of the compounds or the pharmaceutical compositions of the invention.
In another embodiment, the invention provides for the compounds or the pharmaceutical compositions of the invention for use in inhibiting mesenchymal phenotype after epithelial-to- mesenchymal transition (EMT), as well as methods for inhibiting mesenchymal phenotype after EMT, by administration of the compounds or the pharmaceutical compositions of the invention. In various embodiments, the inhibition of mesenchymal phenotype after EMT may comprise treating a subject with chronic kidney disease, immune-complex mediated glomerulonephritis, organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, type 2 diabetes, or an invasive tumor.
In one embodiment of the uses and/or methods of the invention, the subject has an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition. In various embodiments, the cell markers include but are not limited to one or more of vimentin, E-cadherin, collagens I and IV, matrix metalloproteinase 9 (MMP-9), chemokine (C-C motif) ligand 2 (CCL2), also referred to as monocyte chemotactic protein 1 (MCP-1), α5 (IV) chain, (a5 (IV) )3 protomer, and Goodpasture antigen binding protein (GPBP). In another embodiment, the subject has an increase in vimentin expression and a decrease in E-cadherin expression in a relevant tissue sample compared to a control tissue.
In a further embodiment of the uses and/or methods of the invention, the subject has an increased expression of α5(Γν) chain, and/or (a5 (IV))3 protomer in a relevant tissue sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype. In a further embodiment, the subject has an increased expression of (α1)2 2 (IV) protomer and/or an increased expression α1,α2 (IV) chains in a relevant tissu sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
In embodiments of the uses and/or methods for treating an invasive tumor, the invasive tumor is a invasive carcinoma, including but not limited to invasive breast tumors and invasive lung tumors. In a further embodiment, treating the invasive tumor reduces tumor metastases in the subject. In certain embodiments, the compounds or the pharmaceutical compositions ol the invention are used as a mono-therapeutic. In other embodiments, they are administered in combination with one or more other therapeutics. The compounds or the pharmaceutical compositions of the invention may be administered to a mammal or a bird.
In a further aspect, the invention provides methods for detecting EMT in a tissue, comprising contacting tissue from a subject with an amount effective to label the tissue with a detectably labeled compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical compositioi comprising a detectably labeled compound of the invention, for a time and under conditions suitable to promote binding of the detectably labeled compound to the tissue, and then detecting the detectably labeled compound bound to the tissue, thereby detecting EMT in the tissue.
In various embodiments, the tissue may be selected from the group consisting of a tumor, a joint, and tissue from any organ. In one embodiment, the tissue is a kidney, and detecting EMT in the kidney indicates that the subject has chronic kidney disease or immune-complex mediated glomerulonephritis. L another embodiment, the tissue is tissue from any organ, and detecting EMT indicates that the subject has organ fibrosis. In a further embodiment, the tissue is a lung, and detecting EMT in the lung indicates that the subject has pulmonary fibrosis. In another embodiment, the tissue is a joint, and detecting EMT indicates that the subject has rheumatoid arthritis. In one embodiment, the tissue is a tumor, and detecting EMT indicates that the subject has an invasive tumor. For example, the tumor may be an invasive carcinoma, including but not limited to invasive breast tumors and invasive lung tumors.
In an additional embodiment, the invention comprises a method of preparing a compound of Formula II:
Figure imgf000007_0001
(Π)
or a pharmaceutically acceptable salt thereof,
wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci- C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl) sulfanyl(Ci-C6
alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl; ,
R is hydrogen, halogen, cyano, hydroxy, Ci-C6 alkyl, halo(Ci-C6 alkyl), C1- 6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-
C6 alkoxy)Ci-C6 alkyl, formyl(Co-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl;
R3 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-
C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; and
R4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy),
benzyloxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6
alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i_5-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or
(heteroaryl)Ci-C6 alkyl;
comprising reacting a compound of fo
Figure imgf000008_0001
(III)
wherein
X is halogen
M is a monovalent cation; and
with a compound of formula (IV):
Figure imgf000008_0002
(IV)
wherein
XI is leaving group; and
R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl),
(Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C 5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
In a particular embodiment of the above method of preparing a compound of Formula II or a salt thereof, R is CH, R1 is Ci-C6 alkyl, R2 is Ci-Ce alkyl. R A -CH=CH-C(0)(Ci-C6 alkoxy), R4 is Ci-Ce alkoxy, X is fluoro, M is K+, and X1 is bromo.
In further embodiments of the methods of preparing a compound of Formula II, the compound is of one of the following formulas:
Figure imgf000009_0001
(lib)
(Ha)
Figure imgf000009_0002
(He) (lid)
Figure imgf000009_0003
(Ilf)
(He)
Figure imgf000009_0004
(Ilg) (nh)
Figure imgf000009_0005
(Hi) (Ilj)
Figure imgf000009_0006
(Ilk) (HI)
Figure imgf000010_0001
(Ilm).
In an additional embodiment, of the methods of preparing a compound of Formula II, the methods may further comprise hydrogenation of a compound of formula (II) wherein R3 is -CH=CH-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy), and may also further comprise hydrolysis of a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)OH.
BRIEF DESCRIPTION OF THE FIGURES
Figures 1A and IB show the competition of binding of biotinylated T12 to A427 cells with compounds c the disclosure.
Figure 2 shows T12 and T109 reduce tumor growth in BALBc mice inoculated with 4T1 cells.
DETAILED DESCRIPTION OF THE INVENTION
All references cited are herein incorporated by reference in their entirety. Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor
Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D.
Goeddel, 1991. Academic Press, San Diego, CA), "Guide to Protein Purification" in Methods in
Enzymology (M.P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods am Applications (Innis, et al. 1990. Academic Press, San Diego, CA), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R.I. Freshney. 1987. Liss, Inc. New York, NY), Gene Transfer and Expression Protocols, pp. 109-128, ed. E.J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, TX).
As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. "And" as used herein is interchangeably used with "or" unless expressly stated otherwise.
All common terms between different aspects and embodiments of the invention have the same meaning unless the context clearly dictates otherwise. Unless clearly indicated otherwise by the context, embodiments disclosed tor one aspect of the invention can be used in other aspects of the invention as well, and in combination with embodiments disclosed in other aspects of the invention. Thus, the disclosure is intended to include, and the invention includes, such combinations, even where such combinations are not explicitly delineated.
In a first aspect, the present invention provides a compound of Formula I:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)C2-C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, hydroxyl(Ci-C6 alkyl), or formyl;
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(G-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i-5-C(0)(Ci-C6 alkoxy), (aryl)Ci Ce alkyl, or (heteroaryl)Ci-C6 alkyl. The compounds of the invention are new GPBP inhibitors with improved therapeutic profiles relative to prior GPBP inhibitors (e.g. T12, a terphenyl shown previously to be active against
mesenchymal progenitor cancer phenotypes (WO/2014/006020 and WO/2016/107906) and synergistic with doxorubicin). Specifically, the GPBP inhibitors of the invention have improved performance in water solubility, lower epithelial toxicity, and/or synergy with doxorubicin. As used herein a "GPBP inhibitor" refers to any compound or molecule that reduces the activity or the expression of all or individual GPBP isoforms.
The GPBP inhibitors of the invention compromise cell viability after epithelial-to-mesenchymal transition to a much greater extent than they affect epithelial cell viability, and inhibit growth and metastasis of invasive tumors (i.e.: those having predominant mesenchymal phenotype) to a much greater extent than they effect the growth of tumors having predominant epithelial phenotype. As a result, the methods of the invention can be used, for example, to treat invasive tumors as well as disorders mediated by organ fibrosis.
As used herein the term "GPBP" refers to any polypeptide isoform (such as GPBP-1, -2 and -3 a derived polypeptides) expressed from COL4A3BP gene. As used herein, the term "GPBP-1 inhibitor" means any compound that reduces the expression or activity (such as the kinase activity) of GPBP- 1 and which may or may not reduce the expression or activity (such as the kinase activity) of other GPBP isoforms. GPBP-1 is a nonconventional Ser/Thr kinase displaying autophosphorylation activity that bind and phosphorylates the a3NCl domain (Raya et al.1999 and 2000). GPBP-1 forms large multimeric aggregates whose specific kinase activity is much higher than that of aggregates of lower molecular weight (Raya et al. 2000).
In one embodiment of the compound of Formula I, the compound has the formula
Figure imgf000012_0001
wherein:
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-
C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-G5 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)(Ci-C6 alkoxy), and -(CH2)i_5-C(0)NH2; R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy),
-(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-Ce alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH, or -0(CH2)i_5-C(0)(Ci-C6 alkoxy).
In a another embodiment of the compound of Formula I or embodiments thereof, R is selected from N and CR5; R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R3 is Ci-Ce alkyl, -C(0)OH, -(CH2)i_5-C(0)OH, -C(0)(Ci-C6 alkoxy),
-(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i_5-C(0)NH2, -C(0)NH(Ci-C6 alkyl),
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2,
-CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and R4 is hydroxy, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, halo(Ci-C6 alkoxy), benzyloxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-Ce alkoxy), -(CH2)i_ 5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH, or -0(CH2)i_5-C(0)(Ci-C6 alkoxy).
In a further embodiment of the compound of Formula I or embodiments thereof, R is selected fror N and CR5; R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R3 is Ci-Ce alkyl, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-Ce alkoxy), -(CH2)i_5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or
-CH=CH-C(0)(Ci-C6 alkoxy); and R4 is hydroxy, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, halo(Ci-C6 alkoxy; benzyloxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-Ce alkoxy), -(CH2)i_5-C(0)NH2, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, or -0(CH2)i_5-C(0)(Ci-C6 alkoxy).
In an additional embodiment of the compound of Formula I or embodiments thereof, the compound has the formula:
Figure imgf000014_0001
In another embodiment of the compound of Formula I or embodiments thereof, R is hydrogen.
In a further embodiment of the compound of Formula I or embodiments thereof, R3 is C1-C6 alkyl -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH, o -CH=CH-C(0)(Ci-C6 alkoxy).
In an additional embodiment of the compound of Formula I or embodiments thereof, R3 is -(CH2)i-2-C(0)OH or -(CH2)i_2-C(0)(Ci-C6 alkoxy).
In another embodiment of the compound of Formula I or embodiments thereof, R3
is -(CH2)2-C(0)OH or -(CH2)2-C(0)(Ci-C6 alkoxy).
In a further embodiment of the compound of Formula I or embodiments thereof, R3 is
-CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
In an additional embodiment of the compound of Formula I or embodiments thereof, R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
In another embodiment of the compound of Formula I or embodiments thereof, R4 is hydroxy or C1-C6 alkoxy.
In a further embodiment of the compound of Formula I or embodiments thereof, R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
In an additional embodiment of the compound of Formula I or embodiments thereof, R5, if present, is C1-C6 alkyl or halo(Ci-C6 alkyl).
In another embodiment of the compound of Formula I or embodiments thereof, R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R3 is -C(0)OH, -(CH2)i-2-C(0)OH, -C(0)(Ci-C6 alkoxy),-(CH2)i_2-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-2-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i_2-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-2-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and R4 is hydroxy, 0-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
In a further embodiment of the compound of Formula I or embodiments thereof, R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R3 is -(CH2)i-2-C(0)OH, -(CH2)i-2-C(0)(Ci-C6 alkoxy), -(CH2)i_2-C(0)NH2, -(CH2)i_2-C(0)NH(Ci-C6 alkyl) -(CH2)i-2-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and R4 is hydroxy, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
In an additional embodiment of the compound of Formula I or embodiments thereof, R1 is hydrogen; R3 is -(CH2)i_2-C(0)OH, -(CH2)i_2-C(0)(Ci-C6 alkoxy), or -(CH2)i_2-C(0)NH2; R4 is hydroxy or C1-C6 alkoxy; and R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
In another embodiment of the compound of Formula I or embodiments thereof, R1 is hydrogen; R is -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R4 is hydroxy or Ci-C6 alkoxy; and R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
In a further embodiment of the compound of Formula I or embodiments thereof, R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen; R3 is -(CH2)i_2-C(0)OH; and R4 is Ci-C6 alkoxy.
In an additional embodiment of the compound of Formula I or embodiments thereof, R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen; R3 is -CH=CH-C(0)OH; and R4 is Ci-C6 alkoxy.
In a another embodiment of the compound of Formula I or embodiments thereof, R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); R1 is hydrogen; R3 is -(CH2)i-2-C(0)OH or -CH=CH-C(0)OH; and R4 is Ci-C6 alkoxy.
In a further embodiment of the compound of Formula I or embodiments thereof, the compound is:
Figure imgf000016_0001
or T97
harmaceutically acceptable salt thereof. In an additional embodiment of the invention, the GPBP inhibitor may be
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0004
T125 or T122 or a pharmaceutically acceptable salt thereof.
The compounds of the invention include pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, including but not limited to carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based oi the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limitec to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M. et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 1977, 66: 1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters, wherein the alkyl group is straight or branched, substituted or unsubstituted, and C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl and triphenylmethyl. C1-C4 alkyl esters are preferred, such as methyl, ethyl, 2,2,2-trichloroethyl, and tert-butyl esters. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines, wherein the alkyl groups are straight or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
In a second aspect of the invention, the compound of Formula I or any embodiments thereof may be coupled to a detectable label.
The term "coupled" is used to mean that the detectable substance is physically linked to the compound. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase. Examples of suitable prosthetic-group complexes include streptavidin/biotin and avidin/biotin. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. An example of a luminescent material includes luminol. Examples of suitable radioactive material include 125I, 13 35S or 3H.
In certain embodiments, the detectable label is biotin or fluorescein. A third aspect of the invention provides pharmaceutical compositions comprising the compounds disclosed herein and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent. In certain embodiments, the carrier is biotin. In certain embodiments, the biotin is D-biotin.
For administration, the compositions are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compositions may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compositions of this invention may be provided in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and mode: of administration are well known in the pharmaceutical art. The carrier or diluent may include time delaj material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
The compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The compounds of the invention may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
The compositions of the invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier. The compositions include one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired othei active ingredients. The pharmaceutical compositions containing compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known in the art foi the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and
preservative agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases, such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action ove a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectablt aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally 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 pharmaceutical compositions of the present invention may also be prepared in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Pharmaceutical compositions of the present invention may be administered parenterally in a sterilt medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
A fourth aspect of the invention is directed to compounds of the invention, or pharmaceutical compositions thereof, for use as a medicament. The compounds of the invention, or pharmaceutical compositions thereof, may also be used in medical methods, including methods of treating subjects with one or more diseases or disorders in need of treatment for those diseases or disorders. Unless otherwise noted, the methods of administration and/or treatment disclosed herein are to be understood to include both methods of treatment and the corresponding medical uses.
In one embodiment of this aspect of the invention, the invention provides a method for treating antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis or type 2 diabetes, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.
In a further embodiment, the invention provides a method for inhibiting mesenchymal phenotype after epithelial-to-mesenchymal transition (EMT), comprising administering to a subject in need thereof an amount effective to inhibit mesenchymal phenotype after EMT of a compound disclosed herein or a pharmaceutical composition thereof.
Throughout EMT epithelial cells undergo trans-differentiation towards a phenotype with an enhanced migratory capacity and invasiveness, high resistance to apoptosis and an outstanding capacity t( synthesize extracellular matrix (see for review Kalluri et al. , 2009, J. Clin. Invest. 119: 1420-8). Whereas different EMTs have been recognized in embryo implantation and development (type 1); tissue repair and organ fibrosis (type 2); or cancer malignancy and metastasis formation (type 3), the general consensus is that common molecular mechanism must exist among them. Thus, in embodiments of the invention for inhibiting mesenchymal phenotype after EMT, the subject may be one that has or is suspected of having any disorder characterized by EMT, including but not limited to chronic kidney disease, immune-comple: mediated glomerulonephritis, organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor, and type 2 diabetes. As will be understood by those of skill in the art, not all cells undergo EMT at once. EMT transition occurs in mosaic fashion and may occur more prominently at the borders of the affected tissue, such as a tumor. Inhibiting mesenchymal phenotype after EMT may comprise promoting cell death in such cells and/or promoting transition of such cells back to an epithelial phenotype.
In another embodiment, the invention provides a method for treating an invasive tumor, comprising administering to a subject in need thereof an effective amount of a compound disclosed hereii or a pharmaceutical composition thereof.
In some embodiments, the invasive tumor is an invasive carcinoma, including but not limited to ai invasive breast tumor or an invasive lung tumor. In further embodiments treating the invasive tumor reduces tumor metastases in the subject.
As used herein, "treat" or "treating" with regard to tumors means accomplishing one or more of the following: (a) reducing tumor size; (b) reducing tumor growth; (c) reducing or limiting development and/or spreading of metastases; (d) reducing the amount of antitumor drug required to maintain therapeutic objective for subject receiving treatment; (e) reducing circulating cancer cells; and (f) depleting CSC in the tumor.
Thus, in one embodiment, treating the tumor comprises depleting CSC in the tumor. GPBP inhibitors can reduce viability of CSC in tumors. CSC are expected to be responsible for drug resistance because they are not likely to be killed by antimitotic drugs since they divide slowly and they have abundant xenobiotic transporters, among other characteristics. In another embodiment, treating the tumor comprises reducing tumor metastasis. "Inhibiting" tumor cell metastasis may comprise any amount of inhibition compared to no treatment. In various non- limiting embodiments, the methods may comprise inhibiting tumor cell metastasis, by 5%, 10%, 25%, 50%; 100%, or more compared to control (such as no treatment).
The different active compounds can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition, such as in thi pharmaceutical compositions of the invention.
Appropriate dosage levels of the anti-tumor drugs and compounds can be determined by those of skill in the art in light of the teachings herein as well as other clinical factors. Exemplary dosage levels o: the order of from about 0.01 mg to about 50 mg per kilogram of body weight per day, and more preferably between 0.1 mg to about 50 mg per kilogram of body weight per day, are generally useful in the treatment of the above-indicated conditions. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
In therapeutic applications, compositions are administered in an amount sufficient to carry out the methods of the invention. Amounts effective for these uses depend on factors including, but not limited to, the nature of the compound (specific activity, etc.), the route of administration, the stage and severity of the disorder, the weight and general state of health of the subject, and the judgment of the prescribing physician. The active compounds are effective over a wide dosage range. However, it will be understooc that the amount of the compound actually administered will be determined by a physician, in the light of the above relevant circumstances. Therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
In certain embodiments, the invention includes the compounds disclosed herein or pharmaceutical compositions thereof for use in inhibiting mesenchymal phenotype after EMT, wherein EMT has contributed to the pathogenesis of chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor and/or type 2 diabetes.
In certain embodiments, the method for inhibiting mesenchymal phenotype after EMT comprises administering a compound disclosed herein or a pharmaceutical composition thereof to a subject who has chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis, an invasive tumor and/or type 2 diabetes.
E-cadherin expression supports cell-cell attachment in epithelial phenotype and vimentin expression renders cells prone to cell-cell detachment and migration in mesenchymal phenotype.
Collagen IV is a primary component of the extracellular matrix that interacts with cancer stem cells (CSCs) forming a protective shield against conventional anti-tumor therapies (Ye J et ah, 2014, Tumour Biol. 35, 3945-51; Su C et ah, 007, Cancer Invest. 2, 542-9). The subject to be treated may have an issu related to EMT based on an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition. For example, the cell markers may include but are not limited to one or more of vimentin, E-cadherin, collagens I and IV, MMP-9, CCL2 / MCP-1, α5 (IV) chain, (a5 (IV))3 protomer, and Goodpasture antigen binding protein (GPBP). These markers are consistently altered (i.e.: increased (such as vimentin and collagen I and IV, a5 (IV), (a5 (IV))3, MMP-9, CCL2 / MCP-1, and GPBP) or decreased (such as E-cadherin)) after EMT.
Accordingly, in further embodiments, in the methods of the invention the subject has an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition. More specifically, the cell markers include, but are not limited to, one or more of vimentin, E-cadherin, collagens I and IV, MMP-9, CCL2 / MCP-1, α5 (IV) chain, (a5 (IV))3 protomer, and Goodpasture antigen binding protein (GPBP). In certain embodiments, the subject has an increase in vimentin expression and a decrease in E- cadherin expression in a relevant tissue sample compared to a control tissue.
Mesenchymal phenotype expresses, along with the classical collagen IV made of al 2 chains, a collagen IV made of a5 chain. There is evidence that the GPBP inhibitors of the invention and related compounds reduce the expression of the α1 2α5 chains, which provides compelling evidence that collagen IV networks (made up of the 1 2α5 chains) supports mesenchymal phenotype, and is different in composition than the typical collagen IV networks which support epithelial phenotypes (α1α2, α3α4α! and α5α6). Accordingly, mesenchymal collagen IV made of the a5 chain can be used to identify mesenchymal tumor cells: detecting α1 ,α2,α5 chains in a tumor in the absence of significant expression o α3,α4,α6 chains will be indicative of EMT in a carcinoma; detecting a5 and no significant levels of al, a2, a3, a4, and a6 in a tumor will be indicative of sarcoma. Inhibition of the mesenchymal collagen IV made of the α1,α2,α5 chains using GPBP inhibitors such as those of the invention results in either death of mesenchymal or tumor cells, or reversion of the cell phenotype to epithelial (WO 2016/107906).
Thus, in additional embodiments, in the methods of the invention the subject has an increased expression of a5(IV) chain, and/or (a5 (IV))3 protomer in a relevant tissue sample compared to a control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype. The subject may have an increased expression of (al)2 2 (TV) protomer and/or an increased expression α1,α2 (IV) chains in a relevant tissue sample compared to ; control tissue sample, wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype. In certain embodiments, the compound disclosed herein or a pharmaceutical composition thereof is the only therapeutic administered to the subject. In other embodiments, the compound disclosed herein or a pharmaceutical composition is administered in combination with another therapeutic, such as an antitumor agent.
The GPBP inhibitors of the invention can act synergistically with anti-tumor agents to provide a more effective therapeutic option for treating tumors, and the inhibitors of Formula I provide particularly good activity. While not being bound by a specific mechanism of action, the inventors believe that GPBI inhibitors, such as those of Formula I and embodiments thereof, are synergistic with anti-tumor agents (exemplified by doxorubicin) in treating tumors because both compounds act to inhibit GPBP kinase in a different fashion, and because the GPBP inhibitors reduce viability of cancer stem cells (CSC) in the tumor. CSC are expected to be responsible for drug resistance because they are not likely to be killed by antimitotic drugs since they divide slowly and they have abundant xenobiotic transporters, among other characteristics.
While the examples that follow focus on doxorubicin as an exemplary anti-tumor agent which inhibits GPBP, any suitable anti-tumor agent can be used since all tumors possess populations of CSC an< GPBP inhibitors of the invention reduce CSC viability. Thus, combining the GPBP inhibitors of the invention with any anti-tumor agent is likely to provide an improved therapeutic product.
Thus, any suitable anti-tumor drug can be used in combination with the compounds of the present invention, including but not limited to anthracyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, ethylenimines, methylmelarmines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs, pyrimidine analogs, enzymes, podophyllotoxins, platinum-containing agents, interferons, and interleukins. Particular examples of known chemotherapeutic agents to which the cancer may have developed resistance include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, cannustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomiustine, mnitobronitoi, mitolactol, pipobroman, aclacinomycins, actinomycin F(l), anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-l- norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyturidine, doxifluridine, enocitabine, floxuridine, fluorouracil, tegafur, L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin, cisplatin, defofamide, demecolcine, diaziquone, elfomithine, elliptinium acetate, etoglucid, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon- alpha, interferon-beta, interferon-gamma, interleukin- 2, lentinan, lonidamine, prednisone, dexamethasone, leucovorin, mitoguazone, mitoxantrone, mopidamol nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, urethane, vinblastine, vincristine, and vindesine.
In a preferred embodiment, the antitumor drug is selected from the group consisting of paclitaxel, a topoisomerase II inhibitor, 5-fluorouracil (5-FU), and cisplatin. In a preferred embodiment, the antitumor drug is a topoisomerase II inhibitor. In another preferred embodiment, the topisomerase II inhibitor comprises an anthracyclin or podophyllotoxin derivative. In a most preferred embodiment, the anthracyclin drug is doxorubicin and the podophyllotoxin derivative is etoposide.
In certain embodiments, the subject of the disclosed methods is a mammal or a bird. In other embodiments, the mammal is a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
In a fifth aspect, the compounds of the invention, or pharmaceutical compositions thereof, may be used for diagnostic purposes. In one embodiment the compounds of the invention, or pharmaceutical compositions thereof, are for use in the detection of EMT in a tissue of a subject, wherein the compound is detectably labeled and capable of binding to the tissue to detect EMT in the tissue. Also included in this aspect of the invention is a method for detecting EMT in a tissue comprising (a) contacting a tissue ir a subject with an effective amount to label the tissue of a detectably labeled compound of the invention oi a pharmaceutical composition thereof under conditions suitable to promote binding of the detectably labeled compound to the tissue; and (b) detecting the detectably labeled compound bound to the tissue, thereby detecting EMT in the tissue.
Contacting the tissue may be carried out in vivo (i.e.: administering the detectably labeled compounds to the subject as appropriate) or in vitro (i.e.: contacting a tissue biopsy or other tissue specimen obtained from the subject). Methods for detecting the detectably labeled compound will depent on the detectable substance; such detection techniques are well known to those of skill in the art.
In certain embodiments, the tissue is a tumor, a joint, or a tissue from any organ. In further embodiments, where the tissue is a kidney, detecting EMT in the kidney indicates that the subject has chronic kidney disease and/or immune-complex mediated GN. In other embodiments, where the tissue is from any organ, detecting EMT indicates that the subject has organ fibrosis; where the tissue is lung, detecting EMT in the lung indicates that the subject has pulmonary fibrosis; where the tissue is a joint, detecting EMT in the joint indicates that the subject has rheumatoid arthritis; or where the tissue is a tumor, detecting EMT in the tumor indicates that the subject has an invasive tumor. The invasive tumor may be an invasive carcinoma, including but not limited to an invasive breast tumor or an invasive lung tumor.
In the fifth aspect of the invention, the diagnostic methods may be used in mammalian or avian subjects. The mammalian subjects include, but are not limited to, a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
Furthermore, in the fifth aspect of the invention, the compound may be detectably labeled by coupling it to a detectable label selected from the group consisting of an enzyme, a prosthetic group, a fluorescent material, a luminescent material, and a radioactive material, including biotin and fluorescein.
In a sixth aspect, the invention provides a scaleable synthetic process for preparing GPBP inhibitors, including those disclosed herein. In this aspect, the present invention is directed to a method o preparing a compound of formula (II):
Figure imgf000028_0001
(Π)
or a pharmaceutically acceptable salt thereof,
wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
R1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Co-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl;
R3 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or
(heteroaryl)Ci-C6 alkyl;
R4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy),
benzyloxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6
alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i_5-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl;
comprising reacting a compound of formula (III):
Figure imgf000029_0001
(III)
wherein
X is halogen
M is a monovalent cation; and
with a compound of formula (IV):
Figure imgf000029_0002
(IV)
wherein
XI is leaving group; and
R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or
(heteroaryl)Ci-C6 alkyl.
In certain embodiments of this aspect of the invention, X is fluoro, chloro or bromo. In certain embodiments, X is fluoro.
In another embodiment of the synthetic process of the invention or embodiments thereof, M is Li+, Na+, K+ or Cs+; M is Li+, Na+ or K+; M is Na+ or K+; or M is K+.
In a further embodiment of the synthetic process of the invention or embodiments thereof, X1 is halogen, -OTf or -Oms; X1 is halogen; X1 is fluoro, chloro or bromo; or X1 is bromo. In an additional embodiment of the synthetic process of the invention or embodiments thereof, R is CR5. In other embodiments, R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Ci-C6 alkoxy)Ci-C6 alkyl, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6
alkoxy), -(CH2)i-5-C(0)NH2, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl. In further embodiments, R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy)Ci-C6 alkyl, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl. In still further embodiments, R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)Ci-C6 alkyl, (aryl)Ci-C6 alky] and (heteroaryl)Ci-C6 alkyl. In some embodiments, R5 is selected from the group consisting of hydrogen C1-C6 alkyl and (C1-C6 alkoxy)Ci-C6 alkyl and in other embodiments R5 is selected from the group consisting of hydrogen and C1-C6 alkyl. In further embodiments, R5 is C1-C6 alkyl, and in an additional embodiment, R5 is hydrogen.
In an additional embodiment of the synthetic process of the invention or embodiments thereof, R is N.
In another embodiment of the synthetic process of the invention or embodiments thereof, R1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl). In a further embodiment, R1 is hydrogen, halogen, cyano, hydroxy or C1-C6 alkyl, and in a still further embodiment, R1 is hydrogen, cyano or C1-C6 alkyl. In an additional embodiment, R1 is hydrogen. In another embodiment, R1 is C1-C6 alkyl. Moreover, R1 may be hydrogen cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl); R1 may be C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl); R1 may be hydrogen, cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci- C6 alkyl) or (Ci-C6 alkoxy)Ci-C6 alkyl; R1 may be Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci- Ce alkoxy), hydroxy(Ci-C6 alkyl) or (C1-C6 alkoxy)Ci-C6 alkyl; R1 may be hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(Ci-C6 alkyl) or (C1-C6 alkoxy)Ci-C6 alkyl; R1 may be C1-C6 alkyl, C1-C6 alkoxy, hydroxy(Ci-C6 alkyl) or (C1-C6 alkoxy)Ci-C6 alkyl; R1 may be hydrogen, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl); R1 may be Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (C1-C6 alkyl)sulfanyl(Ci-C6 alkyl); R1 may be hydrogen, cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy or halo(Ci-C6 alkoxy); or R1 may be C1-C6 alkyl, halo(Ci-C6 alkyf C1-C6 alkoxy or halo(Ci-C6 alkoxy).
In a further embodiment of the synthetic process of the invention or embodiments thereof, R2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl or formyl(Co-C6 alkyl); R2 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C, alkoxy) or (C1-C6 alkoxy)Ci-C6 alkyl; R is cyano, C1-C6 alkyl, C1-C6 alkoxy or (C1-C6 alkoxy)Ci-C6 alkyl; R2 is C1-C6 alkyl or C1-C6 alkoxy; R2 is C1-C6 alkyl; R2 is cyano, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R2 is Ci-C6 alkyl, amino(Ci-C alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R2 is cyano, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (C1-C6 alkyl)sulfanyl(Ci-C6 alkyl), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R2 is Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C alkoxy) or -(CH2)i_5-C(0)NH2; R2 is cyano, Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R2 is Ci-Ce alkyl, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; or R2 is Ci-C6 alkyl, -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy) or -(CH2)i_5-C(0)NH2.
In an additional embodiment of the synthetic process of the invention or embodiments thereof, R3 is cyano, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, -(CH2)i_5-C(0)NH(Ci-C alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R3A is -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy) R3A is -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R3A is -CH=CH-C(0)(Ci-C6 alkoxy); R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R3A is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl) or -CH=CH-C(0)(Ci-C6 alkoxy); R3A is cyano, Ci-C6 alkyl, halo(Ci-C6 alkyl) C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl,
or -CH=CH-C(0)(Ci-C6 alkoxy); R3A is Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl or -CH=CH-C(0)(Ci-C6 alkoxy); R3A is Ci-C6 alkyl, halo(Ci-C6 alkyl)
or -CH=CH-C(0)(Ci-C6 alkoxy); or R3A is halo(Ci-C6 alkyl), halo(Ci-C6 alkoxy) or -CH=CH-C(0)(Ci-C alkoxy).
In an another embodiment of the synthetic process of the invention or embodiments thereof, R4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy, (aryl)Ci-C6 alkyl, 01 (heteroaryl)Ci-C6 alkyl; R4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R4 is hydroxy, C1-C6 alkoxy, halo(Ci-C6 alkoxy) or benzyloxy; R4 is hydroxy, cyano, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R4 is hydroxy, halogen, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R4 is hydroxy, C1-C6 alkoxy or halo(Ci-C6 alkoxy); R4 is C1-C6 alkoxy or halo(Ci-C6 alkoxy); R4 is hydroxy or C1-C6 alkoxy; R4 is Ci-C6 alkoxy; R4 is cyano, Ci-C6 alkoxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)] 5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(U)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH, -0(CH2)i-5-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; R4 is C1-C6
alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6
alkoxy), -0(CH2)i-5-C(0)OH or-0(CH2)i-5-C(0)(Ci-C6 alkoxy); R4 is cyano, Ci-C6
alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH
or-0(CH2)i_5-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy, -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R4 is cyano, Ci-C6
alkoxy, -(CH2)i-5-C(0)OH or -CH=CH-C(0)OH; R4 is Ci-C6 alkoxy, -(CH2)i_5-C(0)(Ci-C6 alkoxy), or -CH=CH-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy, -(CH2)i_5-C(0)OH or -(CH2)i_5-C(0)(Ci-C6 alkoxy
R4 is cyano, Ci-C6 alkoxy, -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy, or -(CH2)i-5-C(0)OH or -(CH2)i_5-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy, or -(CH2)i_5-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy or -CH=CH-C(0)OH; or R4 is Ci-C6 alkoxy or -CH=CH-C(0)(Ci-C6 alkoxy
In one embodiment of the synthetic process of the invention, R is CH; R1 is C1-C6 alkyl; R2 is Ci- C6 alkyl; R3A -CH=CH-C(0)(Ci-C6 alkoxy); R4 is Ci-C6 alkoxy; X is fluoro; M is K+; and X1 is bromo.
The synthetic processes disclosed herein may be used to prepare compounds of the following formulas:
Figure imgf000032_0001
(lib)
(Ila)
Figure imgf000032_0002
(lie) (lid)
Figure imgf000032_0003
(Ilf)
(He)
Figure imgf000032_0004
Figure imgf000033_0001
(Urn) or a pharmaceutically acceptable salt thereof.
In further embodiments, the synthetic processes disclosed herein may further comprise
hydrogenation of a compound of formula (II) wherein R3 is -CH=CH-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)(O-C6 alkoxy). This embodiment may additionall} comprise hydrolysis of a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)OH.
Definitions
The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3,7- dimethylocta-2,6-dienyl.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the paren molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, -CH2CH2- , -CH2CH2CHC(CH3)-, -CH2CH(CH2CH3)CH2-.
The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from one to six, from one to four, from on to three, from one to two, or from two to three. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. An alkylene chain also may be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.
The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3- butynyl, 2-pentynyl, and 1-butynyl.
The term "aryl," as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3- dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-l-yl, inden 2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen- 1-yl, 5,6,7,8-tetrahydronaphthalen- 1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,
2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,
2,3-dihydrobenzofuran-7-yl, benzo[d][l,3]dioxol-4-yl, benzo[d][l,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-l,3-dion-4-yl, isoindoline-l,3-dion-5-yl, inden- l-on-4-yl, inden- l-on-5-yl, inden- l-on-6-yl, inden- l-on-7-yl, 2,3- dihydrobenzo[b][l,4]dioxan-5-yl, 2,3-dihydrobenzo[b][l,4]dioxan-6-yl, 2H-benzo[b][l,4]oxazin3(4H)- on-5-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-7-yl, 2H- benzo[b][l,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin- 4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin-2(lH)-on-5-yl, quinoxalin-2(lH)-on-6-yl, quinoxalin-2(lH)-on-7-yl, quinoxalin-2(lH)-on-8-yl, benzo[d]thiazol-2(3H)- on-4-yl, benzoLdJthiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo|dJthiazol-2(3H)-on-7 yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
The term "halo" or "halogen" as used herein, means -CI, -Br, -I or -F.
The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms.
The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiet} through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to,
benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-l-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7, 8-tetrahydroquinolin-2-yl, 5,6,7,8- tetrahydroquinolin-3-yl, 5,6,7, 8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin- 1-yl,
thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c] [ 1 ,2,5] oxadiazolyl, and 6,7-dihydrobenzo[c] [ 1 ,2,5]oxadiazol- 4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic eteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionall; substituted with one or two groups which are independently oxo or thia.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio or which have otherwise been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
The present invention may be better understood with reference to the accompanying examples tha are intended for purposes of illustration only and should not be construed to limit the scope of the invention.
EXAMPLES
Example 1: New compounds to specifically target tumor with mesenchymal phenotype
New Goodpasture antigen binding protein (GPBP)-inhibitor compounds with an improved therapeutic profile relative to earlier GPBP inhibitors were sought, e.g. compounds having limited A549 toxicity (IC50 elevated) and synergism with doxorubicin in reducing A549 cell viability (reduction of doxorubicin IC50). A variety of new compounds were synthesized to identify T12 related compounds with improved performance in water solubility, lower epithelial toxicity (higher IC50) or synergy with doxorubicin.
Among a total of 126 compounds synthesized, 99 were terphenyls and the rest synthetic intermediates. All compounds were tested for doxorubicin synergism and compared to T12, the terphenyl shown previously to be active against mesenchymal progenitor cancer phenotypes (WO/2014/006020 anc WO/2016/107906). 33 terphenyls displaying similar doxorubicin synergism to T12 were selected, and a further 14 compounds were selected because they exhibited higher IC50 for the epithelial phenotype (A549).
A representative collection of T12 derivatives with their chemical structure and quantified selection criteria is displayed in Table 1. Displayed are from left to right columns: the chemical structure of the individual compounds determined by ΧΗ and 13C NMR; MW; log S calculated using the Chemdraw Professional 15.0 algorithms. Log S of T12 was -6.49. Asterisks indicate compounds with significant improved solubility with respect to T12; synergy with doxorubicin as fold reduction of doxorubicin IC50 (compound concentration used: 50 uM); normalized synergy as fold with respect to the doxorubicin synergy of T12; the IC50; and the normalized IC50 respect to T12. All ex vivo determinations were done on A549 cell cultures. Table 1
Figure imgf000037_0001
MW Synergy with Normalized 1( 50 Normalized
Structure LogS
(gmd1) Doxorubicin Synergy (μΜ) I ( 50
371.44 -6.86 3.0 0.6 80 1.1
Figure imgf000038_0001
T82 (26)
425.41 -6.86 6.2 1.7 48 0.6
T93 (27)
401.46 -6.91 2.7 0.8 72 1.0
Figure imgf000038_0002
(28)
421.88 -6.60 3.5 1.0 78 1.0
Figure imgf000038_0003
(29)
358.40 -5.01* 2.9 0.6 >400 ND
Figure imgf000038_0004
T97 (30)
374.43 -6.05 5.8 1.4 91 1.0
T109 (40) MW Synergy with Normalized 1( 50 Normalized
Structure LogS
(gmot1) Doxorubicin Synergy (μΜ) I ( 50
428.41 -6.69 3.9 1.0 69 1.0
Figure imgf000039_0001
T123 (41)
404.46 -5.96 4.0 1.0 74 1.1
Figure imgf000039_0002
T125 (42)
424.88 -6.44 3.6 0.9 79 1.1
Figure imgf000039_0003
T122 (43)
358.43 -6.81 5.2 1.0 59 0.8
Figure imgf000039_0004
T78 (55)
412.40 -7.45 5.0 1.2 67 0.7
Figure imgf000039_0005
Ti l l (56)
388.46 -6.72 4.8 1.2 73 0.8
Figure imgf000039_0006
T113 (57) MW Synergy with Normalized 1( 50 Normalized
Structure LogS
(gmot1) Doxorubicin Synergy d I ( 50
408.87 -7.20 4.1 1.0 58 0.6
Figure imgf000040_0001
T112 (58)
345.39 -5.61* 5.4 1.3 110 1.2
T115 (59)
369.41 -6.56 4.1 1.0 80 0.9
Figure imgf000040_0002
T114 (60)
374.43 -6.05 4.8 1.2 105 1.1
T116 (61)
371.44 -6.23 3.8 1.0 48 0.6
Figure imgf000040_0003
T94 (66)
376.45 -5.72* 4.9 1.0 105 1.1
T98 (68) MW Synergy with Normalized 1( 50 Normalized
Structure LogS
(gmd1) Doxorubicin Synergy (μΜ) I ( 50
344.40 -6.69 2.8 0.9 113 1.6
Figure imgf000041_0001
T117 (73)
372.42 -6.47 6.2 1.3 32 0.4
T83 (76)
Figure imgf000041_0002
332.39 -6.43 4.8 0.8 150 2.2 T66 (79)
Figure imgf000041_0003
386.37 -7.68 2.4 0.7 176 2.5
T96 (80)
410.89 -6.87 3.6 1.2 69 1.0
Figure imgf000041_0004
T105 (90)
347.41 -5.28* 3.0 0.7 297 3.3
T104 (91) MW Synergy with Normalized 1( 50 Normalized
Structure LogS
(gmd1) Doxorubicin Synergy (μΜ) I ( 50
390.47 -6.39 1.8 0.6 >100 ND
Figure imgf000042_0001
T107 (92)
376.45 -5.72* 2.8 0.9 108 1.5
T106 (93)
371.44 -6.23 2.5 0.8 84 1.2
Figure imgf000042_0002
T108 (94)
722.97 -10.42 — ND 36 0.44
Figure imgf000042_0003
BIO-SS-T12
(96)
Moreover, the terphenyls displaying better performance with doxorubicin were tested for their affinity for the mesenchymal GPBP multimer as determined by competing biotinylated-T12 binding to A427 cultures using In Cell technology. Specifically, A427 cells were seeded in 96 well plates, fixed, permeabilized and stained with 1 μΜ bioT12 and streptavidin-AF488, in the presence of the indicated competitor (terphenyl) at 50 μΜ. The fluorescence of individual cells was determined using an IN CELL Analyzer 2000. Results are shown in Figures 1A and IB. In the graphs are represented the average of fluorescence (+95% CI) measured in whole cells (Figure 1A) or in the cytoplasm of cells (Figure IB) of each staining/competition. The upper dotted line indicates the average of fluorescence (+95% CI) measured in cells stained without competitor (Cont) and the lower dotted line indicates the average of fluorescence (+95% CI) obtained using T12 as competitor. Two competitors indicated with arrows induced a precipitate formation in the wells and were discarded. The competitors that reduced the fluorescence more than T12 are indicated with their corresponding number and their data were compared with T12 to assess statistical significance, which is shown in the lower tables. T109 achieved statistically significant differences compared with T12.
From these comparative studies T109 was shown to exhibit improved properties over T12. Thus T109 reduced autophosphorylation and doxorubicin IC50 (synergism) more than T12 and more importantly, T109 exhibited higher IC50 for A549 and higher affinity for A427 than T12 (data not shown), revealing its lower inhibitory capacity over epithelial phenotype and higher inhibitory capacity over mesenchymal phenotype. Interestingly, T109 diverged from the original Ti l target sequence only ii a double bond in the propionic chain. This acrylic acid derivative was expected to provide structural rigidity to the substituent representing the side chain of the critical Glu264. Indeed, among all compounds synthesized, those significantly changing propionic acid in the third ring were essentially discarded durinj selection mainly because of low doxorubicin synergism, except for T109.
T109 testing was conducted for efficacy in animal models (A549 nude and 4T1
immunocompetent) to analyze its performance on tumor growth. The mammary fat pad n°4 of five-six weeks old BALB/c female mice were inoculated with 104 4T1 cells, in PBS. Mice were separated into three groups. One group was left untreated, one group was treated with T12 and the third group was treated with T109. Both terphenyls were administered diluted in drinking water at 0.1 mg/ml. The averagt dose of T12 and T109 was 10-12 mg/kg/day. Tumor sizes were measured on the indicated days with a digital caliper and volumes were calculated with the formula Volume = (lengh x width2)/2. Data was analyzed with GraphPad Prism. Results are shown in Figure 2. The graph represents average tumor volume (+SEM) over time. Statistically significant differences were observed in tumor volume and are indicated (*P<0.05, n=6 per group).
T109 displayed a similar anti-tumor effect as T12 in 4T1 and A549 models, however the presence of a hydroxyl group in the second ring improves water solubility and facilitates administration at higher doses in the drinking water than T12. The higher performance of T12 when compared to Tl 1 and the improved performance of T 109 with respect to T12 in vitro and ex vivo suggested that Ti l did not fully mimic interactive a-helix motif stabilizing the GPBP multimer. Indeed, the evidence suggests that the hydroxyl group in the second ring, by electrostatically disturbing carboxyl group of third ring (i.e.
hydrogen bond formation), prevented appropriated disruption of multimeric GPBP, revealing that Ser260 may be modified in the aggregated stated of mesenchymal multimeric GPBP. Accordingly, a MS/MS analysis of yeast recombinant GPBP revealed the presence of Ser260 being phosphorylated (data not 9„
shown) and suggested that phosphorylation/dephosphorization of Ser plays a role in GPBP
multimerization. Collectively, our structure-function studies suggested that propionic acid was the most critical substituent of the terphenyl-based compounds and confirmed the central structural role of Glu264 i stabilizing GPBP multimeric aggregates.
The evidence suggests that multimeric GPBP is mainly extracellular whereas intracellular GPBP i predominantly in a trimeric aggregated form. Recently work found that mesenchymal secreted circulating GPBP can be recaptured by epithelial cells (WO2015/044352) and undergo hyperphosphorylation by AMPK in the cytosol facilitating malignancy spreading (i.e. metastasis formation). A novel strategy has been developed focused on bonding one essential vitamin (D-biotin) as a carrier of the compound T12 (oi the compounds of the invention) through a disulfide linker (Bio-SS-T12) (Table 1). Once the adduct enters the cell the reducing environment will release free T12, or the T12 related compounds of the invention. Accordingly, bio-SS-T12 exhibits an enhanced potential to compromise the viability of carcinoma cell lines A549 and A427 exhibiting epithelial and mesenchymal phenotypes, respectively (data not shown). Thus bio-SS-T12 reduced IC50 for T12 between 2.9 (A427) and 2.3 (A549) times, demonstrating that enhanced intracellular delivery of T12 and T12 related compounds is a therapeutic approach to fight cancer.
Example 2: Terphenyl screening through bioT12 staining competition
Ten thousand A427 cells per well were seeded on 96 well plates and cultured at 37 °C and 5% CO overnight (18h).
Cells were fixed with 4% paraformaldehyde diluted in phosphate buffer saline (PBS) for 20 minutes at room temperature and further permeabilized with 0.2% Triton X100 diluted in PBS for 10 minutes at room temperature.
Cells were blocked first with 2.5% Horse Serum (Vector, S-2012; https://vectorlabs.com/uk/2-5- normal-horse-serum-blocking-solution.html) and later with Avidin/Biotin Blocking (Dako, X0590;
http://www.agilent.com/en/products/immunohistochemistry/ancillaries-for-ihc/blocking-reagents-buffers- diluents/biotin-blocking- system) .
Cells were incubated overnight at 4°C in a humidity chamber, with T12 staining solution with the corresponding competitor. The T12 staining solution is 1 μΜ biotinylated T12 (bioT12), streptavidin- AF488 (Molecular Probes, S32354; https://www.thermofisher.com order/catalog/product/S32354, diluted 1:400) and 0.6 μΜ 4',6-diamidino-2-phenylindole (DAPI; Molecular Probes, D1306;
https://www.thermofisher.com order/catalog/product/D1306) diluted in En Vision FLEX Antibody Diluer (Dako, K8006; http://www.agilent.com/en/products/immunohistochemistry/visualization- systems/envision-flex-optional-reagents/antibody-diluent). T12 staining solutions were incubated for 1 h before they were added to cells. DAPI stains nuclei which are used to identify individual cells.
Once staining was done cells were conserved with a drop of Fluorescence Mounting Medium (Dako, S3023; http://www.agilent.com/en/products/immunohistochemistry/ancillaries-for-ihc/mounting- media/fluorescence-mounting-medium). Plates were stored at 4 °C.
Cells were washed twice with PBS between steps (culture media or buffer changes).
To determine background fluorescence cells were stained without bioT12 in the staining solution. The maximal fluorescence was determined staining cells without competitors.
The fluorescence emitted by the complex T12-biotin-streptavidin-AF488 was measured in individual cells using an IN CELL Analyzer 2000 device (GE). Briefly, DAPI fluorescence emission was used to identify individual cells and green fluorescence (AF488) was measured in each individual cell. Ai average of 540 cells, and at least 300 cells, were measured in each well. Analysis was done at least in duplicates. Finally, the average of fluorescence of whole cells or their cytoplasm and the 95% CI
(confidence interval) were represented. Data was analyzed to determine statistically significant differences (GraphPad Prism).
Example 3: Preparation of T12 and T12 Derivatives
The first step of this synthesis consisted of the regio selective bromination of commercial 3- hydroxybenzaldehyde in accordance with a known procedure (Kaiser et al. J. Org. Chem. 2002, (57, 9248 9256). The resulting bromoaryl 1 was then transformed in boronate 4 with a good overall yield (Scheme 1).
Figure imgf000045_0001
Scheme 1: synthesis of the boronate 4
Boronate 4 was then used with commercial 5-bromosalicylaldehyde to give biphenyl 5 and the formyl group was converted into a cyano group (6) by reaction with iodine in basic medium. Thereafter, the phenol was transformed into the corresponding triflate 7 with a good overall yield (Scheme 2).
Figure imgf000046_0001
(78%) (80%)
Scheme 2: synthesis of triflate 7
Scheme 3 shows the way the triflate 7 was reacted with different commercial boronic acids or boronates to give the compounds 8-13 with moderate yields. The formyl group of the compound 13 was transformed into a cyano group (14). The last step of the synthesis was the basic hydrolysis of the ethyl ester to give the final products 15-20 with excellent yields.
Figure imgf000047_0001
Scheme 3: synthesis of the compounds 15-20
The following step was the hydrogenation of the double bound of the compounds 8-12 to afford the intermediates 21-25 and the hydrolysis of the ethyl ester in basic medium to obtain the final products 26-30 with an excellent overall yield (Scheme 4).
Figure imgf000048_0001
25 (95%) 30 (90%)
Scheme 4: synthesis of the compounds 26-30
Using the same methodology of Suzuki couplings from triflate 31, a new family of compounds (40-43) with a hydroxyl group in the middle ring and an acrylic acid in the third one was obtained. This synthesis is described in Scheme 5:
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0003
Scheme 5: synthesis of compounds 40 - 43
Another family of analogous compounds was obtained (55-61), but in this case the hydroxyl grou] of the middle ring was changed by a methyl group. The main step of this new synthesis was the transformation of commercial 4-bromo-2-methylphenol into the trifluoroboronate 44 (Scheme 6), using the methodology described by Tudge et al. (J. Am. Chem. Soc. 2012, 134, 11667-11673).
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000051_0001
Scheme 6: synthesis of compounds 55 - 61
Moreover, compounds 66 and 68 were synthesized from intermediate 5 (Scheme 7).
Figure imgf000051_0002
Scheme 7: synthesis of compounds 66 and 68 Further, a new and multi-gram scale synthesis of compound T12 was designed (the first synthesis of this compound is described in US Patent No. 8,586,776). This new synthesis is shown in Scheme 8.
Figure imgf000052_0001
73 (75%) 74 (93%)
Figure imgf000052_0002
75 (98%) T12 (98%)
Scheme 8: new multi-gram scale synthesis of compound T12
Intermediates 32 and 72 were used to synthesize compounds 76 and 79-80, respectively (Scheme
9).
Figure imgf000053_0001
Mel = H 77 (si %)
K2C03 f 79 (99%)
acetone V R = e 78 (90%)
Figure imgf000053_0002
72 80 (18%)
Scheme 9: synthesis of compounds 76 and 79-80
A new family of compounds with a methyl group substituent in the 2' position instead of 3' of the second aryl ring was synthesized. The Scheme 10 shows the synthesis of compounds 90-94.
Figure imgf000054_0001
53
Figure imgf000055_0001
Scheme 10: synthesis of compounds 90-94
The Scheme 11 shows the synthesis of an adduct between T12 and D-biotin with the use of commercial 2,2'-dithiodiethanol as a linker. The position chosen to anchor T12 and D-biotin to the linker was the carboxylic acid (Scheme 11).
D-biotin
Figure imgf000055_0002
Scheme 11: synthesis of T12 biotinylated with a disulfide linker (96)
Example 4: Synthetic Procedures
The progress of reactions was monitored by thin-layer chromatography (TLC silica gel 60 F254 Merck) and the flash chromatography (FC) purifications used silica gel 60 (230-400 mesh ASTM Merck) All the compounds were white solids unless otherwise specified. All the NMR spectra were measured with a Bruker Advance AC-300 (300 MHz) apparatus.
2-bromo-5-hydroxybenzaldehyde (1)
Figure imgf000056_0001
A suspension of 3-hydroxybenzaldehyde (48.85 g, 400 mmol) in a 10: 1 mixture of chloroform/acetonitril (330 mL) was cooled with an ice bath. Then, bromine (63.9 g, 1 equiv) was added dropwise and the bath was removed to stir the mixture at room temperature. After 4 h, the reaction was quenched with a saturated NaHC03 solution (150 mL). The phases were separated and the organic layer was washed with water (150 mL). The concentrated organic phase was filtered through a thin pad of Celite and eluted with a 4: 1 mixture of dichloromethane/ethyl acetate. Solvent was removed in vacuo and the remaining solid was crystallized several times from ethyl acetate/hexane to give 44.15 g of 2-bromo-5- hydroxybenzaldehyde as light brown needles. Yield 55%; mp: 132-134 °C. XH NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, / = 8.7 Hz, 1H), 7.34 (d, 7 = 3.1 Hz, 1H), 7.10 (dd, Ji = 8.7 Hz, = 3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5Br02: 199.9472, found: 199.9463.
Ethyl (E)-3-(2-bromo-5-hydroxyphenyl)acrylate (2)
Figure imgf000056_0002
A mixture of 2-bromo-5-hydroxybenzaldehyde (44.25 g), malonic acid (45.81 g, 2 equiv), pyridine (100 mL) and piperidine (5 mL) as catalyst were stirred at 100 °C until completion of the reaction. Thereafter, ice- water (100 mL) was added and the mixture was acidified (pH=l) with concentrated HCl. The resultin precipitate was filtered, washed with acidic water, dried under vacuum and directly used in the next esterification reaction without further purification. To a solution of the precipitate in dry ethanol (100 mL was added a small quantity of H2S04 (1 mL) and the stirred mixture was refluxed overnight. The solvent was evaporated in vacuo and the crude was purified by crystallization from ethanol (TLC hexane/ethyl acetate 5: 1) to give 56.1 g of compound 2 as light brown needles. Yield 94%; mp: 96-98 °C. XH RMN (300 MHz, CD3COCD3) δ ppm: 8.82 (br s, 1H), 7.94 (d, / = 16.1 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.28
(d, / = 2.9 Hz, 1H), 6.88 (dd,
Figure imgf000057_0001
= 8.7 Hz, J2 = 2.9 Hz, 1H), 6.45 (d, J = 16.1 Hz, 1H), 4.24 (q, / = 7.1 Hz: 2H), 1.30 (t, 7 = 7.1 Hz, 3H); 13C RMN (75 MHz, CD3COCD3) δ ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2, 115.8, 62.1, 15.6; HRMS (EI) m/z: calcd for CnHnBr03: 269.9892, found:
269.9886.
Ethyl (E)-3-(2-bromo-5-methoxyphenyl)acrylate (3)
Figure imgf000057_0002
A solution of (E)-ethyl 3-(2-bromo-5-hydroxyphenyl)acrylate (4.9 g), potassium carbonate (3.0 g, 1.2 equiv) and methyl iodide (2.83 g, 1.1 equiv) in dry acetone (20 mL) was heated at 80 °C with a microwave oven until consumption of the starting material. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude was neutralized with 1M HC1 solution and extracted with AcOEt (3x20 mL). The combined organic layers were dried over Na2S04 and filtered. The volatiles were removed in vacuo and the crude was purified by FC (hexane/ AcOEt 10: 1) to afford 4.50 g of compound 3 as a transparent oil. Yield 87%. XH RMN (300 MHz, CDC13) δ ppm: 7.92 (d / = 15.9 Hz, 1H), 7.39 (d, / = 8.7 Hz, 1H), 7.03 (d, / = 3.3 Hz, 1H), 6.72 (dd, Ji = 9.0 Hz, J2 = 3.0 Hz, 1H), 6.30 (d, / = 15.9 Hz, 1H), 4.22 (q, 7 = 7.1 Hz, 2H), 3.74 (s, 3H), 1.29 (t, 7 = 7.2 Hz, 3H); 13C RMN (75 MHz, CDC13) δ ppm: 166.0, 158.8, 142.6, 134.8, 133.7, 120.9, 117.4, 115.7, 112.3, 60.5, 55.3, 14.1. -3-(5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acrylate (4)
Figure imgf000057_0003
(E)-ethyl 3-(2-bromo-5-methoxyphenyl)acrylate (2.03 g), bis(pinacolato)diboron (2.17 g, 1.2 equiv), potassium acetate (2.1 g, 3 equiv), and [l , -bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (156 mg, 0.03 equiv) were dissolved in anhydrous dioxane (25 mL) and the resulting mixture was heated at 100 °C under inert atmosphere until the completion of the reaction. Then, solvent was removed under reduced pressure and the residue was suspended in water and extracted with AcOEt (3x10 mL). The organic layers were dried over Na2S04, filtered and evaporated. The crude was purified by EC (hexane/AcOEt 10: 1) to give 1.64 g of compound 4 as a transparent oil. Yield 70%. lH RMN (300 MHz, CDC13) δ ppm: 8.60 (d, / = 16.2 Hz, 1H), 7.78 (d, / = 8.1 Hz, 1H), 7.16 (d, / = 2.4 Hz, 1H), 6.89 (dd,
Figure imgf000058_0001
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.35 (d, / = 15.9 Hz, 1H), 4.25 (q, / = 7.1 Hz, 2H), 3.82 (s, 3H), 1.35 (s, 12H), 1.34 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 167.0, 161.7, 145.4, 142.1, 138.0, 119.0, 114.9, 110.4, 83.7, 60.2, 55.1, 24.9, 24.7, 14.2. -3-(3'-formyl-4'-hydroxy-4-methoxy-[l,l'-biphenyl]-2-yl)acrylate (5)
Figure imgf000058_0002
5-bromosalicylaldehyde (804 mg), boronate (1.45 g, 1.1 equiv) and palladium tetrakistriphenylphosfine (138 mg, 0.03 equiv) were dissolved in a 10: 1 mixture of dimethoxyethane/ethanol (20 mL). Then, a 2 M aqueous Na2C03 solution (848 mg, 2 equiv) was added to this yellow solution and the resulting mixture was refluxed under inert atmosphere until the completion of the reaction. Thereafter, the mixture was concentrated in vacuo and the residue was taken up in water and extracted with AcOEt (3x10 mL). The combined organic fractions were dried over Na2S04, filtered and evaporated. The crude was purified by FC (hexane/ AcOEt 10: 1) and recrystallized from EtOH to give 823 mg of compound 5. Yield 63%; mp: 95-97 °C. XH RMN (300 MHz, CDCI3) δ ppm: 11.04 (s, 1H), 9.90 (s, 1H), 7.63 (d, / = 15.9 Hz, 1H), 7.48 7.41 (m, 2H), 7.26 (d, / = 8.4 Hz, 1H), 7.18 (d, / = 2.4 Hz, 1H), 7.05 (d, / = 9.3 Hz, 1H), 7.00 (dd,
Figure imgf000058_0003
= 8.7 Hz, = 2.7 Hz, 1H), 6.40 (d, / = 15.9 Hz, 1H), 4.21 (q, / = 7.1 Hz, 2H), 3.87 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 196.5, 166.6, 160.8, 159.1, 143.0, 138.4, 134.5, 133.6, 131.5, 131.4, 120.3, 119.9, 117.7, 116.3, 111.3, 60.5, 55.4, 14.2. -3-(3'-cyano-4'-hydroxy-4-methoxy-[l,l'-biphenyl]-2-yl)acrylate (6)
Figure imgf000058_0004
To a solution of ethyl (E)-3-(3'-formyl-4'-hydroxy-4-methoxy-[l,l'-biphenyl]-2-yl)acrylate (400 mg) in a 4: 1 mixture of ammonium hydroxide/water (5 mL) was added iodine (622 mg, 2 equiv) and the mixture was stirred at room temperature until consumption of the starting material. The reaction was quenched with 5% Na2S203 aqueous solution (2 mL) and neutralized with 1M HCl solution. The resulting mixture was extracted with AcOEt (3x5 mL) and the combined organic layers were dried over Na2S04, filtered and evaporated. The crude was purified by FC (hexane/AcOEt 2: 1) to give 310 mg of compound 6. Yield
78%, mp: 170- 172 °C. ¾ RMN (300 MHz, CDC13) δ ppm: 7.50 (d, / = 15.9 Hz, 1H), 7.29 (d, / = 2.4 Hz, 1H), 7.21 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 7.12 (d, / = 8.7 Hz, 1H), 7.07 (d, / = 2.7 Hz, 1H), 6.91 (d, / = 8.7 Hz, 1H), 6.90 (dd,
Figure imgf000059_0001
= 8.7 Hz, J2 = 2.7 Hz, 1H), 6.30 (d, / = 15.9 Hz, 1H), 4.13 (q, / = 7.1 Hz, 2H). 3.78 (s, 3H), 1.22 (t, 7 = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 167.0, 159.1, 158.9, 143.1, 135.8, 133.7, 133.2, 131.3, 131.2, 119.4, 116.7, 116.2, 115.9, 111.2, 99.4, 60.6, 55.2, 13.9. -3-(3'-cyano-4-methoxy-4'-(((trifluoromethyl)sulfonyl)oxy)-[l,l'-biphenyl]-2-yl)acrylate (7
Figure imgf000059_0002
A solution of ethyl (E)-3-(3'-cyano-4'-hydroxy-4-methoxy-[l,l'-biphenyl]-2-yl)acrylate (302 mg) and pyridine (148 mg, 2 equiv) in dry dichloromethane (10 mL) was chilled in an ice bath. Then, triflic anhydride (395 mg, 1.5 equiv) was added dropwise. The mixture was stirred at room temperature until completion of the reaction. Next, 1M HC1 solution (5 mL) was added and the layers were separated. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude was purified by FC (hexane/AcOEt 4: 1) to afford 342 mg of compound 7. Yield 80%; mp: 115- 117 °C. XI RMN (300 MHz, CDCI3) δ ppm: 7.62-7.38 (m, 4H), 7.27 (d, / = 8.1 Hz, 1H), 7.12 (d, / = 2.7 Hz, 1H), 6.96 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.33 (d, / = 15.9 Hz, 1H), 4.15 (q, / = 7.1 Hz, 2H), 3.82 (s, 3H), 1.23 (t, / = 7.2 Hz, 3H); 19F NMR (282 MHz, CDCI3) δ ppm: -73.02 (s, 3F); 13C RMN (75 MHz, CDC ) δ ρρηι: 166.2, 160.2, 148.6, 141.7, 141.0, 135.9, 135.1, 133.9, 131.5, 130.9, 122.5, 121.3, 118.6 (q, J = 318.9 Hz), 116.3, 113.3, 112.0, 107.3, 60.7, 55.5, 14.2.
General procedure for the synthesis of terphenyls (Suzuki coupling reaction):
Triflate (1 equiv), commercial boronic acid or boronate (1.2 equiv), sodium carbonate (2 equiv) and palladium tetrakistriphenylphosphine (0.01 equiv) were dissolved in a 7:3 mixture of acetonitrile/water (5 mL) and refluxed under inert atmosphere until completion of the reaction. Thereafter, the mixture was neutralized with 1M HC1 solution and was extracted with AcOEt (3x5 mL). The combined organic fractions were dried over Na2S04, filtered and evaporated. The crude was purified by FC.
Ethyl (E)-3-(3,-cyano-4-methoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylate (8)
Figure imgf000060_0001
By Suzuki reaction of triflate 7 and m-tolylboronic acid. The crude was purified by FC (hexane/AcOEt 5: 1) to afford compound 8. Yield 36%, mp: 122-124 °C. lH RMN (300 MHz, CDC13) δ ppm: 7.60-7.52 (m, 2H), 7.48-7.40 (m, 2H), 7.36-7.26 (m, 3H), 7.22-7.14 (m, 2H), 7.11 (d, / = 2.7 Hz, 1H), 6.93 (dd,
Figure imgf000060_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.34 (d, / = 15.9 Hz, 1H), 4.14 (q, / = 7.1 Hz, 2H), 3.78 (s, 3H), 2.35 (s, 3H), 1.21 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 166.4, 159.5, 144.1, 142.5, 139.1, 138.3, 137.6, 134.5, 134.2, 133.7, 132.6, 131.5, 129.9, 129.4, 129.4, 128.5, 125.8, 120.3, 118.5, 116.2, 111.6, 111.2, 60.5, 55.4, 21.3, 14.1.
Ethyl (E)-3-(3,-cyano-4-methoxy-3M-(trifluoromethyl)-[l,l':4,,l"-terphenyl]-2-yl)acrylate (9)
Figure imgf000060_0003
By Suzuki reaction of triflate 7 and 3-(trifluoromethyl)phenylboronic acid. The crude was purified by FC (hexane/AcOEt 10: 1) to afford compound 9. Yield 34%, mp: 133-135 °C. lH RMN (300 MHz, CDCI3) δ ppm: 7.82-7.82 (m, 2H), 7.77-7.57 (m, 6H), 7.31 (d, / = 8.4 Hz, 1H), 7.22 (d, / = 2.7 Hz, 1H), 7.05 (dd, J = 8.7 Hz, = 2.7 Hz, 1H), 6.45 (d, / = 15.6 Hz, 1H), 4.24 (q, / = 7.1 Hz, 2H), 3.90 (s, 3H), 1.32 (t, / = 7.1 Hz, 3H); 19F NMR (282 MHz, CDCI3) δ ppm: -63.11 (s, 3F); 13C RMN (75 MHz, CDC ) δ ppm: 166.5, 159.8, 142.5, 140.3, 138.4, 134.7, 134.5, 133.9, 132.4, 132.1, 131.5, 131.1, 130.0, 129.3, 125.7 (q, / = 3.7 Hz), 125.5 (q, / = 3.6 Hz), 120.6, 118.0, 116.4, 111.8, 111.5, 60.6, 55.5, 14.2.
Ethyl (E)-3-(3,-cyano-4,4"-dimethoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylate (10)
Figure imgf000060_0004
By Suzuki reaction ol triflate 7 and 4-methoxy-3-methylbenzeneboronic acid. The crude was purified by
FC (hexane/AcOEt 4: 1) to afford compound 10. Yield 40%, mp: 145- 147 °C. lH RMN (300 MHz, CDCl: δ ppm: 7.70-7.62 (m, 2H), 7.57-7.37 (m, 4H), 7.30 (d, / = 8.7 Hz, 1H), 7.21 (d, / = 2.7 Hz, 1H), 7.04 (dd, Ji = 8.7 Hz, = 2.7 Hz, 1H), 6.96 (d, / = 8.4 Hz, 1H), 6.43 (d, / = 15.9 Hz, 1H), 4.24 (q, / = 7.1 Hz, 2H) 3.90 (s, 3H), 3.89 (s, 3H), 2.31 (s, 3H), 1.31 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDC13) δ ppm: 166.5, 159.6, 158.3, 144.1, 142.7, 138.6, 134.6, 134.2, 133.8, 132.9, 131.5, 131.0, 129.8, 129.6, 127.4, 127.1, 120.4, 118.9, 116.3, 111.6, 111.1, 110.0, 60.6, 55.5, 55.4, 16.3, 14.2.
Ethyl (E)-3-(3"-chloro-3'-cyano-4,4"-dimethoxy-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (11)
Figure imgf000061_0001
By Suzuki reaction of triflate 7 and 3-chloro-4-methoxyphenylboronic acid. The crude was purified by F( (hexane/AcOEt 3: 1) to afford compound 11. Yield 39%, mp: 156- 158 °C. ¾ RMN (300 MHz, CDCI3) δ ppm: 7.67 (t, / = 1.2 Hz, 1H), 7.66-7.52 (m, 5H), 7.29 (d, / = 8.7 Hz, 1H), 7.21 (d, / = 2.7 Hz, 1H), 7.09- 7.01 (m, 2H), 6.43 (d, / = 15.9 Hz, 1H), 4.24 (q, / = 7.1 Hz, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 1.31 (t, / = 7.1 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 166.5, 159.7, 155.5, 142.6, 142.4, 139.4, 134.6, 134.4, 133.8, 132.6, 131.5, 130.9, 130.5, 129.7, 128.3, 122.9, 120.5, 118.4, 116.4, 112.1, 111.7, 111.2, 60.6, 56.3, 55.5, 14.3.
Ethyl (^-S-iS'-c ano^-methox ^'-ip ridin-S- -tl^'-biphen ll^- acr late (12)
Figure imgf000061_0002
By Suzuki reaction of triflate 7 and 3-pyridineboronic acid neopentylglycol ester. The crude was purified by FC (CH2Cl2/AcOEt 10: 1) to afford compound 12. Yield 21%, mp: 166- 168 °C. lH RMN (300 MHz, CDC ) δ ppm: 8.83 (d, / = 2.4 Hz, 1H), 8.75-8.69 (m, 1H), 8.04-7.98 (m, 1H), 7.75-7.71 (m, 1H), 7.68- 7.54 (m, 3H), 7.51-7.43 (m, 1H), 7.30 (d, / = 8.4 Hz, 1H), 7.22 (d, / = 2.7 Hz, 1H), 7.04 (dd, Ji = 8.4 Hz, Ji = 2.7 Hz, 1H), 6.44 (d, / = 15.9 Hz, 1H), 4.23 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 1.31 (t, / = 7.2 Hz, 3¾ 13C RMN (75 MHz, CDCb) δ ppm: 166.4, 159.8, 149.8, 149.2, 142.4, 140.4, 140.3, 136.2, 134.8, 134.6,
133.8, 133.6, 132.3, 131.5, 129.9, 123.4, 120.7, 117.9, 116.4, 111.8, 111.7, 60.6, 55.5, 14.2.
Ethyl (E)-3-(3'-cyano-3"-formyl-4-methoxy-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (13)
Figure imgf000062_0001
By Suzuki reaction of triflate 7 and 3-formylbenzeneboronic acid. The crude was purified by FC
(hexane/AcOEt 3: 1) to afford compound 13. Yield 34%, mp: 155- 157 °C. ¾ RMN (300 MHz, CDCb) δ ppm: 10.12 (s, 1H), 8.12-8.08 (m, 1H), 8.03-7.89 (m, 2H), 7.75-7.57 (m, 5H), 7.31 (d, 7 = 8.7 Hz, 1H), 7.22 (d, / = 2.4 Hz, 1H), 7.05 (dd,
Figure imgf000062_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.45 (d, / = 15.6 Hz, 1H), 4.24 (q, J = l, Hz, 2H), 3.90 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 191.7, 166.5, 159.8,
142.5, 142.5, 140.2, 138.7, 136.9, 134.7, 134.6, 134.5, 133.9, 132.4, 131.5, 130.1, 130.0, 129.8, 129.6,
120.6, 118.1, 116.4, 111.8, 111.5, 60.7, 55.5, 14.3.
Ethyl (E)-3-(3',3"-dicyano-4-methoxy-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (14)
Figure imgf000062_0003
To a solution of ethyl (E)-3-(3'-cyano-3"-formyl-4-methoxy-[l, :4', l"-terphenyl]-2-yl)acrylate (26 mg) ii a 4: 1 mixture of ammonium hydroxide/water (2 mL) was added iodine (32 mg, 2 equiv) and the mixture was stirred at room temperature until consumption of the starting material. The reaction was quenched with 5% Na2S203 aqueous solution (1 mL) and neutralized with 1M HCl solution. The resulting mixture was extracted with AcOEt (3x5 mL) and the combined organic layers were dried over Na2S04, filtered and evaporated. The crude was not further purified. Yield 99%. XH RMN (300 MHz, CDCb) δ ppm: 7.89 7.83 (m, 2H), 7.76-7.68 (m, 2H), 7.66-7.50 (m, 4H), 7.27 (d, / = 8.4 Hz, 1H), 7.18 (d, / = 2.7 Hz, 1H), 7.02 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 6.41 (d, / = 15.9 Hz, 1H), 4.20 (q, / = 7.1 Hz, 2H), 3.86 (s, 3H), 1.27 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 166.6, 159.8, 142.4, 141.4, 140.5, 138.9, 111.8, 111.2, 60.7, 55.4, 14.1.
General procedure for the hydrolysis of the ethyl or methyl ester group:
To a solution of ethyl/methyl ester in a 4: 1 tetrahydrofuran/water mixture, monohydrated lithium hydroxide (3 equiv) was added and the reaction was stirred at room temperature until consumption of the starting material. THF was removed under reduced pressure and the aqueous layer was acidified with 1 IV HC1 solution and extracted with AcOEt. The organic layers were combined, dried over Na2S04, filtered and removed in vacuo to give the final product without any further purification.
(E)-3-(3'-cyano-4-methoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylic acid (15)
Figure imgf000063_0001
Yield 99%, mp: 221-223 °C. XH RMN (300 MHz, CDCb) δ ppm: 7.69-7.61 (m, 2H), 7.57-7.49 (m, 2H), 7.43-7.34 (m, 3H), 7.31-7.23 (m, 2H), 7.21 (d, / = 2.7 Hz, 1H), 7.03 (dd,
Figure imgf000063_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.41 (d, / = 15.6 Hz, 1H), 3.88 (s, 3H), 2.43 (s, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 168.9, 159.6, 144.3, 143.6, 139.2, 138.4, 137.6, 134.5, 134.3, 133.6, 132.8, 131.5, 130.0, 129.5, 129.4, 128.6, 125.8, 120.2, 118.5, 116.5, 111.8, 111.2, 55.5, 21.4.
(E)-3-(3'-cyano-4-methoxy-3M-(trifluoromethyl)-[l,l':4',lM-terphenyl]-2-yl)acrylic acid (16)
Figure imgf000063_0003
Yield 97%, mp: 182- 184 °C. XH RMN (300 MHz, CDCb) δ ppm: 7.79-7.47 (m, 8H), 7.29-7.12 (m, 2H), 6.98 (dt, Ji = 8.7 Hz, = 2.7 Hz, 1H), 6.35 (dd, = 15.9 Hz, = 2.4 Hz, 1H), 3.82 (s, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -63.05 (s, 3F); 13C RMN (75 MHz, CDCb) δ ppm: 168.4, 159.7, 142.8, 140.2, 120.7, 117.9, 116.2, 111.8, 111.1, 55.3.
(E)-3-(3,-cyano-4,4"-dimethoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylic acid (17)
Figure imgf000064_0001
Yield 96%, mp: 235-237 °C. XH RMN (300 MHz, CDCb) δ ppm: 7.63-7.54 (m, 2H), 7.52-7.31 (m, 4H), 7.23 (d, / = 8.4 Hz, 1H), 7.16 (d, / = 2.7 Hz, 1H), 6.98 (dd,
Figure imgf000064_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.89 (d, / = 8.4 Hz, 1H), 6.35 (d, / = 15.6 Hz, 1H), 3.83 (s, 2x3H), 2.23 (s, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 168.5, 159.5, 158.2, 144.0, 143.2, 138.6, 134.4, 134.2, 133.6, 132.7, 131.4, 130.8, 129.7, 129.5, 127.2, 127.0, 120.3, 118.8, 116.2, 111.6, 110.6, 109.9, 55.3, 55.3, 16.0.
(E)-3-(3"-chloro-3'-cyano-4,4"-dimethoxy-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (18)
Figure imgf000064_0003
Yield 98%, mp: 256-257 °C. XH RMN (300 MHz, CDCb) δ ppm: 7.66-7.45 (m, 6H), 7.26-7.15 (m, 2H), 7.06-6.96 (m, 2H), 6.36 (d, / = 15.9 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 168.4, 159.6, 155.2, 143.0, 142.3, 139.4, 134.5, 134.4, 133.7, 132.4, 131.4, 130.8, 130.3, 129.7, 128.2, 122.8, 120.6, 118.3, 116.3, 112.0, 111.7, 110.9, 56.1, 55.4.
(E)-3-(3'-cyano-4-methoxy-4'-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)acrylic acid (19)
Figure imgf000064_0004
,
Yield 99%, mp: 285-287 °C. XH RMN (300 MHz, DMSO-d6) δ ppm: 8.86 (d, J = 2.1 Hz, 1H), 8.72 (dd, J
= 4.8 Hz, J2 = 1.2 Hz, 1H), 8.12 (dt, Ji = 8.1 Hz, J2 = 2.0 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.72 (dd, Ji = 8.1 Hz, J2 = 2.1 Hz, 1H), 7.60 (dd, Ji = 7.8 Hz, J2 = 4.8 Hz, 1H), 7.51-7.43 (m 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.13 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 3.88 (s, 3H); 13C RMN (75 MHz, DMSO-d6) δ ppm: 167.3, 159.4, 149.7, 149.0, 141.2, 139.9, 139.8, 136.3, 134.9 134.4, 133.2, 132.0, 131.8, 130.2, 123.6, 121.5, 118.0, 116.7, 111.4, 110.7, 55.5.
(E)-3-(3',3"-dicyano-4-methoxy-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (20)
Figure imgf000065_0001
Yield 98%. XH RMN (300 MHz, DMSO-d6) δ ppm: 8.20-8.12 (m, 1H), 8.06-7.89 (m, 3H), 7.82-7.67 (m, 3H), 7.46-7.34 (m, 3H), 7.11 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 3.87 (s, 3H); 13C RMN (75 MHz, DMSO-d6) δ ppm: 168.0, 159.4, 140.9, 140.1, 140.0, 138.4, 134.8, 134.3, 133.7 133.5, 132.4, 132.4, 131.8, 130.2, 129.9, 118.3, 117.9, 116.4, 111.9, 111.3, 110.6, 55.4.
General procedure for the hydrogenation of the acrylic double bound:
A solution of ethyl (E)-acrylate in ethyl acetate (3 mL) was hydrogenated at room temperature and atmospheric pressure using 10% palladium on carbon as catalyst (25% w/w). The progress of the reaction was monitored by TLC and the mixture was filtered over Celite. The filtrates were concentrated under vacuum and the resulting crude was not further purified.
Ethyl 3-(3'-cyano-4-methoxy-3"-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoate (21)
Figure imgf000065_0002
Yield 98%. XH RMN (300 MHz, CDC13) δ ppm: 7.70-7.66 (m, 1H), 7.59-7.51 (m, 2H), 7.45-7.37 (m, 3H) 7.30-7.26 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.84 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 4.09 (q, J = 1.1 Hz, 2H), 3.85 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.48 (t, 7 = 8.1 Hz, 2H), 2.46 (s, 3H),
1.21 (t, 7 = 7.1 Hz, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 172.5, 159.6, 143.9, 140.8, 139.3, 138.4,
137.8, 134.3, 133.9, 131.8, 131.3, 130.0, 129.5, 128.6, 125.8, 118.7, 114.7, 111.9, 111.2, 60.5, 55.3, 35.2,
28.3, 21.5, 14.2.
Ethyl 3-(3'-cyano-4-methoxy-3"-(trifluoromethyl)-[l,l':4',l"-terphenyl]-2-yl)propanoate (22)
Figure imgf000066_0001
Yield 99%. XH RMN (300 MHz, CDCb) δ ppm: 7.88-7.82 (m, 2H), 7.77-7.54 (m, 5H), 7.14 (d, 7 = 8.1 Hz, 1H), 6.88 (d, 7 = 2.4 Hz, 1H), 6.85 (dd, 7i = 8.1 Hz, = 2.7 Hz, 1H), 4.09 (q, 7 = 7.1 Hz, 2H), 3.85 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.49 (t, J = 7.8 Hz, 2H), 1.21 (t, 7 = 7.2 Hz, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -63.12 (s, 3F); 13C RMN (75 MHz, CDCb) δ ppm: 172.5, 159.8, 142.1, 141.8, 139.3, 138.6, 134.5, 134.2, 132.1, 131.5, 131.2, 131.1, 130.0, 129.3, 125.7 (q, 7 = 3.9 Hz), 125.5 (q, 7 = 3.7 Hz), 118.2, 114.7, 111.9, 111.3, 60.6, 55.3, 35.2, 28.2, 14.1.
Ethyl 3-(3'-cyano-4,4"-dimethoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)propanoate (23)
Figure imgf000066_0002
Yield 96%. XH RMN (300 MHz, CDCb) δ ppm: 7.66-7.63 (m, 1H), 7.57-7.49 (m, 2H), 7.47 (dd, 7i = 8.4 Hz, = 2.4 Hz, 1H), 7.39 (d, 7 = 1.8 Hz, 1H), 7.13 (d, 7 = 8.4 Hz, 1H), 6.96 (d, 7 = 8.4 Hz, 1H), 6.87 (d, 7 = 2.4 Hz, 1H), 6.84 (dd, 7i = 8.4 Hz, J2 = 2.7 Hz, 1H), 4.09 (q, 7 = 7.2 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.93 (t, 7 = 7.8 Hz, 2H), 2.48 (t, 7 = 8.0 Hz, 2H), 2.31 (s, 3H), 1.21 (t, 7 = 7.1 Hz, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 172.5, 159.5, 158.3, 143.7, 140.2, 139.3, 134.3, 133.8, 131.9, 131.2, 131.0, 129.8, 127.4, 127.1, 119.0, 114.7, 111.8, 110.9, 110.0, 60.5, 55.4, 55.3, 35.2, 28.3, 16.3, 14.1.
Ethyl 3-(3"-chloro-3'-cyano-4,4"-dimethoxy-[l,l':4',l"-terphenyl]-2-yl)propanoate (24)
Figure imgf000067_0001
Yield 99%. XH RMN (300 MHz, CDC13) δ ppm: 7.68-7.66 (m, 1H), 7.61 (d, / = 2.1 Hz, 1H), 7.59-7.48 (m, 3H), 7.13 (d, / = 8.4 Hz, 1H), 7.07 (d, / = 8.7 Hz, 1H), 6.87 (d, / = 2.4 Hz, 1H), 6.84 (dd, Ji = 8.1 Hz = 2.7 Hz, 1H), 4.09 (q, / = 7.1 Hz, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 2.92 (t, 7 = 7.8 Hz, 2H), 2.48 (t, / = 8.0 Hz, 2H), 1.21 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 172.5, 159.7, 155.4, 142.0, 141.0, 139.3, 134.4, 134.0, 131.6, 131.2, 131.0, 130.5, 129.7, 128.3, 122.9, 118.6, 114.7, 112.1, 111.9, 111.0, 60.5, 56.3, 55.3, 35.2, 28.3, 14.2.
Ethyl 3-(3'-cyano-4-methoxy-4'-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)propanoate (25)
Figure imgf000067_0002
Yield 95%. XH RMN (300 MHz, CDCI3) δ ppm: 8.84 (dd, Ji = 2.4 Hz, = 0.6 Hz, 1H), 8.72 (dd, Ji = 4.Σ Hz, J2 = 1.8 Hz, 1H), 8.04-7.99 (m, 1H), 7.73 (d, / = 1.2 Hz, 1H), 7.64 (dd, Ji = 8.1 Hz, J2 = 1.8 Hz, 1H), 7.57 (d, / = 7.8 Hz, 1H), 7.47 (dd = 7.8 Hz, J2 = 4.8 Hz, = 0.9 Hz, 1H), 7.14 (d, / = 8.1 Hz, 1H), 6.88 (d, / = 2.4 Hz, 1H), 6.85 (dd,
Figure imgf000067_0003
8.4 Hz, = 2.7 Hz, 1H), 4.09 (q, / = 7.1 Hz, 2H), 3.85 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.49 (t, / = 8.0 Hz, 2H), 1.21 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 172.5, 159.8, 149.8, 149.3, 142.0, 140.0, 139.3, 136.2, 134.6, 134.3, 133.7, 131.4, 131.2, 129.9, 123.4, 118.1, 114.8, 112.0, 111.5, 60.6, 55.3, 35.2, 28.2, 14.2.
3-(3'-cyano-4-methoxy-3"-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (26)
Figure imgf000067_0004
Yield 99%. XH RMN (300 MHz, CDCI3) δ ppm: 7.68-7.65 (m, 1H), 7.57-7.50 (m, 2H), 7.45-7.36 (m, 3H) 7.30-7.25 (m, 1H), 7.14 (d, / = 8.1 Hz, 1H), 6.89-6.82 (m, 2H), 3.85 (s, 3H), 2.94 (t, / = 7.8 Hz, 2H), 2.5: (t, / = 7.8 Hz, 2H), 2.45 (s, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 177.9, 159.6, 144.0, 140.7, 138.9,
138.4, 137.8, 134.3, 133.8, 131.8, 131.3, 130.0, 129.5, 128.6, 125.9, 118.7, 114.7, 112.0, 111.2, 55.3,
34.8, 29.7, 27.9, 21.4.
3-(3'-cyano-4-methoxy-3"-(trifluoromethyl)-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (27)
Figure imgf000068_0001
Yield 95%. XH RMN (300 MHz, CDCb) δ ppm: 7.87-7.81 (m, 2H), 7.76-7.53 (m, 5H), 7.14 (d, / = 8.7 Hz, 1H), 6.89-6.83 (m, 2H), 3.85 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.54 (t, / = 7.8 Hz, 2H); 19F NMR (282 MHz, CDCb) δ ppm: -63.10 (s, 3F); 13C RMN (75 MHz, CDCb) δ ppm: 177.6, 159.8, 142.1, 141.7, 138.9, 138.6, 134.5, 134.2, 132.1, 131.5, 131.3, 131.1, 130.0, 129.3, 125.7 (q, / = 3.8 Hz), 125.5 (q, / = 3.4 Hz), 118.1, 114.8, 112.0, 111.4, 55.3, 34.8, 27.9.
3-(3'-cyano-4,4"-dimethoxy-3"-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (28)
Figure imgf000068_0002
Yield 98%. XH RMN (300 MHz, CDCb) δ ppm: 7.63 (t, / = 1.2 Hz, 1H), 7.51 (d, / = 1.2 Hz, 2H), 7.46 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.38 (d, / = 1.8 Hz, 1H), 7.13 (d, / = 8.1 Hz, 1H), 6.95 (d, 7 = 8.4 Hz, 1H), 6.86 (d, / = 2.4 Hz, 1H), 6.84 (dd, Ji = 8.1 Hz, = 2.7 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.53 (t, / = 7.8 Hz, 2H), 2.30 (s, 3H); 13C RMN (75 MHz, CDCb) δ ppm: 177.7, 159.6, 158.3, 143.8, 140.1, 138.9, 134.3, 133.8, 131.9, 131.3, 131.0, 129.8, 129.7, 127.4, 127.1, 119.0, 114.7, 111.9, 110.9, 110.0, 55.4, 55.3, 34.8, 28.0, 16.3.
3-(3"-chloro-3'-cyano-4,4"-dimethoxy-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (29)
Figure imgf000069_0001
Yield 95%. XH RMN (300 MHz, CDC13) δ ppm: 7.65 (d, / = 1.5 Hz, 1H), 7.61 (d, / = 2.1 Hz, 1H), 7.57- 7.47 (m, 3H), 7.13 (d, / = 8.4 Hz, 1H), 7.06 (d, / = 8.4 Hz, 1H), 6.87 (d, / = 2.4 Hz, 1H), 6.84 (dd,
Figure imgf000069_0002
= 8.1 Hz, h = 2.7 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 2.92 (t, J = 7.8 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H); 13C RMN (75 MHz, CDCI3) δ ppm: 177.5, 159.7, 155.4, 142.1, 140.9, 138.9, 134.4, 134.0, 131.7, 131.3, 131.0, 130.5, 129.8, 128.3, 122.9, 118.5, 114.7, 112.1, 112.0, 111.1, 56.3, 55.3, 34.7, 27.9.
3-(3'-cyano-4-methoxy-4'-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)propanoic acid (30)
Figure imgf000069_0003
Yield 90%. XH RMN (300 MHz, CDCI3) δ ppm: 8.78 (br s, 1H), 8.66 (d,
Figure imgf000069_0004
= 8.7 Hz, 1H), 7.72 (d, / = 1.5 Hz, 1H), 7.62 (dd,
Figure imgf000069_0005
= 7.8 Hz, J2 = 1.8 Hz, 1H), 7.54 (d, / = 7.8 Hz, 1H), 7.47 (dd, Ji = 7.8 Hz, J2 = 4.8 Hz, 1H), 7.11 (d, / = 8.4 Hz, 1H), 6.87 (d, / = 2.7 Hz, 1H), 6.82 (dd,
Figure imgf000069_0006
= 8.4 Hz, J2 = 2.7 Hz, 1H), 3.83 (s, 3H), 2.89 (t, / = 8.0 Hz, 2H), 2.46 (t, / = 8.0 Hz, 2H); 13C RMN (75 MHz, CDCl3) 5 ppm: 159.7, 149.2, 148.8, 142.1, 139.6, 139.4, 136.6, 134.6, 134.3, 134.0, 131.3, 131.1, 129.9, 123.6, 118.0, 114.7, 111.9, 111.3, 55.3, 34.9, 28.1.
Ethyl (E)-3-(3'-formyl-4-methoxy-4'-(((trifluoromethyl)sulfonyl)oxy)-[l,l'-biphenyl]-2-yl)acrylat^ (31)
Figure imgf000069_0007
By reaction of compound 5 with triflic anhydride. The crude was purified by FC (hexane/AcOEt 5: 1). Yield 73%. lH NMR (300 MHz, CDCI3) δ ppm: 10.27 (s, 1H), 7.88 (d, / = 2.4 Hz, 1H), 7.59 (dd, Ji = 8.4 Hz, /2 = 2.4 Hz, 1H), 7.52 (d, / = 15.9 Hz, 1H), 7.45 (d, 7 = 8.7 Hz, 1H), 7.27 (d, 7 = 8.7 Hz, 1H), 7.18 (d 2H), 3.86 (s, 3H), 1.25 (t, / = 7.2 Hz, 3H); 19F NMR (282 MHz, CDC13) δ ppm: -73.36 (s, 3F); 13C NMR (75 MHz, CDC ) δ ppm: 186.3, 166.2, 159.8, 148.7, 142.0, 140.8, 136.8, 133.7, 131.9, 131.7, 131.4, 128.1, 122.2, 120.7, 118.6 (q, J = 318.8 Hz), 116.2, 111.7, 60.5, 55.3, 14.0.
Ethyl (E)-3-(3'-formyl-4-methoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylate (32)
Figure imgf000070_0001
By Suzuki reaction of triflate 31 and m-tolylboronic acid. The crude was purified by FC (hexane/AcOEt
7: 1) and recrystallized from ethanol. Yield 56%; mp: 109- 111 °C. XH NMR (300 MHz, CDCb) δ ppm: 10.04 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.70 (d, / = 15.9 Hz, 1H), 7.56-7.48 (m, 2H), 7.43-7.33 (m, 2H), 7.31-7.20 (m, 4H), 7.04 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 6.43 (d, / = 15.9 Hz, 1H), 4.22 (q, / = 7.1 Hz, 2H), 3.90 (s, 3H), 2.45 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 192.4, 166.7, 159.3, 144.9, 143.2, 139.2, 138.2, 137.3, 134.9, 134.1, 133.7, 133.6, 131.7, 130.9, 130.7, 128.9, 128.4, 128.3, 127.3, 119.9, 116.3, 111.4, 60.5, 55.5, 21.4, 14.3.
Ethyl (E)-3 3'-formyl-4-methoxy-3M trifluoromethyl)-[l,l,:4,,lM-terphenyl]-2-yl)acrylate (33)
Figure imgf000070_0002
By Suzuki reaction of triflate 31 and 3-trifluoromethylboronic acid. The crude was purified by FC
(hexane/AcOEt 7: 1) and recrystallized from ethanol. Yield 52%. mp: 107- 109 °C. XH NMR (300 MHz, CDCb) δ ppm: 9.92 (s, 1H), 7.91 (d, 7 = 1.8 Hz, 1H), 7.68-7.60 (m, 2H), 7.59-7.46 (m, 4H), 7.41 (d, / = 8.1 Hz, 1H), 7.26 (d, / = 8.4 Hz, 1H), 7.14 (d, / = 2.7 Hz, 1H), 6.96 (dd,
Figure imgf000070_0003
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.36 (d, / = 15.9 Hz, 1H), 4.14 (q, / = 7.2 Hz, 2H), 3.81 (s, 3H), 1.21 (t, 7 = 7.1 Hz, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -63.06 (s, 3F); 13C NMR (75 MHz, CDCb) δ ppm: 191.3, 166.6, 159.5, 142.9, 142.8, 140.2, 138.4, 135.2, 133.7, 133.7, 133.5, 133.4, 131.6, 131.1 (q, / = 32.3 Hz), 130.7, 129.1, 128.9, 126.5 (q, / = 3.7 Hz), 125.0 (q, / = 3.7 Hz), 123.9 (q, / = 270.8 Hz), 120.1, 116.3, 111.5, 60.5, 55.4, 14.2. Ethyl (E)-3-(3'-formyl-4,4"-dimethoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylate (34)
Figure imgf000071_0001
By Suzuki reaction of triflate 31 and 4-methoxy-3-methylbenzeneboronic acid. The crude was purified b) FC (hexane/AcOEt 3: 1) and recrystallized from ethanol. Yield 66%. mp: 143- 145 °C. XH NMR (300 MHz, CDCls) δ ppm: 10.05 (s, 1H), 7.96-7.93 (m, 1H), 7.70 (d, J = 15.9 Hz, 1H), 7.52-7.48 (m, 2H), 7.3^ (d, J = 8.7 Hz, 1H), 7.25-7.20 (m, 3H), 7.03 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.30 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 192.6, 166.7, 159.3, 158.0, 144.7, 143.2, 138.7, 134.9, 134.2, 133.7, 133.6, 132.4, 131.7, 130.7, 129.1, 128.8, 128.5, 126.9, 119.9, 116.3, 111.4, 109.7, 60.5, 55.< (2x), 16.3, 14.2
Ethyl (E)-3 3M-chloro-3'-formyl-4,4M-dimethoxy-[l,l':4,,lM-terphenyl]-2-yl)acrylate (35)
Figure imgf000071_0002
By Suzuki reaction of triflate 31 and 3-chloro-4-methoxyphenylboronic acid. The crude was purified by FC (hexane/AcOEt 5: 1) and recrystallized from ethanol. Yield 60%. mp: 141- 143 °C. XH NMR (300 MHz, CDCI3) δ ppm: 10.04 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 15.9 Hz, 1H), 7.54 (dd, Ji = 7.8 Hz, J2 = 2.1 Hz, 1H), 7.51-7.44 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.29 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.03 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.43 (d, J = 15.( Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.90 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) 5 ppm: 191.9, 166.7, 159.4, 155.1, 143.1, 142.9, 139.5, 135.1, 133.9, 133.7, 133.6, 131.7, 131.5, 130.7, 130.6, 129.7, 128.8, 122.8, 120.0, 116.3, 111.8, 111.5, 60.5, 56.3, 55.5, 14.3.
Ethyl (E)-3-(3,-(hydroxymethyl)-4-methoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylate (36)
Figure imgf000072_0001
To a chilled solution of compound 32 in ethanol (5 mL) was added sodium borohydride (2 equiv) and the mixture was stirred at room temperature. The solvent was removed under vacuum and the crude was dissolved in AcOEt (5 mL) and washed with water (3 mL). The organic layer was concentrated in vacuo and the resulting oil was not further purified. Yield 99%. XH NMR (300 MHz, CDC13) δ ppm: 7.81 (d, / = 15.9 Hz, 1H), 7.49 (d, / = 1.5 Hz, 1H), 7.40-7.26 (m, 4H), 7.25-7.17 (m, 4H), 7.02 (dd, = 8.4 Hz, J2 = 2.7 Hz, 1H), 6.42 (d, / = 15.9 Hz, 1H), 4.66 (s, 2H), 4.22 (q, / = 7.1 Hz, 2H), 3.89 (s, 3H), 2.42 (s, 3H), 1.30 (t, / = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 167.0, 159.0, 144.0, 140.1, 140.1, 138.7, 138.1, 137.9, 135.3, 133.6, 131.6, 129.9, 129.9, 129.9, 129.0, 128.1, 128.0, 126.2, 119.2, 116.3, 111.1, 63.0, 60.5, 55.4, 21.4, 14.2.
Ethyl (E)-3 3' hydroxymethyl)-4-methoxy-3M^
(37)
Figure imgf000072_0003
By reduction of aldehyde 33 with NaBH4. Yield 99%. XH NMR (300 MHz, CDC ) δ ppm: 7.78 (d, / = 16.2 Hz, 1H), 7.73-7.49 (m, 5H), 7.40-7.28 (m, 3H), 7.21 (d, / = 2.7 Hz, 1H), 7.02 (dd,
Figure imgf000072_0004
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.41 (d, / = 15.9 Hz, 1H), 4.60 (s, 2H), 4.21 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -62.98 (s, 3F); 13C NMR (75 MHz, CDCb) δ ppm: 167.1,
159.1, 143.9, 141.0, 139.6, 138.6, 138.0, 135.0, 133.5, 132.6, 131.5, 130.7 (q, 7 = 32.0 Hz), 130.3, 129.9,
129.2, 128.7, 126.0 (q, / = 3.7 Hz), 124.1 (q, / = 3.7 Hz), 124.1 (q, / = 270.8 Hz), 119.3, 116.3, 111.2, 62.8, 60.6, 55.4, 14.2.
Ethyl (E)-3 3' hydroxymethyl)-4,4'^dimethoxy-3M-methyl-[l,l,:4 l,^terphenyl]-2-yl)acrylate (3^
Figure imgf000073_0001
By reduction of aldehyde 34 with NaBH4. Yield 97%. XH NMR (300 MHz, CDC13) δ ppm: 7.83 (d, / = 15.9 Hz, 1H), 7.49 (d, / = 1.8 Hz, 1H), 7.39 (d, / = 8.4 Hz, 1H), 7.34 (d, / = 7.8 Hz, 1H), 7.29-7.20 (m, 4H), 7.04 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.91 (d, / = 8.1 Hz, 1H), 6.43 (d, / = 15.9 Hz, 1H), 4.69 (s, 2H), 4.24 (q, / = 7.2 Hz, 2H), 3.91 (s, 6H), 2.30 (s, 3H), 1.32 (t, / = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 167.0, 158.9, 157.1, 144.1, 139.9, 138.4, 138.2, 135.4, 133.5, 132.1, 131.5, 131.5, 130.0, 129.9, 129.0, 127.5, 126.4, 119.1, 116.2, 111.1, 109.6, 63.2, 60.5, 55.4, 55.3, 16.3, 14.2.
Ethyl (E)-3 3M-chloro-3' hydroxymethyl)-4,4,^dimethoxy 1,l':4 lM-terphenyl]-2-yl)acrylate (39)
Figure imgf000073_0002
By reduction of aldehyde 35 with NaBH4. Yield 99%. XH NMR (300 MHz, CDC ) δ ppm: 7.76 (d, / = 15.9 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.21 (m, 4H), 7.19 (d, / = 2.7 Hz, 1H), 7.00 (dd,
Figure imgf000073_0003
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.98 (d, / = 8.4 Hz, 1H), 6.40 (d, / = 15.9 Hz, 1H), 4.61 (s, 2H), 4.20 (q, / = 7.1 Hz, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 167.1, 159.0, 154.3, 143.9, 139.0, 138.4, 138.1, 135.1, 133.5, 133.5, 131.5, 130.9, 130.2, 129.9, 129.1, 128.6, 122.1, 119.1, 116.2, 111.7, 111.1, 62.8, 60.5, 56.1, 55.4, 14.2.
(E)-3 3'-(hydroxymethyl)-4-methoxy-3M-methyl-[l,l':4,,lM-terphenyl]-2-yl)acrylic acid (40)
Figure imgf000073_0004
By basic hydrolysis of ester 36. Yield 96%; mp: 130-132 °C. XH NMR (300 MHz, CDCb) δ ppm: 7.76 (d / = 15.9 Hz, 1H), 7.46 (d, / = 1.5 Hz, 1H), 7.32-7.09 (m, 8H), 6.99 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.3' (d, / = 15.9 Hz, 1H), 4.58 (s, 2H), 3.85 (s, 3H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 169.3, 127.9, 126.1, 119.0, 116.3, 111.2, 62.4, 55.3, 21.3.
(E)-3-(3'-(hydroxymethyl)-4-methoxy-3M-(tri^ acid (41)
Figure imgf000074_0001
By basic hydrolysis of ester 37. Yield 98%. mp: 162- 164 °C. XH NMR (300 MHz, CDC13) δ ppm: 7.72 (d / = 15.9 Hz, 1H), 7.68-7.47 (m, 5H), 7.35-7.25 (m, 3H), 7.20 (d, / = 2.4 Hz, 1H), 6.99 (dd,
Figure imgf000074_0002
= 8.4 Hz, J = 2.7 Hz, 1H), 6.38 (d, / = 15.9 Hz, 1H), 4.52 (s, 2H), 3.85 (s, 3H); 19F NMR (282 MHz, CDCI3) δ ppm: 61.44 (s, 3F); 13C NMR (75 MHz, CDCI3) δ ppm: 169.1, 158.9, 144.1, 141.0, 139.4, 138.4, 138.0, 135.1, 133.2, 132.4, 131.5, 130.4 (q, / = 32.0 Hz), 130.0, 129.7, 128.9, 128.5, 125.7 (q, / = 3.7 Hz), 123.8 (q, / = 3.7 Hz), 119.2, 116.1, 111.1, 61.9, 55.2.
(E)-3 3' hydroxymethyl)-4,4,^dimethoxy-3M-methyl-[l,l':4,,lM-terphenyl]-2-yl)acrylic acid (42)
Figure imgf000074_0003
By basic hydrolysis of ester 38. Yield 99%. mp: 144- 146 °C. XH NMR (300 MHz, CDCI3) δ ppm: 7.83 (d / = 15.9 Hz, 1H), 7.52 (d, / = 1.5 Hz, 1H), 7.42-7.20 (m, 7H), 7.06 (dd, Ji = 8.7 Hz, /2 = 2.7 Hz, 1H), 6.9: (d, / = 8.1 Hz, 1H), 6.45 (d, / = 15.9 Hz, 1H), 4.67 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 169.2, 158.8, 156.9, 144.5, 139.7, 138.2, 138.0, 135.5, 133.2, 132.1, 131.5, 131.3, 129.9, 129.7, 128.6, 127.4, 126.2, 118.9, 116.2, 111.1, 109.5, 62.3, 55.2, 55.2, 16.0.
(E)-3 3M hloro-3' hydroxymethyl)-4,4M-dimethoxy-[l,l':4,,lM-terphenyl]-2-yl)acrylic acid (43)
Figure imgf000075_0001
By basic hydrolysis of ester 39. Yield 98%. mp: 195- 197 °C. XH NMR (300 MHz, CDC13) δ ppm: 7.72 (d / = 15.9 Hz, 1H), 7.48-7.45 (m, 1H), 7.43 (d, / = 2.1 Hz, 1H), 7.37-7.18 (m, 5H), 7.00 (dd, Ji = 8.7 Hz, J = 2.4 Hz, 2H), 6.38 (d, / = 15.9 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 169.1, 158.8, 154.0, 144.2, 138.8, 138.2, 137.9, 135.2, 133.5, 133.1, 131.5, 130.6, 129.8, 129.6, 128.7, 128.4, 121.8, 119.0, 116.1, 111.6, 111.0, 61.9, 55.9, 55.2.
Potassium (4-hydroxy-3-methylphenyl)trifluoroborate (44)
Figure imgf000075_0002
A mixture of 4-bromo-2-methylphenol (561 mg), tetrahydroxydiboron (807 mg, 3 equiv), XPhos palladium (II) biphenyl preformed catalyst (9 mg, 0.4% mol), XPhos (14 mg, 1% mol) and KOAc (883 mg, 3 equiv) was dissolved in ethanol (25 mL) in a two-neck round-bottom flask. The mixture was then heated at 80 °C under N2 atmosphere until consumption of starting material (the mixture turned orange, TLC hexane/ AcOEt 5: 1). The reaction was cooled to room temperature, filtered through a thin pad of Celite (eluting with 3x15 mL of AcOEt) and concentrated. The crude reaction was dissolved in AcOEt (1 mL) and washed with water (15 mL) and brine (15 mL). The combined aqueous layers were further extracted with AcOEt (3x10 mL). The combined organics were dried over Na2S04, filtered and concentrated. The concentrated crude reaction was taken up in MeOH (25 mL) and cooled with an ice bath. To this cooled mixture was added 3 mL of a 4.5M aqueous KHF2 solution (1.05 g, 4.5 equiv) and the reaction was stirred for 10 min at 0 °C and for 1 h at room temperature. The resulting mixture was the concentrated and lyophilized overnight to remove any traces of water. The compound was purified with continuous Soxhlet extraction (overnight) with acetone (150 mL). The collected solvent was removed in vacuo until a minimal volume of acetone remained (3 mL). The addition of Et20 (25 mL) led to the precipitation of 460 mg of potassium trifluoroborate salt 44. Yield 72%. XH NMR (300 MHz, MeOD-d^) , ppm: 7.22 (s, 1H), 7.16 (d, / = 7.8 Hz, 1H), 6.62 (d, / = 7.8 Hz, 1H), 2.15 (s, 3H); 13C NMR (75 MHz, MeOD-cU) δ ppm: 154.8, 135.3, 131.0, 123.4, 114.6, 16.4.
Ethyl (E)-3-(4'-hydroxy-4-methoxy-3'-methyl-[l,l'-biphenyl]-2-yl)acrylate (45)
Figure imgf000076_0001
By Suzuki reaction of compounds 44 and 3. The crude was purified by FC (hexane/AcOEt 5: 1). Yield 76%; mp: 128- 130 °C. lH RMN (300 MHz, CDC13) δ ppm: 7.79 (d, / = 16.2 Hz, 1H), 7.27 (d, / = 8.7 Hz. 1H), 7.18 (d, / = 2.7 Hz, 1H), 7.05-6.93 (m, 3H), 6.78 (d, / = 8.1 Hz, 1H), 6.39 (d, / = 15.9 Hz, 1H), 5.64 (s, 1H), 4.24 (q, / = 7.1 Hz, 2H), 3.87 (s, 3H), 2.27 (s, 3H), 1.30 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCl3) 5 ppm: 167.3, 158.6, 153.5, 144.4, 136.0, 133.3, 132.4, 131.7, 131.6, 128.6, 123.8, 118.6, 116.3, 114.6, 110.9, 60.5, 55.4, 15.8, 14.3.
Ethyl (E)-3-(4-methoxy-3'-methyl-4'-(((trifluorom
Figure imgf000076_0002
By reaction of compound 45 with triflic anhydride. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 77%; mp: 67-69 °C. lH RMN (300 MHz, CDCI3) δ ppm: 7.64 (d, / = 16.2 Hz, 1H), 7.30 (d, / = 8.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.19 (d, / = 2.7 Hz, 1H), 7.15 (dd, Ji = 7.8 Hz, J2 = 2.4 Hz, 1H), 6.99 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.40 (d, / = 15.9 Hz, 1H), 4.22 (q, / = 7.1 Hz, 2H), 3.86 (s, 3H), 2.43 (s, 3H), 1.30 (t, / = 7.2 Hz, 3H); 19F NMR (282 MHz, CDC13) δ ppm: -74.34 (s, 3F); 13C RMN (75 MHz, CDC13) 5 ppm: 166.4, 159.3, 147.6, 142.8, 139.8, 133.5, 133.5, 133.3, 131.3, 130.6, 129.0, 120.9, 119.8, 118.6 (q / = 318.2 Hz), 116.0, 111.2, 60.3, 55.1, 16.2, 14.0.
Ethyl (E)-3-(4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (47)
Figure imgf000076_0003
By Suzuki reaction of triflate 46 and m-tolylboronic acid. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 57%. lH RMN (300 MHz, CDC13) δ ppm: 7.83 (d, / = 15.9 Hz, 1H), 7.37 (d, / = 8.4 Hz, 1H) 7.37-7.12 (m, 8H), 7.03 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.43 (d, / = 15.9 Hz, 1H), 4.24 (q, / = 7.2 Hz, 2H), 3.90 (s, 3H), 2.44 (s, 3H), 2.33 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C RMN (75 MHz, CDC13) δ ppm:
166.9, 158.9, 144.0, 141.5, 140.9, 138.4, 137.7, 135.7, 135.2, 133.6, 131.7, 131.7, 130.0, 129.6, 127.9,
127.5, 127.4, 126.3, 119.2, 116.2, 111.1, 60.4, 55.4, 21.5, 20.5, 14.3.
Ethyl (E)-3 4-methoxy-3,-methyl-3M-(trifluoromethyl)-[l,l':4,,lM-terphenyl]-2-yl)acrylate (48)
Figure imgf000077_0001
By Suzuki reaction of triflate 46 and 3-(trifluoromethyl)phenylboronic acid. The crude was purified by F( (hexane/AcOEt 10: 1). Yield 59%. lH RMN (300 MHz, CDCI3) δ ppm: 7.80 (d, / = 15.9 Hz, 1H), 7.68- 7.54 (m, 4H), 7.34 (d, / = 8.4 Hz, 1H), 7.29-7.15 (m, 4H), 7.03 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.42 (d / = 15.9 Hz, 1H), 4.23 (q, / = 7.1 Hz, 2H), 3.89 (s, 3H), 2.31 (s, 3H), 1.31 (t, 7 = 7.1 Hz, 3H); 19F NMR (282 MHz, CDC ) δ ppm: -63.00 (s, 3F); 13C RMN (75 MHz, CDC ) δ ppm: 166.8, 159.0, 143.8, 142.3, 139.3, 135.3, 135.2, 133.6, 132.6 (2x), 132.0, 131.6, 130.6 (q, / = 32.0 Hz), 129.6, 128.6, 127.7, 126.0 (q / = 3.8 Hz), 123.7 (q, / = 3.7 Hz), 119.3, 116.3, 111.2, 60.4, 55.5, 20.4, 14.3.
Ethyl (E)-3-(4,4"-dimethoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (49)
Figure imgf000077_0002
By Suzuki reaction of triflate 46 and 4-methoxy-3-methylbenzeneboronic acid. The crude was purified b) FC (hexane/AcOEt 10: 1). Yield 54%. lH RMN (300 MHz, CDCb) δ ppm: 7.84 (d, / = 15.9 Hz, 1H), 7.3^ (d, / = 8.4 Hz, 1H), 7.27 (d, / = 7.8 Hz, 1H), 7.22 (d, / = 2.4 Hz, 1H), 7.21-7.11 (m, 4H), 7.02 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.90 (d, / = 9.0 Hz, 1H), 6.42 (d, / = 15.9 Hz, 1H), 4.24 (q, / = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.31 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCb) δ ρρηι: 166.9, 158.9, 156.8, 144.0, 140.7, 138.1, 135.7, 135.3, 133.6, 133.5, 131.7 (2x), 131.6, 129.8, 127.5, 127.4, 126.2, 119.1, 116.2, 111.1, 109.5, 60.4, 55.4, 55.3, 20.6, 16.3, 14.3. Ethyl (E)-3-(3''-chloro-4,4M-dimethoxy-3'-methyl-[l,l,:4,,lM-terphenyl]-2-yl)acrylate (50)
Figure imgf000078_0001
By Suzuki reaction of triflate 46 and 3-chloro-4-methoxyphenylboronic acid. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 46%. lH RMN (300 MHz, CDC13) δ ppm: 7.79 (d, / = 16.2 Hz, 1H), 7.4] (d, J = 2.1 Hz, 1H), 7.34 (d, / = 8.7 Hz, 1H), 7.27-7.11 (m, 5H), 7.04-6.98 (m, 2H), 6.41 (d, / = 15.9 Hz, 1H), 4.23 (q, / = 7.2 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 2.32 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C RMN (75 MHz, CDC ) δ ppm: 166.9, 159.0, 154.0, 143.9, 139.2, 138.7, 135.5, 135.3, 134.9, 133.6, 131.9, 131.6, 131.0, 129.6, 128.5, 127.5, 122.0, 119.2, 116.3, 111.7, 111.1, 60.4, 56.2, 55.5, 20.5, 14.3.
Ethyl (E)-3-(4-methoxy-3,-methyl-4,-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)acrylate (51)
Figure imgf000078_0002
By Suzuki reaction of triflate 46 and 3-pyridineboronic acid neopentylglycol ester. The crude was purifiei by FC (CH2Cl2/AcOEt 10: 1). Yield 33%. XH RMN (300 MHz, CDCb) δ ppm: 8.69-8.58 (m, 2H), 7.79 (d / = 15.9 Hz, 1H), 7.75-7.69 (m, 1H), 7.42-7.31 (m, 2H), 7.29-7.15 (m, 4H), 7.02 (dd, Ji = 8.7 Hz, = 2.' Hz, 1H), 6.42 (d, / = 15.9 Hz, 1H), 4.23 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 2.32 (s, 3H), 1.30 (t, / = 7.2 Hz 3H); 13C RMN (75 MHz, CDCb) δ ppm: 166.8, 159.0, 149.9, 148.1, 143.7, 139.5, 137.1, 137.0, 136.5, 135.5, 135.2, 133.6, 132.0, 131.6, 129.7, 127.7, 123.0, 119.3, 116.2, 111.2, 60.4, 55.4, 20.4, 14.3.
Ethyl (E)-3-(3"-formyl-4-methoxy-3'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (52)
Figure imgf000078_0003
By Suzuki reaction ol triflate 46 and 3-formylbenzeneboronic acid. The crude was purified by FC
(hexane/AcOEt 10: 1). Yield 30%, mp: 155- 157 °C. lH RMN (300 MHz, CDC13) δ ppm: 10.08 (s, 1H), 7.94-7.86 (m, 2H), 7.80 (d, / = 15.9 Hz, 1H), 7.67-7.57 (m, 1H), 7.34 (d, / = 8.4 Hz, 1H), 7.30-7.15 (m, 5H), 7.02 (dd, Ji = 8.7 Hz, = 2.7 Hz, 1H), 6.42 (d, / = 15.9 Hz, 1H), 4.23 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 2.31 (s, 3H), 1.30 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 192.0, 166.9, 159.0, 143.8 142.5, 139.2, 136.4, 135.3, 135.2, 135.1, 133.6, 131.9, 131.6, 130.6, 129.6, 128.9, 128.0, 127.7, 119.3, 116.2, 111.1, 60.4, 55.4, 20.4, 14.3.
Ethyl (E)-3-(3"-cyano-4-methoxy-3'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (53)
Figure imgf000079_0001
By reaction of compound 52 with iodine in basic medium. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 98%. lH RMN (300 MHz, CDCI3) δ ppm: 7.78 (d, / = 15.9 Hz, 1H), 7.70-7.61 (m, 3H), 7.56 (d, / = 7.8 Hz, 1H), 7.34 (d, / = 8.4 Hz, 1H), 7.25-7.15 (m, 4H), 7.02 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.42 (d, / = 15.9 Hz, 1H), 4.23 (q, / = 7.1 Hz, 2H), 3.89 (s, 3H), 2.30 (s, 3H), 1.31 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 166.8, 159.1, 143.7, 142.8, 139.6, 138.4, 135.2, 135.1, 133.7, 133.6, 132.7, 132.1, 131.6, 130.6, 129.5, 129.0, 127.8, 119.4, 118.8, 116.3, 112.4, 111.2, 60.4, 55.5, 20.4, 14.3.
Ethyl (E)-3-(3"-(hydroxymethyl)-4-methoxy-3'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (54)
Figure imgf000079_0002
By reduction of aldehyde 52 with NaBH4. The crude was purified by FC (hexane/AcOEt 4: 1). Yield 97% lH RMN (300 MHz, CDCI3) δ ppm: 7.81 (d, / = 15.9 Hz, 1H), 7.46-7.17 (m, 8H), 7.14 (dd,
Figure imgf000079_0003
= 7.8 Hz, = 1.5 Hz, 1H), 7.01 (dd, Ji = 8.7 Hz, = 2.7 Hz, 1H), 6.41 (d, / = 15.9 Hz, 1H), 4.75 (s, 2H), 4.22 (q, , = 7.1 Hz, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 1.29 (t, / = 7.2 Hz, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 166.9, 158.9, 143.9, 141.8, 140.8, 140.5, 138.6, 135.6, 135.2, 133.6, 131.8, 131.6, 129.6, 128.5, 128.3, 127.8, 127.4, 125.4, 119.2, 116.2, 111.1, 65.3, 60.4, 55.4, 20.5, 14.3. (E)-3-[4-methoxy-3,,3"-dimethyl-(l,l':4,,l"-terphenyl)-2-yl]acrylic acid (55)
Figure imgf000080_0001
By basic hydrolysis of ester 47. Yield 96%; mp: 197- 199 °C. XH NMR (300 MHz, CDC13) δ ppm: 7.78 (d / = 15.9 Hz, 1H), 7.36-7.26 (m, 2H), 7.25-7.07 (m, 7H), 6.99 (dd,
Figure imgf000080_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.37 (d, J = 15.6 Hz, 1H), 3.86 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 169.1, 158.8, 144.8, 141.4, 140.8, 138.3, 137.6, 135.6, 135.2, 133.4, 131.6, 131.6, 129.9, 129.5, 127.9, 127.5, 127.3, 126.2, 119.0, 116.2, 111.2, 55.4, 21.3, 20.4.
(£).3.(4-methoxy-3,-methyl-3M trifluoromethyl)-[l,l':4,,lM-terphenyl]-2-yl)acrylic acid (56)
Figure imgf000080_0003
By basic hydrolysis of ester 48. Yield 98%, mp: 185- 187 °C. XH RMN (300 MHz, CDCI3) δ ppm: 7.82 (d / = 15.9 Hz, 1H), 7.67-7.49 (m, 4H), 7.33 (d, / = 8.4 Hz, 1H), 7.28-7.18 (m, 3H), 7.16 (dd, Ji = 7.8 Hz, J = 1.8 Hz, 1H), 7.02 (dd,
Figure imgf000080_0004
= 8.4 Hz, = 2.7 Hz, 1H), 6.40 (d, / = 15.9 Hz, 1H), 3.88 (s, 3H), 2.29 (s, 3H); 19F NMR (282 MHz, CDC ) δ ppm: -63.03 (s, 3F); 13C RMN (75 MHz, CDCI3) δ ppm: 167.0, 159.0, 145.1, 142.2, 139.2, 139.2, 135.4, 135.2, 133.4, 132.5, 131.9, 131.6, 130.5 (q, / = 32.0 Hz), 129.5, 128.5, 127.6, 125.9 (q, / = 3.8 Hz), 123.6 (q, / = 3.8 Hz), 118.9, 116.4, 111.3, 55.4, 20.3.
(E)-3-(4,4M-dimethoxy-3',3M-dimethyl-[l,l':4,,lM-terphenyl]-2-yl)acrylic acid (57)
Figure imgf000080_0005
,
By basic hydrolysis of ester 49. Yield 98%, mp: 198-200 °C. XH RMN (300 MHz, CDC13) δ ppm: 7.80 (d
/ = 15.9 Hz, 1H), 7.32 (d, 7 = 8.4 Hz, 1H), 7.23 (d, 7 = 7.8 Hz, 1H), 7.19 (d, / = 2.7 Hz, 1H), 7.18-7.07 (m, 4H), 7.00 (dd,
Figure imgf000081_0001
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.87 (d, / = 9.0 Hz, 1H), 6.38 (d, / = 15.9 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 169.3, 158.8, 156.7, 145.0, 140.6, 138.0, 135.7, 135.3, 133.5, 133.4, 131.7, 131.6, 131.5, 129.7, 127.4, 127.3, 126.1, 118.8, 116.3, 111.2, 109.5, 55.4, 55.3, 20.5, 16.2.
(E)-3-(3"-chloro-4,4"-dimethoxy-3'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (58)
Figure imgf000081_0002
By basic hydrolysis of ester 50. Yield 98%, mp: 200-202 °C. XH RMN (300 MHz, CDCI3) δ ppm: 7.76 (d / = 15.9 Hz, 1H), 7.37 (d, / = 2.4 Hz, 1H), 7.30 (d, / = 8.7 Hz, 1H), 7.24-7.07 (m, 5H), 7.01-6.95 (m, 2ff 6.36 (d, / = 15.9 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 169.1, 158.9, 153.9, 144.7, 139.0, 138.6, 135.4, 135.3, 134.8, 133.4, 131.8, 131.6, 130.8, 129.5, 128.5, 127.4, 121.9, 119.0, 116.3, 111.7, 111.2, 56.1, 55.4, 20.4.
(E)-3-(4-methoxy-3,-methyl-4,-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)acrylic acid (59)
Figure imgf000081_0003
By basic hydrolysis of ester 51. Yield 99%, mp: 228-230 °C. XH RMN (300 MHz, CDCI3) δ ppm: 8.62- 8.50 (m, 2H), 7.81-7.74 (m, 1H), 7.76 (d, / = 15.9 Hz, 1H), 7.47-7.38 (m, 1H), 7.32 (d, / = 8.7 Hz, 1H), 7.25-7.12 (m, 4H), 7.02 (dd, Ji = 8.7 Hz, = 2.7 Hz, 1H), 6.41 (d, / = 15.9 Hz, 1H), 3.88 (s, 3H), 2.30 (s 3H); 13C RMN (75 MHz, CDCI3) δ ppm: 168.9, 158.9, 148.9, 147.1, 144.0, 139.6, 137.5, 137.3, 136.2, 135.3, 135.0, 133.4, 131.9, 131.4, 129.5, 127.6, 123.3, 119.5, 116.0, 111.2, 55.2, 20.1.
(E)-3-(3"-cyano-4-methoxy-3'-methyl-[l,l,:4',l"-terphenyl]-2-yl)acrylic acid (60)
Figure imgf000082_0001
By basic hydrolysis of ester 53. Yield 96%. XH RMN (300 MHz, CDC13) δ ppm: 7.73 (d, / = 15.9 Hz, 1H), 7.67-7.57 (m, 3H), 7.55-7.48 (m, 1H), 7.29 (d, / = 8.4 Hz, 1H), 7.21-7.10 (m, 4H), 6.99 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.37 (d, / = 15.9 Hz, 1H), 3.85 (s, 3H), 2.25 (s, 3H); 13C RMN (75 MHz, CDC1 5 ppm: 169.1, 159.0, 144.5, 142.7, 139.5, 138.2, 135.1, 135.0, 133.7, 133.4, 132.6, 131.9, 131.5, 130.5, 129.4, 129.0, 127.7, 119.2, 118.7, 116.2, 112.1, 111.3, 55.4, 20.2.
(E)-3-(3"-(hydroxymethyl)-4-methoxy-3'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (61)
Figure imgf000082_0002
By basic hydrolysis of ester 54. Yield 96%, mp: 176-178 °C. XH RMN (300 MHz, CDCI3) δ ppm: 7.88 (d / = 15.9 Hz, 1H), 7.45-7.16 (m, 8H), 7.12 (dd, Ji = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.04 (dd,
Figure imgf000082_0003
= 8.7 Hz, J2 = 2.7 Hz, 1H), 6.41 (d, / = 15.9 Hz, 1H), 4.73 (s, 2H), 3.89 (s, 3H), 2.31 (s, 3H); 13C RMN (75 MHz, CDCl3) 5 ppm: 171.9, 158.9, 146.1, 141.7, 140.7, 140.6, 138.4, 135.8, 135.3, 133.1, 131.8, 131.7, 129.7, 128.5, 128.3, 127.9, 127.4, 125.5, 118.3, 116.7, 111.3, 65.2, 55.5, 20.5.
Ethyl 3-(4'-hydroxy-4-methoxy-3'-methyl-[l,l'-biphenyl]-2-yl)propanoate (62)
Figure imgf000082_0004
By hydrogenation of compound 5. Yield 96%. XH NMR (300 MHz, CDC ) δ ppm: 7.11 (d, J = 8.1 Hz, 1H), 7.03 (d, / = 2.1 Hz, 1H), 6.98 (dd, Ji = 8.1 Hz, J2 = 2.1 Hz, 1H), 6.83-6.76 (m, 3H), 4.08 (q, / = 7.1 Hz, 2H), 3.83 (s, 3H), 2.93 (t, / = 8.0 Hz, 2H), 2.44 (t, / = 8.0 Hz, 2H), 2.28 (s, 3H), 1.21 (t, J = 7.1 Hz, , ,
3H); 13C NMR (75 MHz, CDCb) δ ppm: 173.2, 158.6, 152.9, 139.4, 134.4, 133.4, 131.9, 131.4, 127.9,
123.5, 114.6, 114.4, 111.4, 60.5, 55.2, 35.3, 28.6, 15.9, 14.1.
Ethyl 3-(4-methoxy-3'-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[l,l'-biphenyl]-2-yl)propanoate (63)
Figure imgf000083_0001
By reaction of compound 62 with triflic anhydride. The resulting crude was purified by FC
(hexane/AcOEt 10: 1). Yield 85%. 13C NMR (75 MHz, CDCb) δ ppm: 172.5, 159.3, 147.3, 141.5, 139.2, 133.0, 132.6, 131.1, 130.5, 128.5, 120.9, 116.4, 114.5, 112.6, 60.3, 55.2, 35.1, 28.3, 14.0.
Ethyl 3-(3"-formyl-4-methoxy-3'-methyl-[l,l':4,,l"-terphenyl]-2-yl)propanoate (64)
Figure imgf000083_0002
By Suzuki reaction of triflate 63 and 3-formylbenzeneboronic acid. The crude was purified by FC
(hexane/AcOEt 10: 1). Yield 83%. lH NMR (300 MHz, CDCb) δ ppm: 10.09 (s, 1H), 7.93-7.86 (m, 2H), 7.69-7.58 (m, 2H), 7.29-7.16 (m, 4H), 6.87 (d, / = 2.4 Hz, 1H), 6.83 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.09 (q, / = 7.2 Hz, 2H), 3.84 (s, 3H), 2.99 (t, J = 8.0 Hz, 2H), 2.50 (t, / = 8.1 Hz, 2H), 2.32 (s, 3H), 1.22 (t, / = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 192.3, 172.8, 159.0, 142.6, 140.9, 139.3, 138.7, 136.4, 135.2, 135.0, 134.0, 131.5, 131.2, 130.5, 129.5, 128.8, 128.1, 127.0, 114.5, 111.5, 60.3, 55.2, 35.4, 28.5, 20.4, 14.1.
Ethyl 3-(3"-cyano-4-methoxy-3'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoate (65)
Figure imgf000084_0001
By reaction of aldehyde 64 with iodine in basic medium. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 97%. lH NMR (300 MHz, CDC13) δ ppm: 7.69-7.51 (m, 4H), 7.24-7.14 (m, 4H), 6.86 (d, / = 2.7 Hz, 1H), 6.82 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.09 (q, / = 7.1 Hz, 2H), 3.84 (s, 3H), 2.97 (t, / = 8.0 Hz, 2H), 2.49 (t, / = 8.1 Hz, 2H), 2.29 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 172.8, 159.0, 142.9, 141.2, 139.3, 137.9, 134.9, 133.9, 133.7, 132.7, 131.6, 131.2, 130.5, 129.4, 129.0, 127.1, 118.8, 114.5, 112.4, 111.6, 60.4, 55.3, 35.4, 28.5, 20.4, 14.1.
3-(3"-cyano-4-methoxy-3'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (66)
Figure imgf000084_0002
By basic hydrolysis of ester 65. Yield 99%. XH NMR (300 MHz, CDCI3) δ ppm: 7.70-7.50 (m, 4H), 7.23- 7.15 (m, 4H), 6.86 (d, / = 2.4 Hz, 1H), 6.83 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 3.84 (s, 3H), 2.97 (t, / = 8 J Hz, 2H), 2.53 (t, / = 8.0 Hz, 2H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 178.5, 159.1, 142.9, 141.1, 138.9, 137.9, 135.0, 133.9, 133.7, 132.7, 131.6, 131.3, 130.5, 129.5, 129.0, 127.1, 118.8, 114.6, 112.3, 111.6, 55.3, 35.0, 28.2, 20.4.
Ethyl 3-(3"-(hydroxymethyl)-4-methoxy-3'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoate (67)
Figure imgf000084_0003
By reduction of aldehyde 64 with NaBH4. Yield 99%. XH NMR (300 MHz, CDC ) δ ppm: 7.48-7.29 (m, 4H), 7.25 (d, / = 7.8 Hz, 1H), 7.21-7.13 (m, 3H), 6.86 (d, / = 2.7 Hz, 1H), 6.82 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.77 (s, 2H), 4.09 (q, / = 7.1 Hz, 2H), 3.84 (s, 3H), 2.98 (t, J = 8.0 Hz, 2H), 2.49 (t, / = 8.0 Hz, 2H), 2.31 (s, 3H), 1.21 (t, / = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 172.9, 158.9, 142.0, 140.7 65.4, 60.4, 55.3, 35.5, 28.6, 20.6, 14.2.
3-(3' ' -(hydroxymethyl)-4-methoxy-3' -methyl- [1 ,1 ' :4' ,1 ' ' -terphenyl] -2-yl)propanoic acid (68)
Figure imgf000085_0001
By basic hydrolysis of ester 67. Yield 97%. XH NMR (300 MHz, CDC13) δ ppm: 7.45-7.29 (m, 4H), 7.25 (d, / = 7.5 Hz, 1H), 7.22-7.11 (m, 3H), 6.85 (d, / = 2.4 Hz, 1H), 6.82 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.75 (s, 2H), 3.84 (s, 3H), 2.97 (t, / = 8.0 Hz, 2H), 2.52 (t, / = 8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) 5 ppm: 178.0, 158.9, 142.0, 140.6, 140.1 (2x), 139.0, 135.1, 134.3, 131.4, 131.3, 129.6, 128.6, 128.3, 127.9, 126.7, 125.4, 114.5, 111.6, 65.3, 55.3, 35.0, 28.3, 20.5.
4-hydroxy-3'-methyl-[l,l'-biphenyl]-2-carbaldehyde (69)
Figure imgf000085_0002
In a two-neck round-bottom flask, 2-bromo-5-hydroxybenzaldehyde (18.09 g), m-tolylboronic acid (12.6 g, 1.03 equiv), sodium carbonate (19.08 g, 2 equiv) and palladium tetrakistriphenylphosphine (780 mg, 0.75% mol) were dissolved in a 7:3 mixture of acetonitrile/water (160 mL) and the resulting mixture was refluxed under N2 atmosphere until completion of the reaction (TLC hexane/ AcOEt 5: 1). The reaction mixture was cooled and filtered through a thin pad of Celite and the volatiles were removed under vacuum. The aqueous phase was neutralized with 1M HCl solution and extracted with AcOEt (3x50 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The resulting crude was triturated with hexane (3x30 mL) and filtered to eliminate the product of homocoupling reaction. The filtered solid was crystallized several times from EtOH to afford 16.5 g of compound 69 as a brown solid
Yield 86%; mp: 148-150 °C. XH NMR (300 MHz, CDCI3) δ ppm: 9.93 (s, 1H), 7.63 (t, / = 8.1 Hz, 2H), 7.52 (d, / = 2.7 Hz, 1H), 7.24 (d, / = 7.8 Hz, 1H), 7.20-7.13 (m, 3H), 5.73 (s, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDC13) δ ppm: 192.8, 155.3, 139.3, 138.1, 137.3, 134.5, 132.4, 130.9, 128.6, 128.3, 127.4, 121.4, 112.9, 21.4; HRMS (EI) m/z: calcd for C14H12O2: 212.0837, found: 212.0827. 2,3'-dimethyl-[l,l'-biphenyl]-4-ol (70)
Figure imgf000086_0001
To solution of 4-hydroxy-3'-methyl-[l, l'-biphenyl]-2-carbaldehyde (8.87 g) in ethylene glycol (125 mL) were added KOH (9.43 g, 4 equiv) and hydrazine monohydrate (14.23 mL, 7 equiv). The reaction mixturt was heated at 195 °C until completion (TLC hexane/ethyl acetate 5: 1). The solution was cooled to rt, ther poured into a mixture of concentrated HCl and ice. The acidic aqueous layer was extracted with Et20. Th organic extract was dried over Na2S04 and evaporated to give 8.2 g of compound 70 as a brown oil in sufficient purity for use in the next step. Yield 99%. XH NMR (300 MHz, CDC13) δ ppm: 7.33-7.26 (m, 1H), 7.17-7.07 (m, 4H), 6.76 (d, / = 2.7 Hz, 1H), 6.72 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.92 (s, 1H), 2.4 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 154.5, 141.5, 137.6, 137.0, 134.9, 131.0, 130.1, 127.9, 127.2, 126.5, 116.9, 112.6, 21.4, 20.6.
2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoromethanesulfonate (71)
Figure imgf000086_0002
A solution of 2,3'-dimethyl-[l, l'-biphenyl]-4-ol (14.48 g) and pyridine (11.55 g, 2 equiv) in dry dichloromethane (200 mL) was chilled in an ice bath. Then, triflic anhydride (24.7 g, 1.2 equiv) was added dropwise and the mixture was stirred at room temperature until the reaction was completed (TLC hexane/ethyl acetate 10: 1). Then, the mixture was washed with 1M HCl (3x75 mL) and brine (75 mL), dried over Na2S04, filtered and concentrated under vacuum to afford 22.8 g of triflate 71 as an orange oil (it crystallizes on fridge). Yield 95%. lH NMR (300 MHz, CDCI3) δ ppm: 7.36-7.26 (m, 2H), 7.22-7.06 (m, 5H), 2.41 (s, 3H), 2.29 (s, 3H); 19F NMR (282 MHz, CDCI3) δ ppm: -73.38 (s, 3F); 13C NMR (75 MHz, CDCI3) δ ppm: 148.4, 142.5, 140.0, 138.3, 138.0, 131.3, 129.7, 128.2 (2x), 126.0, 122.6, 118.8 (q, 7= 318.9 Hz), 118.3, 21.4, 20.6.
Potassium 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoroborate (72)
Figure imgf000087_0001
A mixture of 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoromethanesulfonate (22.8 g), tetrahydroxydiboron (18.56 g, 3 equiv), XPhos palladium (II) biphenyl preformed catalyst (68 mg, 0.125% mol), XPhos (83 mg, 0.25% mol) and KOAc (20.32 g, 3 equiv) was dissolved in ethanol (300 mL) in a two-neck round- bottom flask. The mixture was then heated at 80 °C under N2 atmosphere until consumption of starting material (the mixture turned orange, TLC hexane/ AcOEt 10: 1). The reaction was cooled to room temperature, filtered through a thin pad of Celite (eluting with 3x25 mL of AcOEt) and concentrated. The crude reaction was dissolved in AcOEt (150 mL) and washed with water (100 mL) and brine (50 mL). The combined aqueous layers were further extracted with AcOEt (3x25 mL). The combined organics were dried over Na2S04, filtered and concentrated. The concentrated crude reaction was taken up in MeOH (200 mL) and cooled with an ice bath. To this cooled mixture was added 70 mL of a 4.5M aqueous KHF2 solution (24.26 g, 4.5 equiv) and the reaction was stirred for 30 min at 0 °C and for 3 h at room temperature. The resulting mixture was then concentrated and lyophilized overnight to remove any traces of water. The compound was purified with continuous Soxhlet extraction (overnight) with acetone (300 mL). The collected solvent was removed in vacuo and the remaining solid was triturated with hexan (2x50 mL) and ether (2x50 mL) to remove impurities and give 16.91 g of potassium trifluoroborate salt 72. Yield 85%; mp > 255 °C. lH NMR (300 MHz, MeOD-cU) δ ppm: 8.70 (br s, 1H), 8.66 (d, / = 7.5Hz, 1H), 8.56-8.49 (m, 1H), 8.40-8.32 (m, 3H), 8.24 (d, / = 7.5Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H); 13C NMR (75 MHz, MeOD-cU) δ ppm: 163.4, 159.1, 157.2, 153.9, 152.1, 149.9, 149.3, 147.8, 147.8, 146.8, 146.3, 40.7, 39.9.
(£).3.(4-hydroxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (73)
Figure imgf000087_0002
In a two-neck round-bottom flask, (E)-ethyl 3-(2-bromo-5-hydroxyphenyl)acrylate (10.02 g), potassium 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoroborate (11.0 g, 1.03 equiv), sodium carbonate (7.83 g, 2 equiv) and palladium tetrakistrifenilfosfine (320 mg, 0.75% mol) were dissolved in a 7:3 mixture of
acetonitrile/water (150 mL) and the reaction mixture was refluxed under N2 atmosphere until consumptio of starting material (TLC hexane/ AcOEt 5: 1). The reaction mixture was cooled and filtered through a thir pad of Celite and the volatiles were removed under vacuum. The aqueous phase was neutralized with 1M
HC1 solution and extracted with AcOEt (3x50 mL). The combined organic layers were concentrated and the resulting crude was dissolved in a 4: 1 mixture of tetrahydrofuran/water (100 mL). Then,
monohydrated litium hydroxide (4.65 g, 3 equiv) was added and the mixture was stirred overnight at 50 °C. The organic solvent was removed in vacuo and the aqueous phase was acidified (pH=l) with 2 M HC1. The resulting precipitate was filtered and the filtrate was extracted with CH2CI2 (3x50 mL). The organic phases were joined, washed with brine, concentrated in vacuo and added to the previous precipitate. This solid was triturated with hexane (3x30 mL) and filtered to remove the product of homocoupling reaction. The filtered solid was crystallized several times from MeOH (TLC
CH2Cl2/MeOH 5: 1) to give 9.61 g of terphenyl 73 as a pale brown solid. Yield 75%; pf: 208-210 °C. lH NMR (300 MHz, MeOD-cU) δ ppm: 9.03 (d, J = 16.2 Hz, 1H), 8.64-8.39 (m, 9H), 8.29 (dd, Ji = 8.4 Hz, J = 2.7 Hz, 1H), 7.70 (d, J = 15.9 Hz, 1H), 3.66 (s, 3H), 3.57 (s, 3H); 13C NMR (75 MHz, MeOD-cU) δ ppm: 187.1, 177.1, 163.8, 161.6, 160.9, 159.1, 157.8, 155.1, 154.5, 153.4, 151.9, 151.8, 149.9, 149.5, 148.2, 147.7, 147.5, 146.3, 139.0, 137.7, 132.8, 40.7, 39.9.
Methyl (E)-3-(4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (74)
Figure imgf000088_0001
(E)-3-(4-hydroxy-3',3"-dimethyl-[l, :4',l"-terphenyl]-2-yl)acrylic acid (9.17 g) and potassium carbonate (9.20 g, 2.5 equiv) were dissolved in a 1: 1 mixture of dry dimethylformamide/acetone (100 mL). Then, methyl iodide (9.45 g, 2.5 equiv) was added dropwise and the reaction mixture was heated to 50 °C until consumption of starting material (TLC hexane/ AcOEt 10: 1; the reaction vessel was sealed with a teflon cap to prevent the evaporation of methyl iodide). The solvents were removed under vacuum and the resulting crude was dissolved in AcOEt (60 mL). The organic phase was then washed with water (50 mL' saturated NH4C1 solution (2x50 mL), water (50 mL) and brine (50 mL). The organic phase was dried ovei Na2S04, filtered and concentrated in vacuo. The resulting solid was crystallized several times from EtOH to afford 9.25 g of compound 74. Yield 93%; pf: 95-97 °C. lH NMR (300 MHz, CDCI3) δ ppm: 7.84 (d, j = 15.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.34 (t, 7 = 7.5 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.24-7.12 (m, 6H), 7.03 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 167.3, 158.9, 144.2, 141.5, 140.9, 138.4, 137.7, 135.7, 135.3, 133.5, 131.7 (2x), 130.0, 129.6, 127.9, 127.5, 127.4, 126.3, 118.8, 116.2, 111.2, 55.4, 51.6,
21.5, 20.5.
Methyl 3-(4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoate (75)
Figure imgf000089_0001
A solution of methyl (E)-3-(4-methoxy-3',3"-dimethyl-[l,r:4', l"-terphenyl]-2-yl)acrylate (9.10 g) in AcOEt (150 mL) was hydrogenated overnight at room temperature and 2 atm of pressure using 10% palladium on carbon as catalyst (910 mg, 10% w/w). Thereafter, the mixture was filtered over Celite and the filtrates concentrated in vacuo to give 8.97 g of compound 75 as a transparent oil. Yield 98%. XH NMR (300 MHz, CDC13) δ ppm: 7.33 (t, J = 5.7 Hz, 1H), 7.26-7.16 (m, 6H), 7.14 (dd,
Figure imgf000089_0002
= 5.7 Hz, J2 = 1.2 Hz, 1H), 6.85 (d, / = 1.8 Hz, 1H), 6.83 (dd,
Figure imgf000089_0003
= 6.0 Hz, J2 = 1.8 Hz, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 2.99 (t, / = 6.0 Hz, 2H), 2.51 (t, / = 6.0 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCI3) < ppm: 173.4, 158.9, 141.6, 140.4, 140.0, 139.3, 137.6, 135.1, 134.4, 131.4, 131.3, 130.0, 129.6, 127.9, 127.5, 126.7, 126.3, 114.4, 111.5, 55.3, 51.6, 35.3, 28.5, 21.5, 20.6.
3-(4-methoxy-3',3" -dimethyl-[l,l ' :4',1 ' ' -terphenyl]-2-yl)propanoic acid (T12)
Figure imgf000089_0004
To a solution of methyl 3-(4-methoxy-3',3"-dimethyl-[l, :4',l"-terphenyl]-2-yl)propanoate (8.95 g) in a 4: 1 tetrahydrofuran/water mixture (100 mL), monohydrated lithium hydroxide (3.0 g, 3 equiv) was added and the mixture was stirred at room temperature until completion of the reaction (TLC hexane/ AcOEt 5: 1). THF was removed under reduced pressure, the aqueous phase was acidified with 2 M HC1 solution until reach pH=l and was extracted with DCM (3x50 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and removed in vacuo to afford 8.44 g of 3-(4-methoxy-3',3"- dimethyl-[l,r:4', l"-terphenyl]-2-yl)propanoic acid (T12) as a white solid. Yield 98%; mp: 85-87 °C. To formulate this final product as a sodium salt, a 0.2 M NaOH solution (936 mg, 1 equiv) was added to this solid and the mixture was stirred at room temperature until the solution became clear. The solution was then freeze-dried and the resulting white powder was stored in a desiccator.
(E)-3-(3'-formyl-4-methoxy-3"-methyl-[l,l':4,,l"-terphenyl]-2-yl)acrylic acid (76)
Figure imgf000090_0001
By basic hydrolysis of ester 32. Yield 99%; mp: 191-192 °C. XH NMR (300 MHz, CDC13) δ ppm: 10.04 (s, 1H), 7.96 (m, 1H), 7.77 (d, / = 15.6 Hz, 1H), 7.51 (d, / = 1.8 Hz, 2H), 7.36 (d, / = 8.1 Hz, 2H), 7.31- 7.20 (m, 4H), 7.06 (dd, Ji = 8.4 Hz, = 2.7 Hz, 1H), 6.42 (d, / = 15.6 Hz, 1H), 3.90 (s, 3H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 192.4, 171.6, 159.4, 145.5, 145.0, 139.0, 138.2, 137.2, 134.9, 134.4, 133.6, 133.3, 131.8, 130.9, 130.7, 129.0, 128.4, 128.4, 127.3, 119.0, 116.8, 111.6, 55.5, 21.4.
4-hydroxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-carbaldehyde (77)
Figure imgf000090_0002
By Suzuki reaction of compounds 72 and 1. The crude was purified by FC (hexane/AcOEt 5: 1) and recrystallized from ethanol. Yield 81%; mp: 144-146 °C. lH NMR (300 MHz, CDCI3) δ ppm: 10.03 (s, 1H), 7.58 (d, / = 2.7 Hz, 1H), 7.42 (d, / = 8.4 Hz, 1H), 7.37-7.29 (m, 2H), 7.26-7.15 (m, 6H), 5.95 (s, 1H), 2.43 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 193.0, 155.5, 141.7, 141.2, 139.1, 137.8, 136.2, 135.6, 134.5, 132.4, 132.1, 129.9, 129.8, 128.1, 127.8, 127.6, 126.2, 121.6, 113.0, 21.5, 20.6.
4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-carbaldehyde (78)
Figure imgf000090_0003
By reaction of compound 77 with methyl iodide. The crude was purified by FC (hexane/AcOEt 10: 1).
Yield 90%; mp: 90-92. XH NMR (300 MHz, CDC13) δ ppm: 10.05 (s, 1H), 7.54 (d, / = 2.7 Hz, 1H), 7.43 (d, / = 8.4 Hz, 1H), 7.37-7.29 (m, 2H), 7.26-7.14 (m, 6H), 3.92 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 192.5, 159.1, 141.6, 141.2, 139.0, 137.8, 136.2, 135.5, 134.5, 132.1, 132.1, 129.9, 129.8, 128.0, 127.7, 127.6, 126.2, 121.4, 109.8, 55.6, 21.5, 20.5.
4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-carboxylic acid (79)
Figure imgf000091_0001
To a solution of compound 78 (82 mg) in a 1: 1 mixture of water/methanol (6 mL) was added KOH (56 mg, 4 equiv) and the mixture was heated to 60 °C. Then, an excess of H2O2 (10 equiv) was added and the reaction was heated until consumption of the starting material (TLC hexane/AcOEt 10: 1). The volatiles were removed in vacuo, the aqueous phase was acidified with 1 M HC1 and extracted with DCM (3x5 mL). The organic layers were dried over Na2C03, filtered and concentrated to give 82 mg of compound
79 without any further purification. Yield 95%; mp: 158-160 °C. XH NMR (300 MHz, CDC ) δ ppm: 7.5 (d, / = 2.7 Hz, 1H), 7.38 (d, / = 8.7 Hz, 1H), 7.36-7.13 (m, 8H), 3.91 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 173.8, 158.4, 141.5, 140.7, 139.4, 137.5, 135.6, 135.0, 132.5, 130.4, 130.0, 130.0, 129.5, 127.8, 127.4, 126.3, 126.1, 118.4, 115.1, 55.5, 21.4, 20.5.
'-dimethyl-4-(trifluoromethoxy)-[l,l':4',l"-terphenyl]-2-carboxylic acid (80)
Figure imgf000091_0002
By Suzuki reaction of compound 72 and 2-bromo-5-(trifluoromethoxy)benzoic acid. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 18%; mp: 138-140 °C. XH NMR (300 MHz, CDCb) δ ppm: 7.85-7.79 (m, 1H), 7.48-7.40 (m, 2H), 7.34-7.27 (m, 1H), 7.25-7.13 (m, 6H), 2.40 (s, 3H), 2.30 (s, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -58.35 (s, 3F); 13C NMR (75 MHz, CDCb) δ ppm: 170.9, 148.0, 141.8, 141.6, 141.3, 138.4, 137.7, 135.3, 132.9, 130.8, 130.2, 130.0, 129.7, 128.0, 127.6, 126.3, 125.9, 124.3, 123.0, 21.5, 20.5. Ethyl (E)-3-(2'-tormyl-4'- hydroxy-4-methoxy-[l,l'-Wphenyl]-2-yl)acrylate (81)
Figure imgf000092_0001
By Suzuki reaction of boronate 4 and compound 1. The crude was purified by FC (hexane/AcOEt 5: 1). Yield 80%. lH NMR (300 MHz, CDC13) δ ppm: 9.56 (s, 1H), 7.42 (d, / = 16.2 Hz, 1H), 7.36 (d, / = 2.4 Hz, 1H), 7.18-7.02 (m, 4H), 6.92 (dd, Ji = 8.4 Hz, = 2.4 Hz, 1H), 6.30 (d, / = 15.9 Hz, 1H), 4.12 (q, / = 7.1 Hz, 3H), 3.81 (s, 3H), 1.20 (t, 7 = 7.2 Hz, 3H); 13C NMR (75 MHz, CDC ) δ ppm: 192.1, 167.3, 159.4, 156.5, 142.9, 135.4, 135.1, 134.9, 133.1, 133.0, 131.1, 121.5, 119.6, 115.9, 113.3, 111.0, 60.9, 55.4, 14.1.
Ethyl 3-(4'-hydroxy-4-methoxy-2'-methyl-[l,l'-biphenyl]-2-yl)propanoate (82)
Figure imgf000092_0002
By hydrogenation of compound 81. Yield 98%. XH NMR (300 MHz, CDCb) δ ppm: 7.00 (d, / = 8.4 Hz, 1H), 6.96 (d, / = 8.1 Hz, 1H), 6.83 (d, / = 2.7 Hz, 1H), 6.79 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 6.75 (d, / = 2.4 Hz, 1H), 6.68 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.10 (q, / = 7.2 Hz, 2H), 3.83 (s, 3H), 2.85-2.58 (m, 2H), 2.39 (t, / = 8.0 Hz, 2H), 2.00 (s, 3H), 1.20 (t, / = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 173.4, 158.6, 154.9, 139.9, 137.8, 133.5, 132.7, 131.3, 130.9, 116.6, 114.2, 112.4, 111.4, 60.5, 55.2, 34.9, 28.6, 20.1, 14.1.
Ethyl 3-(4-methoxy-2'-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[l,l'-biphenyl]-2-yl)propanoate (83)
Figure imgf000092_0003
By reaction of compound 82 with triflic anhydride. The crude was purified by FC (hexane/AcOEt 10: 1).
Yield 32%. lH NMR (300 MHz, CDC13) δ ppm: 7.35-7.18 (m, 3H), 7.06 (d, / = 8.1 Hz, 1H), 6.93 (d, / = 2.7 Hz, 1H), 6.89 (dd,
Figure imgf000093_0001
= 8.4 Hz, J2 = 2.7 Hz, 1H), 6.75 (d, / = 2.4 Hz, 1H), 6.68 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.14 (q, / = 7.1 Hz, 2H), 3.92 (s, 3H), 2.88-2.58 (m, 2H), 2.45 (t, J = 7.8 Hz, 2H), 2.18 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 19F NMR (282 MHz, CDC ) δ ppm: -73.43 (s, 3F); 13C NMR (75 MHz, CDC ) δ ppm: 172.5, 159.3, 148.5, 141.0, 139.5, 139.4, 131.7, 131.6, 130.6, 122.4, 118.7 (q, / = 318.7 Hz), 118.2, 114.4, 111.7, 60.4, 55.2, 34.8, 28.4, 20.2, 14.1.
Ethyl 3-(3"-chloro-4,4"-dimethoxy-2'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoate (84)
Figure imgf000093_0002
By Suzuki reaction of triflate 83 and 3-chloro-4-methoxyphenylboronic acid. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 65%. lH NMR (300 MHz, CDCb) δ ppm: 7.67 (d, / = 2.4 Hz, 1H), 7.50 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.43 (d, / = 1.8 Hz, 1H), 7.38 (dd,
Figure imgf000093_0003
= 7.5 Hz, J2 = 1.8 Hz, 1H), 7.17 (c 7 = 7.8 Hz, 1H), 7.03 (t, / = 8.4 Hz, 2H), 6.86 (d, / = 2.7 Hz, 1H), 6.82 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 4.06 (q, / = 7.1 Hz, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 2.87-2.59 (m, 2H), 2.40 (t, / = 7.7 Hz, 2H), 2.12 (s, 3H), 1.19 (t, / = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 172.8, 158.9, 154.3, 139.7, 139.6, 138.4, 136.9, 134.5, 133.3, 130.8, 130.5, 128.8, 128.2, 126.1, 123.8, 122.7, 114.3, 112.2, 111.5, 60.3, 56.2, 55.2, 35.0, 28.6, 20.2, 14.1.
Ethyl 3-(4-methoxy-2,-methyl-4,-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)propanoate (85)
Figure imgf000093_0004
By Suzuki reaction of triflate 83 and 3-pyridineboronic acid neopentylglycol ester. The crude was purifiei by FC (DCM/AcOEt 10: 1). Yield 98%. lH NMR (300 MHz, CDCb) δ ppm: 8.92-8.88 (m, 1H), 8.62-8.5( (m, 1H), 7.95-7.89 (m, 1H), 7.50-7.34 (m, 3H), 7.22 (d, / = 7.8 Hz, 1H), 7.04 (d, / = 8.1 Hz, 1H), 6.86 (d / = 2.7 Hz, 1H), 6.82 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 4.05 (q, / = 7.2 Hz, 2H), 3.84 (s, 3H), 2.86-2.59 (m, 2H), 2.41 (t, 7 = 7.8 Hz, 2H), 2.14 (s, 3H), 1.18 (t, 7 = 7.2 Hz, 3H); 13C NMR (75 MHz, CDC13) δ ppm: 172.7, 159.0, 148.3, 148.3, 140.6, 139.6, 137.2, 136.7, 136.4, 134.2, 133.0, 130.7, 128.6, 124.2,
123.5, 114.3, 111.5, 60.3, 55.2, 34.9, 28.5, 20.2, 14.1.
Ethyl 3-(4,4"-dimethoxy-2',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoate (86)
Figure imgf000094_0001
By Suzuki reaction of triflate 83 and 3-methyl-4-methoxyphenylboronic acid. The crude was purified by FC (hexane/AcOEt 10: 1). Yield 66%. lH NMR (300 MHz, CDCI3) δ ppm: 7.49-7.43 (m, 3H), 7.40 (dd, 7 = 7.8 Hz, 72 = 2.1 Hz, 1H), 7.15 (d, 7 = 7.8 Hz, 1H), 7.06 (d, 7 = 8.1 Hz, 1H), 6.91 (d, J = 9.3 Hz, 1H), 6.87 (d, 7 = 2.7 Hz, 1H), 6.82 (dd, 7i = 8.4 Hz, 72 = 2.7 Hz, 1H), 4.06 (q, 7 = 7.1 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.88-2.61 (m, 2H), 2.41 (t, 7 = 7.5 Hz, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 1.19 (t, 7 = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 172.9, 158.8, 157.3, 139.9, 139.8, 138.9, 136.5, 133.6, 133.1, 130.9, 130.3, 129.4, 128.2, 126.8, 125.2, 123.8, 114.3, 111.4, 110.1, 60.3, 55.4, 55.2, 35.0, 28.6, 20.2, 16.4, 14.1.
Ethyl 3-(3"-formyl-4-methoxy-2'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoate (87)
Figure imgf000094_0002
By Suzuki reaction of triflate 83 and 3-formylbenzeneboronic acid. The crude was purified by FC (hexane/AcOEt 5: 1). Yield 83%. lH NMR (300 MHz, CDCI3) δ ppm: 10.1 (s, 1H), 8.18-8.14 (m, 1H), 7.95-7.84 (m, 2H), 7.62 (t, 7 = 7.7 Hz, 1H), 7.54 (d, 7 = 1.8 Hz, 1H), 7.48 (dd, 7i = 7.8 Hz, 72 = 1.8 Hz, 1H), 7.22 (d, 7 = 7.8 Hz, 1H), 7.05 (d, 7 = 8.4 Hz, 1H), 6.87 (d, 7 = 2.4 Hz, 1H), 6.83 (dd, 7i = 8.4 Hz, 72 = 2.7 Hz, 1H), 4.06 (q, 7 = 7.1 Hz, 2H), 3.85 (s, 3H), 2.88-2.59 (m, 2H), 2.41 (t, 7 = 7.8 Hz, 2H), 2.15 (s, 3H), 1.19 (t, 7 = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 192.4, 172.8, 159.0, 141.9, 140.5, 139.6, 138.5, 137.1, 136.9, 133.1, 132.9, 130.7, 130.7, 129.4, 128.7, 128.5, 128.1, 124.2, 114.3, 111.5, 60.3, 55.2, 34.9, 28.6, 20.2, 14.1. Ethyl 3-(3"-(hydroxymethyl)-4-methoxy-2'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoate (88)
Figure imgf000095_0001
By reduction of aldehyde 87 with NaBH4. Yield 99%. XH NMR (300 MHz, CDC13) δ ppm: 7.68-7.63 (m, 1H), 7.58 (dt, Ji = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.53-7.49 (m, 1H), 7.49-7.40 (m, 2H), 7.38-7.30 (m, 1H), 7.1' (d, / = 7.8 Hz, 1H), 7.06 (d, / = 8.4 Hz, 1H), 6.87 (d, / = 2.7 Hz, 1H), 6.82 (dd,
Figure imgf000095_0002
= 8.4 Hz, J2 = 2.7 Hz, 1H), 4.78 (s, 2H), 4.05 (q, / = 7.1 Hz, 2H), 3.85 (s, 3H), 2.88-2.59 (m, 2H), 2.41 (t, / = 7.7 Hz, 2H), 2.14 (s, 3H), 1.19 (t, / = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 172.8, 158.8, 141.4, 141.3, 139.8, 139.7, 136.7, 133.4, 130.8, 130.4, 128.9, 128.7, 126.3, 125.7, 125.7, 124.2, 114.3, 111.5, 65.4, 60.3, 55.2, 35.0, 28.6, 20.2, 14.1.
Ethyl 3-(3"-cyano-4-methoxy-2'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoate (89)
Figure imgf000095_0003
By reaction of compound 87 with iodine in basic medium. The crude was purified by FC (hexane/AcOEt
5: 1). Yield 94%. XH NMR (300 MHz, CDCI3) δ ppm: 7.92 (t, / = 1.8 Hz, 1H), 7.86 (dt,
Figure imgf000095_0004
= 7.8 Hz, J2 = 1.7 Hz, 1H), 7.63 (dt,
Figure imgf000095_0005
= 7.8 Hz, J2 = 1.4 Hz, 1H), 7.55 (t, 7 = 7.7 Hz, 1H), 7.46 (d, / = 1.8 Hz, 1H), 7.4] (dd, Ji = 7.8 Hz, J2 = 2.1 Hz, 1H), 7.22 (d, / = 7.8 Hz, 1H), 7.04 (d, / = 8.4 Hz, 1H), 6.87 (d, / = 2.4 Hz, 1H), 6.83 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.06 (q, / = 7.1 Hz, 2H), 3.85 (s, 3H), 2.87-2.59 (m, 2H), 2.4 (t, J = 7.8 Hz, 2H), 2.14 (s, 3H), 1.19 (t, / = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 172.7, 159.0, 142.2, 140.9, 139.6, 137.7, 137.3, 132.9, 131.4, 130.8, 130.7, 130.6, 130.6, 129.5, 128.6, 124.2, 118.9, 114.3, 112.9, 111.5, 60.3, 55.2, 34.9, 28.5, 20.2, 14.1.
3-(3"-chloro-4,4"-dimethoxy-2'-methyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoic acid (90)
Figure imgf000096_0001
By basic hydrolysis of ester 84. Yield 97%. XH NMR (300 MHz, CDC13) δ ppm: 7.66 (d, 7 = 2.4 Hz, 1H), 7.50 (dd, Ji = 8.4 Hz, 72 = 2.4 Hz, 1H), 7.42 (d, 7 = 1.8 Hz, 1H), 7.37 (dd, 7i = 7.8 Hz, 72 = 1.8 Hz, 1H), 7.15 (d, 7 = 7.8 Hz, 1H), 7.04 (d, 7 = 8.4 Hz, 1H), 7.01 (d, 7 = 8.7 Hz, 1H), 6.86 (d, 7 = 2.7 Hz, 1H), 6.82 (dd, 7i = 8.4 Hz, 72 = 2.7 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 2.86-2.57 (m, 2H), 2.44 (t, 7 = 7.7 Hz, 2H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 178.5, 158.9, 154.3, 139.5, 139.2, 138.4, 136.8, 134.4, 133.3, 130.9, 130.5, 128.8, 128.2, 126.1, 123.8, 122.7, 114.3, 112.2, 111.6, 56.2, 55.2, 34.6, 28.2, 20.2.
3-(4-methoxy-2'-methyl-4'-(pyridin-3-yl)-[l,l'-biphenyl]-2-yl)propanoic acid (91)
Figure imgf000096_0002
By basic hydrolysis of ester 85. Yield 98%. XH NMR (300 MHz, CDCI3) δ ppm: 8.86-8.78 (m, 1H), 8.55- 8.48 (m, 1H), 7.99-7.92 (m, 1H), 7.47-7.35 (m, 3H), 7.19 (d, 7 = 7.8 Hz, 1H), 7.00 (d, 7 = 8.4 Hz, 1H), 6.86 (d, 7 = 2.7 Hz, 1H), 6.79 (dd, 7i = 8.4 Hz, 72 = 2.7 Hz, 1H), 3.81 (s, 3H), 2.83-2.55 (m, 2H), 2.40 (t, , = 7.8 Hz, 2H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 175.4, 158.9, 147.2 (2x), 140.8, 139.6, 137.3, 137.0, 136.1, 135.1, 132.9, 130.7, 130.6, 128.6, 124.2, 123.9, 114.3, 111.4, 55.1, 34.7, 28.5, 20.1.
3-(4,4"-dimethoxy-2',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoic acid (92)
Figure imgf000096_0003
By basic hydrolysis of ester 86. Yield 96%. XH NMR (300 MHz, CDCI3) δ ppm: 7.47-7.41 (m, 3H), 7.40 (dd, 7i = 7.8 Hz, 72 = 1.8 Hz, 1H), 7.12 (d, 7 = 7.8 Hz, 1H), 7.05 (d, 7 = 8.1 Hz, 1H), 6.90 (d, 7 = 9.0 Hz, 1H), 6.85 (d, 7 = 2.4 Hz, 1H), 6.81 (dd, 7i = 8.4 Hz, 72 = 2.7 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.85-2.59 (m, 2H), 2.43 (t, 7 = 7.7 Hz, 2H), 2.30 (s, 3H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 178.1, 114.3, 111.5, 110.1, 55.4, 55.2, 34.6, 28.3, 20.2, 16.4.
3-(3' ' -(hydroxymethyl)-4-methoxy-2' -methyl- [1 ,1 ' :4' ,1 ' ' -terphenyl] -2-yl)propanoic acid (93)
Figure imgf000097_0001
By basic hydrolysis of ester 88. Yield 96%. XH NMR (300 MHz, CDC13) δ ppm: 7.65-7.61 (m, 1H), 7.59- 7.53 (m, 1H), 7.51-7.47 (m, 1H), 7.47-7.39 (m, 2H), 7.36-7.30 (m, 1H), 7.16 (d, / = 7.8 Hz, 1H), 7.05 (d, / = 8.1 Hz, 1H), 6.86 (d, / = 2.4 Hz, 1H), 6.82 (dd, Ji = 8.4 Hz, J2 = 2.7 Hz, 1H), 4.75 (s, 2H), 3.83 (s, 3H), 2.87-2.58 (m, 2H), 2.44 (t, / = 7.7 Hz, 2H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 178.4, 158.9, 141.2, 141.2, 139.8, 139.6, 139.3, 136.7, 133.4, 130.9, 130.4, 128.9, 128.7, 126.4, 125.8, 125.7, 124.3, 114.3, 111.6, 65.3, 55.2, 34.6, 28.3, 20.2.
3-(3"-cyano-4-methoxy-2'-methyl-[l,l':4',l"-terphenyl]-2-yl)propanoic acid (94)
Figure imgf000097_0002
By basic hydrolysis of ester 89. Yield 99%. XH NMR (300 MHz, CDCI3) δ ppm: 7.91 (t, / = 1.5 Hz, 1H), 7.86 (dt, Ji = 7.8 Hz, J2 = 1.5 Hz, 1H), 7.63 (dt, Ji = 7.8 Hz, J2 = 1.4 Hz, 1H), 7.55 (t, / = 7.7 Hz, 1H), 7.4 (d, 7 = 1.8 Hz, 1H), 7.40 (dd, Λ = 7.8 Hz, J2 = 2.1 Hz, 1H), 7.20 (d, / = 7.8 Hz, 1H), 7.04 (d, / = 8.1 Hz, 1H), 6.86 (d, / = 2.4 Hz, 1H), 6.83 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 3.84 (s, 3H), 2.85-2.56 (m, 2H), 2.4 (t, 7 = 7.7 Hz, 2H), 2.13 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 178.1, 159.0, 142.2, 140.8, 139.1, 137.8, 137.3, 132.9, 131.4, 130.8, 130.8, 130.6, 130.6, 129.5, 128.7, 124.2, 118.9, 114.4, 112.9, 111.6, 55.2, 34.5, 28.2, 20.2.
2-((2-hydroxyethyl)disulfanyl)ethyl 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4- yl)pentanoate (95) To a solution of D-biotin (300 mg, 1.23 mmol), EDC methiodide (486 mg, 1.64 mmol) and DMAP (200 mg, 1.64 mmol) in dry DMF (4 mL) were added a solution of 2-hydroxyethyl disulfide (200 μί, 1.64 mmol) and Et3N (454 μί, 3.27 mmol) in dry DMF (4 mL). The reaction mixture was heated up at 65 °C and stirred overnight. The reaction mixture was concentrated in vacuo and taken up in DCM and washed with 1M HC1. The organic layer was dried over Na2S04 and filtered. The volatiles were removed in vacuum and the resulting crude was purified by FC (DCM:MeOH 19: 1 9: 1) to afford 47 mg of compound 95. Yield 10%. lH RMN (300 MHz, MeOD-cU) δ ppm: 4.50 (dd, Ji = 7.9 Hz, J2 = 4.9 Hz, 1H): 4.34 (t, / = 6.5 Hz, 2H), 4.30 (dd, Ji = 8.1 Hz, = 4.5 Hz, 1H), 3.79 (t, / = 6.5 Hz, 2H), 3.25-3.17 (m, 1H), 2.97 (t, / = 6.4 Hz, 2H), 2.93 (dd, Ji = 7.8 Hz, J2 = 5.1 Hz, 1H), 2.85 (t, J = 6.4 Hz, 2H), 2.71 (d, J = 12.7 Hz, 1H), 2.38 (t, J = 7.3 Hz, 2H), 1.86-1.51 (m, 4H), 1.56-1.41 (m, 2H); 13C RMN (75 MHz, MeOD < ) δ ppm: 175.1, 166.1, 63.4, 61.6, 61.2, 56.9, 42.2, 41.1, 38.2, 34.7, 29.7, 29.4, 25.9.
2 (2 (3 4-methoxy-3S3M-dimethyl-[l,l':4Sl^^
5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)pentanoate (96)
Figure imgf000098_0001
Oxalyl chloride (16 μί, 0.18 mmol) was added to a solution of T12 (44 mg, 0.12 mmol) in 1,2- dichloroethane (2 mL), followed by the addition of 1-2 drops of DMF. The reaction mixture was refluxed for 1 h. Next, the reaction mixture was warmed at room temperature and cooled in an ice bath. Then, a solution of compound 95 (46 mg, 0.12 mmol) and Et3N (50 μί, 0.36 mmol) in DCE (1 mL) was added at 0°C and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and the resulting crude was purified by preparative TLC (DCM/EtOAc 1:4 and 4-5 drops of MeOH) to give 34 mg of compound 96 as a transparent oil. Yield 40%. XH RMN (300 MHz, CDC13) δ ppm: 7.32 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.23-7.09 (m, 6H), 6.84 (d, J = 2.7 Hz, 1H), 6.82 (dd, Ji = 8.1 Hz, j = 2.7 Hz, 1H), 5.77 (s, 1H), 5.31 (s, 1H), 4.54-4.43 (m, 1H), 4.30 (dt,
Figure imgf000098_0002
= 6.6 Hz, J2 = 4.5 Hz, 5H), 3.84 (s, 3H), 3.14 (ddd, Ji = 8.3 Hz, J2 = 6.5 Hz, h= 4.5 Hz, 1H), 2.99 (t, / = 7.8 Hz, 2H), 2.87 (m, 5H), 2.72 (d, / = 12.6 Hz, 1H), 2.52 (dd,
Figure imgf000099_0001
= 8.8 Hz, J2 = 7.1 Hz, 2H), 2.42 (s, 3H), 2.35 (t, J = 7.4 Hz, 2H), 2.31 (s
3H), 1.80-1.53 (m, 4H), 1.53-1.35 (m, 2H); 13C RMN (75 MHz, CDC13) δ ppm: 173.5, 172.8, 163.6,
159.0, 141.7, 140.6, 140.1, 139.3, 137.8, 135.2, 134.5, 131.5, 131.4, 130.2, 129.7, 128.1, 127.6, 126.8,
126.5, 114.7, 111.6, 62.4, 62.2, 62.1, 60.2, 55.5, 55.4, 40.7, 37.4, 37.3, 35.4, 33.9, 28.6, 28.5, 28.4, 24.8,
21.6, 20.7.
Example 5: Scaleable Synthesis of GPBP Inhibitors
This example expands upon the disclosure provided above relating to Scheme 8. The first step of this synthesis consisted of the regio selective bromination of commercial 3-hydroxybenzaldehyde in accordance with a known procedure (Studies toward the Total Synthesis of Mumbaistatin, a Highly Poteri Glucose-6-phosphate Translocase Inhibitor. Synthesis of a Mumbaistatin Analogue; F. Kaiser, L.
Schwink, J. Velder and H-G. Schmalz; J. Org. Chem. 2002, 67, 9248-9256). The resulting bromoaryl la was then coupled with commercial m-tolylboronic acid to obtain biphenyl 2a which was then transformec in trifluoroborate 5a following the procedure described by Tudge et al. (Scope of the Palladium-Catalyzei Aryl Borylation Utilizing Bis-Boronic Acid; J. Am. Chem. Soc. 2012, 134, 11667-11673) with a good overall yield (Scheme 1). Compound 5a was then coupled with bromoaryl 6a (it was previously synthesized from compound la and malonic acid) to afford terphenylic compound 7a with good yield. The later 3 steps (O-methylation, double bound hydrogenation and methyl ester hydrolysis) were carried with an excellent yield to give compound T12 (Scheme 12). Compound T12 was finally formulated as a sodium salt.
Figure imgf000100_0001
Scheme 12: scale-up synthesis of terphenyl T12
The progress of the reactions was monitored by thin-layer chromatography (TLC silica gel 60 F25^
Merck). All the compounds were white solids unless otherwise specified. All the NMR spectra were measured with a Bruker Advance AC-300 (300 MHz) apparatus.
2-bromo-5-hydroxybenzaldehyde (la)
Figure imgf000101_0001
A suspension of 3-hydroxybenzaldehyde (48.85 g, 400 mmol) in a 10: 1 mixture of chloroform/acetonitril (330 mL) was cooled with an ice bath. Then, bromine (63.9 g, 1 equiv) was added dropwise and the bath was removed to stir the mixture at room temperature. After 4 h, the reaction was quenched with a saturated NaHC03 solution (150 mL). The phases were separated and the organic layer was washed with water (150 mL). The concentrated organic phase was filtered through a thin pad of Celite and eluted with a 4: 1 mixture of dichloromethane/ethyl acetate. Solvent was removed in vacuo and the remaining solid was crystallized several times from ethyl acetate/hexane to give 44.15 g of 2-bromo-5- hydroxybenzaldehyde as light brown needles. Yield 55%; mp: 132-134 °C. XH NMR (300 MHz,
CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, / = 8.7 Hz, 1H), 7.34 (d, 7 = 3.1 Hz, 1H), 7.10 (dd, Ji = 8.7 Hz, = 3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5Br02: 199.9472, found: 199.9463.
4-hydroxy-3'-methyl-[l,l'-biphenyl]-2-carbaldehyde (2a)
Figure imgf000101_0002
In a two-neck round-bottom flask, 2-bromo-5-hydroxybenzaldehyde (18.09 g), m-tolylboronic acid (12.6 g, 1.03 equiv), sodium carbonate (19.08 g, 2 equiv) and palladium tetrakistriphenylphosphine (780 mg, 0.75% mol) were dissolved in a 7:3 mixture of acetonitrile/water (160 mL) and the resulting mixture was refluxed under N2 atmosphere until completion of the reaction (TLC hexane/ethyl acetate 5: 1). The reaction mixture was cooled and filtered through a thin pad of Celite and the volatiles were removed under vacuum. The aqueous phase was neutralized with 1M HC1 solution and extracted with AcOEt (3x5' mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The resulting crudf was triturated with hexane (3x30 mL) and filtered to eliminate the product of homocoupling reaction. The filtered solid was crystallized several times from EtOH to afford 16.5 g of compound 31a as a brown solid. Yield 86%; mp: 148-150 °C. XH NMR (300 MHz, CDC13) δ ppm: 9.93 (s, 1H), 7.63 (t, / = 8.1 Hz, 2H), 7.52 (d, / = 2.7 Hz, 1H), 7.24 (d, / = 7.8 Hz, 1H), 7.20-7.13 (m, 3H), 5.73 (s, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDC ) δ ppm: 192.8, 155.3, 139.3, 138.1, 137.3, 134.5, 132.4, 130.9, 128.6, 128.3, 127.4, 121.4, 112.9, 21.4; HRMS (EI) m/z: calcd for C14H12O2: 212.0837, found: 212.0827.
2,3'-dimethyl-[l,l'-biphenyl]-4-ol (3a)
Figure imgf000102_0001
A solution of 4-hydroxy-3'-methyl-[l,l'-biphenyl]-2-carbaldehyde (10.1 g) in ethyl acetate (150 mL) was hydrogenated overnight at room temperature and 20 atm of pressure using 10% palladium on carbon as catalyst (2 g, 20% w/w). Thereafter, the mixture was filtered over Celite and the filtrates concentrated in vacuo to give 9.34 g of compound 3a as a transparent oil. Yield 99%. lU NMR (300 MHz, CDCI3) δ ppm 7.33-7.26 (m, 1H), 7.17-7.07 (m, 4H), 6.76 (d, / = 2.7 Hz, 1H), 6.72 (dd, Ji = 8.1 Hz, J2 = 2.7 Hz, 1H), 4.92 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCb) δ ppm: 154.5, 141.5, 137.6, 137.0, 134.9, 131.0, 130.1, 127.9, 127.2, 126.5, 116.9, 112.6, 21.4, 20.6.
2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoromethanesulfonate (4a)
Figure imgf000102_0002
A solution of 2,3'-dimethyl-[l,l'-biphenyl]-4-ol (9.34 g) and pyridine (7.45 g, 2 equiv) in dry
dichloromethane (150 mL) was chilled in an ice bath. Then, triflic anhydride (15.9 g, 1.2 equiv) was added dropwise and the mixture was stirred at room temperature until the reaction was completed (TLC hexane/ethyl acetate 10: 1). Then, the mixture was washed with 1M HC1 (3x50 mL) and brine (50 mL), dried over Na2S04, filtered and concentrated under vacuum to afford 14.83 g of triflate 4a as an orange oi (it crystallizes on fridge). Yield 95%. lH NMR (300 MHz, CDCb) δ ppm: 7.36-7.26 (m, 2H), 7.22-7.06 (m, 5H), 2.41 (s, 3H), 2.29 (s, 3H); 19F NMR (282 MHz, CDCb) δ ppm: -73.38 (s, 3F); 13C NMR (75 MHz, CDCb) δ ppm: 148.4, 142.5, 140.0, 138.3, 138.0, 131.3, 129.7, 128.2 (2x), 126.0, 122.6, 118.8 (q, 7= 318.9 Hz), 118.3, 21.4, 20.6.
Potassium 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoroborate (5a)
Figure imgf000102_0003
A mixture of 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoromethanesulfonate (14.83 g), tetrahydroxydiboron (12.07 g, 3 equiv), XPhos palladium (II) biphenyl preformed catalyst (141 mg, 0.4% mol), XPhos (214 mg, 1% mol) and KOAc (13.21 g, 3 equiv) was dissolved in ethanol (350 mL) in a two-neck round- bottom flask. The mixture was then heated at 80 °C under N2 atmosphere until consumption of starting material (the mixture turned orange, TLC hexane/ AcOEt 10: 1). The reaction was cooled to room temperature, filtered through a thin pad of Celite (eluting with 3x20 mL of AcOEt) and concentrated. The crude reaction was dissolved in AcOEt (100 mL) and washed with water (100 mL) and brine (50 mL). The combined aqueous layers were further extracted with AcOEt (3x20 mL). The combined organics were dried over Na2S04, filtered and concentrated. The concentrated crude reaction was taken up in MeOH (150 mL) and cooled with an ice bath. To this cooled mixture was added a 4.5M aqueous KHF2 solution (15.77 g, 4.5 equiv) and the reaction was stirred for 30 min at 0 °C and for 3 h at room
temperature. The resulting mixture was then concentrated and lyophilized overnight to remove any traces of water. The compound was purified with continuous Soxhlet extraction (overnight) with acetone (300 mL). The collected solvent was removed in vacuo and the remaining solid was triturated with hexane (2x30 mL) and ether (2x30 mL) to remove impurities and give 11.0 g of potassium trifluoroborate salt 5a
Yield 85%; pf > 255 °C. XH NMR (300 MHz, MeOD-cU) δ ppm: 8.70 (br s, 1H), 8.66 (d, / = 7.5Hz, 1H), 8.56-8.49 (m, 1H), 8.40-8.32 (m, 3H), 8.24 (d, / = 7.5Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H); 13C NMR (75 MHz, MeOD-cU) δ ppm: 163.4, 159.1, 157.2, 153.9, 152.1, 149.9, 149.3, 147.8, 147.8, 146.8, 146.3, 40.7
39.9.
Ethyl (E)-3-(2-bromo-5-hydroxyphenyl)acrylate (6a)
Figure imgf000103_0001
A mixture of 2-bromo-5-hydroxybenzaldehyde (44.25 g), malonic acid (22.9 g, 1 equiv), pyridine (100 mL) and piperidine (5 mL) as catalyst were stirred overnight at 100 °C. Thereafter, ice- water (100 mL) was added and the mixture was acidified (pH=l) with concentrated HC1. The resulting precipitate was filtered, washed with 1M HC1 solution (4x100 mL) and dried under vacuum to give 47.6 g of (E)-3-(2- bromo-5-hydroxyphenyl)acrylic acid as a brown solid. To a solution of this compound in dry ethanol (10( mL) was added a small quantity of H2S04 (1 mL) and the stirred mixture was refluxed overnight. The solvent was evaporated in vacuo and the crude was purified by crystallization from ethanol to give 48.83 g of compound 6a as light brown needles. Yield 82%; mp: 96-98 °C. lH RMN (300 MHz, CD3COCD3) δ ppm: 8.82 (br s, 1H), 7.94 (d, J = 16.1 Hz, 1H), 7.49 (d, / = 8.7 Hz, 1H), 7.28 (d, / = 2.9 Hz, 1H), 6.88 (dd, Ji = 8.7 Hz, J2 = 2.9 Hz, 1H), 6.45 (d, / = 16.1 Hz, 1H), 4.24 (q, / = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C RMN (75 MHz, CD3COCD3) δ ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2, 115.8, 62.1, 15.6; HRMS (ΕΙ) m/z: calcd for CnHnBr03: 269.9892, found: 269.9886.
(E)-3-(4-hydroxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylic acid (7a)
Figure imgf000104_0001
In a two-neck round-bottom flask, (E)-ethyl 3-(2-bromo-5-hydroxyphenyl)acrylate (10.02 g), potassium 2,3'-dimethyl-[l,l'-biphenyl]-4-yl trifluoroborate (11.0 g, 1.03 equiv), sodium carbonate (7.83 g, 2 equiv) and palladium tetrakistrifenilfosfine (320 mg, 0.75% mol) were dissolved in a 7:3 mixture of
acetonitrile/water (150 mL) and the reaction mixture was refluxed under N2 atmosphere until consumptio of starting material (TLC hexane/AcOEt 5: 1). The reaction mixture was cooled and filtered through a thir pad of Celite and the volatiles were removed under vacuum. The aqueous phase was neutralized with 1M HC1 solution and extracted with AcOEt (3x50 mL). The combined organic layers were concentrated and the resulting crude was dissolved in a 4: 1 mixture of tetrahydrofuran/water (100 mL). Then,
monohydrated litium hydroxide (4.65 g, 3 equiv) was added and the mixture was stirred overnight at 50 °C. The organic solvent was removed in vacuo and the aqueous phase was acidified (pH=l) with 2 M HC1. The resulting precipitate was filtered and the filtrate was extracted with CH2C12 (3x50 mL). The organic phases were joined, washed with brine, concentrated in vacuo and added to the previous precipitate. This solid was triturated with hexane (3x30 mL) and filtered to remove the product of homocoupling reaction. The filtered solid was crystallized several times from MeOH (TLC
CH2Cl2/MeOH 5: 1) to give 9.61 g of terphenyl 7a as a pale brown solid. Yield 75%; pf: 208-210 °C. XH NMR (300 MHz, MeOD-cU) δ ppm: 9.03 (d, / = 16.2 Hz, 1H), 8.64-8.39 (m, 9H), 8.29 (dd, Ji = 8.4 Hz, J = 2.7 Hz, 1H), 7.70 (d, / = 15.9 Hz, 1H), 3.66 (s, 3H), 3.57 (s, 3H); 13C NMR (75 MHz, MeOD-cU) δ ppm: 187.1, 177.1, 163.8, 161.6, 160.9, 159.1, 157.8, 155.1, 154.5, 153.4, 151.9, 151.8, 149.9, 149.5, 148.2, 147.7, 147.5, 146.3, 139.0, 137.7, 132.8, 40.7, 39.9.
Methyl (E)-3-(4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)acrylate (8a)
Figure imgf000104_0002
(E)-3-(4-hydroxy-3',3"-dimethyl-[l, :4',l"-terphenyl]-2-yl)acrylic acid (9.17 g) and potassium carbonate (9.20 g, 2.5 equiv) were dissolved in a 1: 1 mixture of dry dimethylformamide/acetone (100 mL). Then, methyl iodide (9.45 g, 2.5 equiv) was added dropwise and the reaction mixture was heated to 50 °C until consumption of starting material (TLC hexane/ AcOEt 10: 1; the reaction vessel was sealed with a teflon cap to prevent the evaporation of methyl iodide). The solvents were removed under vacuum and the resulting crude was dissolved in AcOEt (60 mL). The organic phase was then washed with water (50 mL' saturated NH4C1 solution (2x50 mL), water (50 mL) and brine (50 mL). The organic phase was dried ovei Na2S04, filtered and concentrated in vacuo. The resulting solid was crystallized several times from EtOH to afford 9.25 g of compound 8a. Yield 93%; pf: 95-97 °C. lH NMR (300 MHz, CDCI3) δ ppm: 7.84 (d, j = 15.9 Hz, 1H), 7.36 (d, / = 8.7 Hz, 1H), 7.34 (t, 7 = 7.5 Hz, 1H), 7.29 (d, / = 7.8 Hz, 1H), 7.24-7.12 (m, 6H), 7.03 (dd, Ji = 8.7 Hz, J2 = 2.7 Hz, 1H), 6.44 (d, / = 15.9 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCI3) δ ppm: 167.3, 158.9, 144.2, 141.5, 140.9, 138.4, 137.7, 135.7, 135.3, 133.5, 131.7 (2x), 130.0, 129.6, 127.9, 127.5, 127.4, 126.3, 118.8, 116.2, 111.2, 55.4, 51.6, 21.5, 20.5.
Methyl 3-(4-methoxy-3',3"-dimethyl-[l,l,:4,,l"-terphenyl]-2-yl)propanoate (9a)
Figure imgf000105_0001
A solution of methyl (E)-3-(4-methoxy-3',3"-dimethyl-[l,r:4', l"-terphenyl]-2-yl)acrylate (9.10 g) in AcOEt (150 mL) was hydrogenated overnight at room temperature and 2 atm of pressure using 10% palladium on carbon as catalyst (910 mg, 10% w/w). Thereafter, the mixture was filtered over Celite and the filtrates concentrated in vacuo to give 8.97 g of compound 9a as a transparent oil. Yield 98%. XH NMR (300 MHz, CDCI3) δ ppm: 7.33 (t, J = 5.7 Hz, 1H), 7.26-7.16 (m, 6H), 7.14 (dd,
Figure imgf000105_0002
= 5.7 Hz, J2 = 1.2 Hz, 1H), 6.85 (d, / = 1.8 Hz, 1H), 6.83 (dd,
Figure imgf000105_0003
= 6.0 Hz, J2 = 1.8 Hz, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 2.99 (t, / = 6.0 Hz, 2H), 2.51 (t, / = 6.0 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCI3) < ppm: 173.4, 158.9, 141.6, 140.4, 140.0, 139.3, 137.6, 135.1, 134.4, 131.4, 131.3, 130.0, 129.6, 127.9, 127.5, 126.7, 126.3, 114.4, 111.5, 55.3, 51.6, 35.3, 28.5, 21.5, 20.6.
3-(4-methoxy-3',3" -dimethyl-[l,l ' :4',1 ' ' -terphenyl]-2-yl)propanoic acid (T12)
Figure imgf000105_0004
To a solution of methyl 3-(4-methoxy-3',3"-dimethyl-[l, :4',l"-terphenyl]-2-yl)propanoate (8.95 g) in a 4: 1 tetrahydrofuran/water mixture (100 mL), monohydrated lithium hydroxide (3.0 g, 3 equiv) was added and the mixture was stirred at room temperature until completion of the reaction (TLC hexane/ AcOEt 5: 1). THF was removed under reduced pressure, the aqueous phase was acidified with 2 M HC1 solution until reach pH=l and was extracted with DCM (3x50 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and removed in vacuo to afford 8.44 g of 3-(4-methoxy-3',3"- dimethyl-[l,r:4',l"-terphenyl]-2-yl)propanoic acid (T12) as a white solid. Yield 98%; mp: 85-87 °C. To formulate this final product as a sodium salt, a 0.2 M NaOH solution (936 mg, 1 equiv) was added to this solid and the mixture was stirred at room temperature until the solution became clear. The solution was then freeze-dried and the resulting white powder was stored in a desiccator.

Claims

WHAT IS CLAIMED:
1. A compound of formula (I):
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)C2-C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, hydroxyl(Ci-C6 alkyl), or formyl;
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(G-C6 alkoxy), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(G-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl; and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i-5-C(0)(Ci-C6 alkoxy), (aryl)Ci Ce alkyl, or (heteroaryl)Ci-C6 alkyl.
2. The compound of claiml, wherein the compound has the formula:
Figure imgf000108_0001
wherein:
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6
alkyl)sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)(Ci-C6 alkoxy), and -(CH2)i-5-C(0)NH2;
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-G alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R3 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-Ce alkyl)sulfanyl(Ci-C6 alkyl), -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i-5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH, or -0(CH2)i-5-C(0)(Ci-C6 alkoxy).
3. The compound of claim 1 or 2, wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-Ce alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- Ce alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy);
R3 is Ci-C6 alkyl, -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)(Ci-C6 alkoxy), -C(0)NH2, -(CH2)i_5-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or
-CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH,
-CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH, or -0(CH2)i_5-C(0)(Ci-C6 alkoxy).
The compound of claim 1 or 2, wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (Ci- Ce alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy);
R3 is Ci-C6 alkyl, -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), benzyloxy,
-(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2,
-(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH,
-CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i_5-C(0)OH, or -0(CH2)i_5-C(0)(Ci-C6 alkoxy).
The compound of any one of claims 1-4, wherein the compound has the formula:
Figure imgf000109_0001
The compound of any one of claims 1-4, wherein the compound has the formula:
7. The compound of any one of claims 1-6, wherein R is hydrogen.
8. The compound of any one of claims 1-7, wherein R3 is Ci-C6 alkyl, -C(0)OH, -(CH2)i-5-C(0)OH, -C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy).
9. The compound of any one of claims 1-7, wherein R3 is -(CH2)i_2-C(0)OH or -(CH2)i_2-C(0)(Ci-C alkoxy).
10. The compound of any one of claims 1-7, wherein R3 is -(CH2)2-C(0)OH or -(CH2)2-C(0)(Ci-C6 alkoxy).
11. The compound of any one of claims 1-7, wherein R3 is -CH=CH-C(0)OH or
-CH=CH-C(0)(Ci-C6 alkoxy).
12. The compound of any one of claims 1-11, wherein R4 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
13. The compound of any one of claims 1-11, wherein R4 is hydroxy or C1-C6 alkoxy.
14. The compound of any one of claims 1-13, wherein R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl) 0-C6 alkoxy, or halo(Ci-C6 alkoxy).
15. The compound of any one of claims 1-13, wherein R5, if present, is C1-C6 alkyl or halo(Ci-C6 alkyl).
16. The compound of any one of claims 1-6, wherein
R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy); RJ is -C(0)OH, -(CH2)i-2-C(0)OH, -C(0)(Ci-C6 alkoxy),-(CH2)i-2-C(0)(Ci-C6 alkoxy),
-C(0)NH2, -(CH2)i-2-C(0)NH2, -C(0)NH(Ci-C6 alkyl), -(CH2)i-2-C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -(CH2)i-2-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or
-CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy. The compound of any one of claims 1-6, wherein
R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy);
R3 is -(CH2)i-2-C(0)OH, -(CH2)i-2-C(0)(Ci-C6 alkoxy), -(CH2)i-2-C(0)NH2,
-(CH2)i-2-C(0)NH(Ci-C6 alkyl), -(CH2)i-2-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, or -CH=CH-C(0)(Ci-C6 alkoxy); and
R4 is hydroxy, C1-C6 alkoxy, halo(Ci-C6 alkoxy), or benzyloxy.
The compound of any one of claims 1-6, wherein R1 is hydrogen;
R3 is -(CH2)i-2-C(0)OH, -(CH2)i-2-C(0)(Ci-C6 alkoxy), or -(CH2)i-2-C(0)NH2; R4 is hydroxy or C1-C6 alkoxy; and
R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
The compound of any one of claims 1-6, wherein R1 is hydrogen;
R3 is -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy); R4 is hydroxy or C1-C6 alkoxy; and
R5, if present, is C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, or halo(Ci-C6 alkoxy).
The compound of any one of claims 1-6, wherein RJ, it present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy,
Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
R1 is hydrogen;
R3 is -(CH2)i-2-C(0)OH; and
R4 is Ci-C6 alkoxy.
21. The compound of any one of claims 1-6, wherein
R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, and amino(Ci-C6 alkyl);
R1 is hydrogen;
R3 is -CH=CH-C(0)OH; and
R4 is Ci-C6 alkoxy.
22. The compound of any one of claims 1-6, wherein
R5, if present, is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, or halo(Ci-C6 alkoxy);
R1 is hydrogen;
R3 is -(CH2)i-2-C(0)OH or -CH=CH-C(0)OH; and R4 is Ci-C6 alkoxy.
23. The compound of claim 1, which is:
Figure imgf000112_0001
T80 T85
Figure imgf000113_0001
112 A compound which is:
Figure imgf000114_0001
Figure imgf000115_0001
T112
T115
Figure imgf000115_0002
T114 T116
Figure imgf000115_0003
T117 T123
Figure imgf000115_0004
T125 or T122 or a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 1-24 coupled to a detectable label.
26. The compound of claim 25 wherein the detectable label is selected from the group consisting of ai enzyme, a prosthetic group, a fluorescent material, a luminescent material and a radioactive material.
27. A pharmaceutical composition comprising a compound according to any one of claims 1-26 and a least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
28. The pharmaceutical composition of claim 27, wherein the composition comprises a carrier, and wherein the carrier comprises biotin.
The pharmaceutical composition of claim 28, wherein the biotin is D-biotin.
30. A compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for use as a medicament.
31. A compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for use in the treatment of antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, endoplasmic reticulum (ER) stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune-complex mediated glomerulonephritis (GN), organ fibrosis, pulmonary fibrosis, rheumatoid arthritis or type 2 diabetes.
32. A compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for use in inhibiting mesenchymal phenotype after epithelial-to- mesenchymal transition (EMT).
33. A compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for use in the treatment of an invasive tumor.
34. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of chronic kidney disease.
35. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis immune-complex mediated glomerulonephritis (GN).
36. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of organ fibrosis.
37. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of pulmonary fibrosis.
38. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of rheumatoid arthritis.
39. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of an invasive tumor.
40. The compound or composition of claim 32, wherein EMT has contributed to the pathogenesis of type 2 diabetes.
41. The compound or composition of any one of claims 31-40, wherein the treatment of, or inhibiting, is with a subject having altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, and wherein the altered expression is indicative ol an epithelial-to- mesenchymal phenotype transition.
42. The compound or composition of claim 41, wherein the cell markers include one or more of
vimentin, E-cadherin, collagens I and IV, matrix metalloproteinase 9 (MMP-9), chemokine (C-C motif) ligand 2 (CCL2) / monocyte chemotactic protein 1 (MCP-1), α5 (IV) chain, (a5 (IV) )3 protomer, and Goodpasture antigen binding protein (GPBP).
43. The compound or composition of claim 42, wherein the subject has an increase in vimentin
expression and a decrease in E-cadherin expression in a relevant tissue sample compared to a control tissue.
44. The compound or composition according to of any one of claims 31-43, wherein the treatment or inhibiting is in a subject having an increased expression of a5(IV) chain, and/or (a5 (IV))3 protomer in a relevant tissue sample compared to a control tissue sample, and wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
45. The compound or composition of claim 44, wherein the subject has an increased expression of (α1)2 2 (IV) protomer and/or an increased expression α1,α2 (IV) chains in a relevant tissue sample compared to a control tissue sample, and wherein the increased expression is indicative of an epithelial-to-mesenchymal phenotype transition and/or an invasive tumor phenotype.
46. The compound or composition according to any one of claims 33, 39, and 41-45, wherein the invasive tumor is an invasive carcinoma.
47. The compound or composition of claim 46, wherein the invasive carcinoma is an invasive breast tumor or an invasive lung tumor.
48. The compound or composition according to any one of claims 33, 39, and 41-47, wherein
treatment of the invasive tumor reduces tumor metastases.
49. The compound or composition of any one of claims 31-48, wherein the compound is used as a mono-therapeutic or wherein the compound is used in combination with an anti-tumor agent.
50. The compound or composition of any one of claims 31-49, wherein the treatment of, or inhibiting, is with mammal or a bird.
51. The compound or composition of claim 50, wherein the treatment of, or inhibiting, is with a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
52. A compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for use in the detection of EMT in a tissue of a subject, wherein the compound is detectably labeled and capable of binding to the tissue to detect EMT in the tissue.
53. The compound or composition of claim 52, wherein the tissue is selected from the group
consisting of a tumor, a joint, and tissue from any organ.
54. The compound or composition of claim 53, wherein the tissue is a kidney, and detecting EMT in the kidney indicates that the subject has chronic kidney disease.
55. The compound or composition of claim 54, wherein the tissue is a kidney, and detecting EMT in the kidney indicates that the subject has immune-complex mediated GN.
56. The compound or composition of claim 53, wherein the tissue is tissue from any organ, and
wherein detecting EMT indicates that the subject has organ fibrosis.
57. The compound or composition of claim 53, wherein the tissue is a lung, and wherein detecting EMT in the lung indicates that the subject has pulmonary fibrosis.
58. The compound or composition of claim 53, wherein the tissue is a joint, and wherein detecting EMT indicates that the subject has rheumatoid arthritis.
59. The compound or composition of claim 53, wherein the tissue is a tumor, and wherein detecting EMT indicates that the subject has an invasive tumor.
60. The compound or composition of claim 59 wherein the tumor is an invasive carcinoma.
61. The compound or composition of claim 60 wherein the tumor is an invasive breast tumor or an invasive lung tumor.
62. The compound or composition of any one of claims 52-61, wherein the subject is a mammal or bird.
63. The compound or composition of claim 62, wherein the subject is a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
64. The compound or composition of any one of claims 52-63, wherein the compound is detectably labeled by binding to a detectable label selected from the group consisting of an enzyme, a prosthetic group, a fluorescent material, a luminescent material, and a radioactive material.
65. The compound or composition of claim 64, wherein the compound is detectably labeled by
binding to a detectable label selected from the group consisting of biotin and fluorescein.
66. A method for treating antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, ER stress-mediated disorders, aberrant apoptosis, chronic kidney disease, immune- complex mediated GN, organ fibrosis, pulmonary fibrosis, rheumatoid arthritis or type 2 diabetes comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29.
67. A method for inhibiting mesenchymal phenotype after epithelial-to-mesenchymal transition (EMT), comprising administering to a subject in need thereof an amount effective to inhibit mesenchymal phenotype after EMT of a compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29.
68. A method for treating an invasive tumor, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29.
69. The method of claim 67, wherein the subject has chronic kidney disease.
70. The method of claim 67, wherein the subject has immune-complex mediated GN.
71. The method of claim 67, wherein the subject has organ fibrosis.
72. The method of claim 67, wherein the subject has pulmonary fibrosis.
73. The method of claim 67, wherein the subject has rheumatoid arthritis.
74. The method of claim 67, wherein the subject has an invasive tumor.
75. The method of claim 67, wherein the subject has type 2 diabetes.
76. The method of any one of claims 66-75, wherein the subject has an altered expression of cell markers in a relevant tissue sample compared to a control tissue sample, wherein the altered expression is indicative of an epithelial-to-mesenchymal phenotype transition.
77. The method ol claim 76, wherein the cell markers include one or more ol vimentin, E-cadherin, collagens I and IV, MMP-9, CCL2 / MCP-1, α5 (IV) chain, (<x5 (IV))3 protomer, and Goodpastun antigen binding protein (GPBP).
78. The method of claim 77, wherein the subject has an increase in vimentin expression and a decreas in E-cadherin expression in a relevant tissue sample compared to a control tissue.
79. The method of any one of claims 66-78, wherein the subject has an increased expression of a5(IV chain, and/or (a5 (IV))3 protomer in a relevant tissue sample compared to a control tissue sample, wherein the increase expression is indicative of an epithelial-to-mesenchymal phenotype transitioi and/or an invasive tumor phenotype.
80. The method of claim 79, wherein the subject has an increased expression of (α1)2 2 (IV)
protomer and/or an increased expression α1,α2 (IV) chains in a relevant tissue sample compared to a control tissue sample, wherein the increase expression is indicative of an epithelial-to- mesenchymal phenotype transition and/or an invasive tumor phenotype.
81. The method of any one of claims 68, 74, and 76-80, wherein the invasive tumor is an invasive carcinoma.
82. The method of claim 81, wherein the invasive carcinoma is an invasive breast tumor or an invasiv lung tumor.
83. The method of any one of claims 68, 74, and 76-82, wherein treating the invasive tumor reduces tumor metastases in the subject.
84. The method of any one of claims 66-83, wherein the compound is the only therapeutic
administered to the subject.
85. The method of any one of claims 66-84, wherein the subject is a mammal or a bird.
86. The method of claim 85, wherein the subject is a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
87. A method for detecting EMT in a tissue, comprising
(a) contacting a tissue in a subject with an effective amount to label the tissue of a detectably labeled compound according to any one of claims 1-26 or a pharmaceutical composition according to any one of claims 27-29 for a time and under conditions suitable to promote binding of the detectably labeled compound to the tissue; and
(b) detecting the detectably labeled compound bound to the tissue, thereby detecting EMT in the tissue.
88. The method of claim 87, wherein the tissue is selected from the group consisting of a tumor, a joint, and tissue from any organ.
89. The method of claim 88, wherein the tissue is a kidney, and detecting EMT in the kidney indicate; that the subject has chronic kidney disease.
90. The method of claim 88, wherein the tissue is a kidney, and detecting EMT in the kidney indicate; that the subject has immune-complex mediated GN.
91. The method of claim 88, wherein the tissue is tissue from any organ, and wherein detecting EMT indicates that the subject has organ fibrosis.
92. The method of claim 88, wherein the tissue is a lung, and wherein detecting EMT in the lung indicates that the subject has pulmonary fibrosis.
93. The method of claim 88, wherein the tissue is a joint, and wherein detecting EMT indicates that the subject has rheumatoid arthritis.
94. The method of claim 88, wherein the tissue is a tumor, and wherein detecting EMT indicates that the subject has an invasive tumor.
95. The method of claim 94 wherein the tumor is an invasive carcinoma, including but not limited to invasive breast tumors and invasive lung tumors.
96. The method of any one of claims 87-95, wherein the subject is a mammal or bird.
97. The method of claim 96, wherein the subject is a human, dog, cat, cattle, horse, donkey, pig, chicken, turkey, sheep, or goat.
98. The method of any one of claims 87-97, wherein the compound is detectably labeled by binding t( a detectable label selected from the group consisting of an enzyme, a prosthetic group, a fluorescent material, a luminescent material, and a radioactive material.
99. The method of claim 98, wherein the compound is detectably labeled by binding to a detectable label selected from the group consisting of biotin and fluorescein. A method ol preparing a compound of formula (II):
Figure imgf000122_0001
(Π)
or a pharmaceutically acceptable salt thereof,
wherein
R is selected from N and CR5;
R5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(Ci-C6 alkyl)amino, hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6
alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl;
R1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl);
R2 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(C0-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl;
R3 is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or
(heteroaryl)Ci-C6 alkyl;
R4 is hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo(Ci-C6 alkoxy),
benzyloxy, -(CH2)i_5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6
alkoxy), -0(CH2)i-5-C(0)OH, -0(CH2)i-5-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl;
comprising reacting a compound of formula (III):
Figure imgf000123_0001
(III)
wherein
X is halogen
M is a monovalent cation; and
with a compound of formula (IV):
Figure imgf000123_0002
(IV)
wherein
XI is leaving group; and
R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C alkyl), (Ci-Ce alkyl) sulfanyl(Ci-C6 alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i-5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or
(heteroaryl)Ci-C6 alkyl.
101. The method of claim 100, wherein X is fluoro, chloro or bromo.
102. The method of claim 100, wherein X is fluoro.
103. The method of any of claims 100-102, wherein M is Li+, Na+, K+ or Cs+.
104. The method of any of claims 100-102, wherein M is Li+, Na+ or K+.
105. The method of any of claims 100-102, wherein M is Na+ or K+.
106. The method of any of claims 100-102, wherein M is K+.
107. The method of any of claims 100-106, wherein X1 is halogen, -OTf or -OMs.
108. The method of any of claims 100-106, wherein X1 is halogen.
109. The method of any of claims 100-106, wherein X1 fluoro, chloro or bromo.
110. The method of any of claims 100-106, wherein X1 is bromo.
111. The method of any of claims 100- 110, wherein R is CR5.
1 12. The method of any of claims 100- 111, wherein
R5 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy)Ci-C6 alkyl, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-5-C(0)NH2, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl.
1 13. The method of any of claims 100- 1 1 1 , wherein
R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-Ce alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy)Ci-C6 alkyl, (aryl)Ci-C6 alkyl, and (heteroaryl)Ci-C6 alkyl.
114. The method of any of claims 100- 111, wherein
R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, (Ci-C6 alkoxy)Ci-C6 alkyl, (aryl)O-Ce alkyl, and (heteroaryl)Ci-C6 alkyl.
115. The method of any of claims 100- 111, wherein
R5 is selected from the group consisting of hydrogen, C1-C6 alkyl and (C1-C6 alkoxy)Ci-C6 alkyl.
116. The method of any of claims 100- 111, wherein
R5 is selected from the group consisting of hydrogen and C1-C6 alkyl.
1 17. The method of any of claims 100- 111, wherein
R5 is Ci-C6 alkyl.
118. The method of any of claims 100- 111, wherein
R5 is hydrogen.
1 19. The method of claim 100, wherein R is N.
120. The method of any of claims 100- 119, wherein
R1 is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6
alkoxy), hydroxy(Ci-C6 alkyl), (C1-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl).
121. The method of any of claims 100- 119, wherein
R1 is hydrogen, halogen, cyano, hydroxy or Ci-Ce alkyl.
122. The method of any of claims 100- 119, wherein
R1 is hydrogen, cyano or Ci-Ce alkyl.
123. The method of any of claims 100- 119, wherein
R1 is hydrogen.
124. The method of any of claims 100- 119, wherein R1 is Ci- e alkyl.
125. The method of any of claims 100- 119, wherein
R1 is hydrogen, cyano, Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl).
126. The method of any of claims 100- 119, wherein
R1 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl).
127. The method of any of claims 100- 119, wherein
R1 is hydrogen, cyano, Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl) or (Ci-C6 alkoxy)Ci-C6 alkyl.
128. The method of any of claims 100- 119, wherein
R1 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl) or (Ci-C6 alkoxy)Ci-C6 alkyl.
129. The method of any of claims 100- 119, wherein
R1 is hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy(Ci-C6 alkyl) or (Ci-C6 alkoxy)Ci-C6 alkyl.
130. The method of any of claims 100- 119, wherein
R1 is Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy(Ci-C6 alkyl) or (Ci-C6 alkoxy)Ci-C6 alkyl.
131. The method of any of claims 100- 119, wherein
R1 is hydrogen, Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl).
132. The method of any of claims 100- 119, wherein
R1 is Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), or (Ci-C6 alkyl) sulfanyl(Ci-C6 alkyl).
133. The method of any of claims 100- 119, wherein
R1 is hydrogen, cyano, Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy or halo(Ci-C6 alkoxy).
134. The method of any of claims 100- 119, wherein
R1 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy or halo(Ci-C6 alkoxy).
135. The method of any of claims 100- 134, wherein
R2 is cyano, Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci- Ce alkoxy)Ci-C6 alkyl or formyl(Co-C6 alkyl).
136. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy) or (Ci-C6 alkoxy)Ci-C6 alkyl.
137. The method of any of claims 100- 134, wherein
R2 is cyano, C1-C6 alkyl, C1-C6 alkoxy or (C1-C6 alkoxy)Ci-C6 alkyl.
138. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl or Ci-C6 alkoxy.
139. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl.
140. The method of any of claims 100- 134, wherein
R2 is cyano, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (0-C6 alkyl) sulfanyl(Ci-C6
alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
141. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl, amino(Ci-C6 alkyl), -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
142. The method of any of claims 100- 134, wherein
R2 is cyano, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (C1-C6 alkyl) sulfanyl(Ci-C6 alkyl), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
143. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6
alkyl), -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy) or -(CH2)i_5-C(0)NH2.
144. The method of any of claims 100- 134, wherein
R2 is cyano, C1-C6 alkyl, amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci- C6 alkyl.
145. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl, (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-C6 alkyl.
146. The method of any of claims 100- 134, wherein
R2 is Ci-C6 alkyl, -(CH2)i_5-C(0)OH, -(CH2)i_5-C(0)(Ci-C6 alkoxy) or -(CH2)i_5-C(0)NH2.
147. The method of any of claims 100- 146, wherein R is cyano, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i_
5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-C6 alkyl), -(CH2)i_5-C(0)N(Ci-C6 alkyl)2, -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
148. The method of any of claims 100- 146, wherein
R3A is -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
149. The method of any of claims 100- 146, wherein
R3A is -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
150. The method of any of claims 100- 146, wherein
R3A is -CH=CH-C(0)(Ci-C6 alkoxy).
151. The method of any of claims 100- 146, wherein
R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl),
(Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C alkyl)sulfanyl(Ci-C6 alkyl), -CH=CH-C(0)(Ci-C6 alkoxy), (aryl)Ci-C6 alkyl, or (heteroaryl)Ci-Ce alkyl.
152. The method of any of claims 100- 146, wherein
R3A is Ci-C6 alkyl, halo(Ci-C6 alkyl), Ci-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, formyl(Ci-C6 alkyl), amino(Ci-C6 alkyl), sulfanyl(Ci-C6 alkyl), (Ci-C6 alkyl)sulfanyl(Ci-C6 alkyl) or -CH=CH-C(0)(Ci-C6 alkoxy).
153. The method of any of claims 100- 146, wherein
R3A is cyano, C1-C6 alkyl, halo(Ci-C6 alkyl), C1-C6 alkoxy, halo(Ci-C6 alkoxy), hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl, or -CH=CH-C(0)(Ci-C6 alkoxy).
154. The method of any of claims 100- 146, wherein
R3A is Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy(Ci-C6 alkyl), (Ci-C6 alkoxy)Ci-C6 alkyl
or -CH=CH-C(0)(Ci-C6 alkoxy).
155. The method of any of claims 100- 146, wherein
R3A is Ci-C6 alkyl, halo(Ci-C6 alkyl) or -CH=CH-C(0)(Ci-C6 alkoxy).
156. The method of any of claims 100- 146, wherein
R3A is halo(Ci-C6 alkyl), halo(Ci-C6 alkoxy) or -CH=CH-C(0)(Ci-C6 alkoxy).
157. The method of any of claims 100- 156, wherein R4 is hydroxy, halogen, cyano, Ci-C6 alkyl, Ci-Ce alkoxy, halo(Ci-C6 alkoxy), benzyloxy, (aryl)O-Ce alkyl, or (heteroaryl)Ci-C6 alkyl.
158. The method of any of claims 100- 156, wherein
R4 is hydroxy, halogen, cyano, Ci-C6 alkyl, Ci-C6 alkoxy or halo(Ci-C6 alkoxy).
159. The method of any of claims 100- 156, wherein
R4 is hydroxy, Ci-Ce alkoxy, halo(Ci-C6 alkoxy) or benzyloxy.
160. The method of any of claims 100- 156, wherein
R4 is hydroxy, cyano, Ci-Ce alkoxy or halo(Ci-C6 alkoxy).
161. The method of any of claims 100- 156, wherein
R4 is hydroxy, halogen, Ci-Ce alkoxy or halo(Ci-C6 alkoxy).
162. The method of any of claims 100- 156, wherein
R4 is hydroxy, Ci-Ce alkoxy or halo(Ci-C6 alkoxy).
163. The method of any of claims 100- 156, wherein
R4 is Ci-C6 alkoxy or halo(Ci-C6 alkoxy).
164. The method of any of claims 100- 156, wherein
R4 is hydroxy or Ci-Ce alkoxy.
165. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy.
166. The method of any of claims 100- 156, wherein
R4 is cyano, Ci-Ce alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-Ce alkoxy), -(CH2)i- 5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-Ce alkyl), -(CH2)i-5-C(0)N(Ci-Ce
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6
alkoxy), -0(CH2)i-s-C(0)OH, -0(CH2)i-5-C(0)(Ci-Ce alkoxy), (aryl)Ci-Ce alkyl, or
(heteroaryl)Ci-C6 alkyl.
167. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i- 5-C(0)NH2, -(CH2)i-5-C(0)NH(Ci-Ce alkyl), -(CH2)i-5-C(0)N(Ci-Ce
alkyl)2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH
or-0(CH2)i-5-C(0)(Ci-Ce alkoxy).
168. The method of any of claims 100- 156, wherein R4 is cyano, Ci-Ce alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -(CH2)i-
5-C(0)NH2, -CH=CH-C(0)OH, -CH=CH-C(0)(Ci-C6 alkoxy), -0(CH2)i-5-C(0)OH or-0(CH2)i_5-C(0)(Ci-C6 alkoxy).
169. The method of any of claims 100- 156, wherein
R4 is Ci-C6 alkoxy, -(CH2)i-5-C(0)OH, -(CH2)i-5-C(0)(Ci-C6 alkoxy), -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
170. The method of any of claims 100- 156, wherein
R4 is cyano, Ci-Ce alkoxy, -(CH2)i_5-C(0)OH or -CH=CH-C(0)OH.
171. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy, -(CH2)i-5-C(0)(Ci-C6 alkoxy), or -CH=CH-C(0)(Ci-C6 alkoxy).
172. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy, -(CH2)i_5-C(0)OH or -(CH2)i-5-C(0)(Ci-C6 alkoxy).
173. The method of any of claims 100- 156, wherein
R4 is cyano, Ci-Ce alkoxy, -CH=CH-C(0)OH or -CH=CH-C(0)(Ci-C6 alkoxy).
174. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy, or -(CH2)i-5-C(0)OH or -(CH2)i-5-C(0)(Ci-C6 alkoxy).
175. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy, or -(CH2)i-5-C(0)(Ci-Ce alkoxy).
176. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy or -CH=CH-C(0)OH.
177. The method of any of claims 100- 156, wherein
R4 is Ci-Ce alkoxy or -CH=CH-C(0)(Ci-C6 alkoxy).
178. The method of claim 100, wherein
R is CH;
R1 is Ci-Ce alkyl;
R2 is Ci-Ce alkyl;
R3A -CH=CH-C(0)(Ci-C6 alkoxy);
R4 is Ci-Ce alkoxy;
X is fluoro;
M is K+; and
XI is bromo.
179. The method ol any of claims 100-178, wherein the compound is of formula (11a):
Figure imgf000130_0001
(Ila)
or a pharmaceutically acceptable salt thereof.
180. The method of any of claims 100-178, wherein the compound is of formula (lib):
Figure imgf000130_0002
(lib)
or a pharmaceutically acceptable salt thereof.
181. The method of any of claims 100-178, wherein the compound is of formula (lie):
Figure imgf000130_0003
(lie)
or a pharmaceutically acceptable salt thereof.
182. The method of any of claims 100-178, wherein the compound is of formula (lid):
Figure imgf000130_0004
(lid)
or a pharmaceutically acceptable salt thereof.
183. The method of any of claims 100-178, wherein the compound is of formula (He):
Figure imgf000130_0005
or a pharmaceutically acceptable salt thereof.
184. The method of any of claims 100-178, wherein the compound is of formula (lit):
Figure imgf000131_0001
(Ilf)
or a pharmaceutically acceptable salt thereof.
185. The method of any of claims 100- 178, wherein the compound is of formula (Ilg):
Figure imgf000131_0002
or a pharmaceutically acceptable salt thereof.
186. The method of any of claims 100- 178, wherein the compound is of formula (Ilh):
Figure imgf000131_0003
(Ilh)
or a pharmaceutically acceptable salt thereof.
187. The method of any of claims 100- 178, wherein the compound is of formula (Hi):
Figure imgf000131_0004
(Hi)
or a pharmaceutically acceptable salt thereof.
188. The method of any of claims 100- 178, wherein the compound is of formula (Ilj):
Figure imgf000131_0005
(Ilj)
or a pharmaceutically acceptable salt thereof.
189. The method ol any of claims 100-178, wherein the compound is of formula (Ilk):
Figure imgf000132_0001
(Ilk) or a pharmaceutically acceptable salt thereof.
190. The method of any of claims 100-178, wherein the compound is of formula (III):
Figure imgf000132_0002
(III) or a pharmaceutically acceptable salt thereof.
191. The method of any of claims 100-178, wherein the compound is of formula (Ilm):
Figure imgf000132_0003
(Ilm) or a pharmaceutically acceptable salt thereof.
192. The method of claim 100, wherein R3A is -CH=CH-C(0)(Ci-C6 alkoxy), further comprising: hydrogenation of a compound of formula (II) wherein R3 is -CH=CH-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)(C!-C6 alkoxy).
193. The method of claim 178 further comprising:
hydrogenation of a compound of formula (II) wherein R3 is -CH=CH-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy).
194. The method of claim 192, further comprising:
hydrolysis of a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)OH.
195. The method of claim 193, further comprising:
hydrolysis of a compound of formula (II) wherein R3 is -(CH2)2-C(0)(Ci-C6 alkoxy) to provide a compound of formula (II) wherein R3 is -(CH2)2-C(0)OH.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054530A1 (en) * 2009-11-05 2011-05-12 Fibrostatin, S.L. Gpbp inhibition using q2 peptidomimetics
WO2014006020A1 (en) * 2012-07-02 2014-01-09 Fibrostatin, S.L. Gpbp-1 inhibition and its therapeutic use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054530A1 (en) * 2009-11-05 2011-05-12 Fibrostatin, S.L. Gpbp inhibition using q2 peptidomimetics
WO2014006020A1 (en) * 2012-07-02 2014-01-09 Fibrostatin, S.L. Gpbp-1 inhibition and its therapeutic use

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