EP3893936A2 - Procédés pour traitement du vih et du sida et élimination de réservoirs latents d'une infection par le vih à l'aide d'antagonistes de la sélectine, de la galectine et de siglec - Google Patents

Procédés pour traitement du vih et du sida et élimination de réservoirs latents d'une infection par le vih à l'aide d'antagonistes de la sélectine, de la galectine et de siglec

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Publication number
EP3893936A2
EP3893936A2 EP19828513.2A EP19828513A EP3893936A2 EP 3893936 A2 EP3893936 A2 EP 3893936A2 EP 19828513 A EP19828513 A EP 19828513A EP 3893936 A2 EP3893936 A2 EP 3893936A2
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European Patent Office
Prior art keywords
compound
chosen
groups
alkyl
alkenyl
Prior art date
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EP19828513.2A
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German (de)
English (en)
Inventor
John L. Magnani
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Glycomimetics Inc
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Glycomimetics Inc
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Publication of EP3893936A2 publication Critical patent/EP3893936A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • seleetin antagonists such as pan-selectin and/or E-selectin antagonists
  • the seleetin antagonists may be heterobifunctional antagonists that inhibit both a seleetin (one or more of E-, L-, and P-seleetin) and, for example, CXCR4 chemokine receptors or galectin-3. Additional antagonists, for example, that affect NK cell activity, such as antagonists of galectin-9, and receptors Siglec-7 and/or Siglec-9 (or a heterobifunctional or heterotrifunctional antagonist to both), are also disclosed for the treatment of HIV and/or AIDS, which may be administered with or without the administration of the disclosed seleetin antagonists.
  • the present disclosure provides methods of treating HIV or AIDS comprising administering to a subject in need thereof an effective amount of at least one antagonist chosen from seleetin antagonists, galectin antagonists, and Siglec antagonists.
  • the at least one antagonist is chosen from seleetin antagonists.
  • the seleetin antagonist is chosen from E-seiectin antagonists.
  • the at least one antagonist is chosen from galectin antagonists.
  • the galectin antagonist is chosen from galectin- 3 antagonists and galeetin-9 antagonists.
  • the at least one antagonist is chosen from Siglec antagonists.
  • the Siglec antagonist is chosen from SigIec-7 antagonists and SigIec-9 antagonists.
  • the at least one antagonist is a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the seleetin antagonist binds at or near the binding site on E-selectin to inhibit E-selectin interaction with sialyl Le a and/or sialyl Le x .
  • Also disclosed herein are methods of reducing and/or eliminating latent reservoirs of HIV infection comprising administering to a subject in need thereof an effective amount of at least one antagonist chosen from seleetin antagonists, galectin antagonists, and Siglec antagonists.
  • the at least one antagonist is chosen from seleetin antagonists.
  • the seleetin antagonist is chosen from E-selectin antagonists.
  • the at least one antagonist is chosen from galectin antagonists.
  • the galectin antagonist is chosen from galectin- 3 antagonists and galectin-9 antagonists.
  • the at least one antagonist is chosen from Siglec antagonists.
  • the Siglec antagonist is chosen from Siglec-7 antagonists and Siglec-9 antagonists.
  • the at least one antagonist is a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the seleetin antagonist binds at or near the binding site on E-selectin to inhibit E-selectin interaction with sialyl Le a and/or sialyl Le x .
  • the method further comprises administering to the subject an anti-viral therapy.
  • the anti-viral therapy is administered after the administration of the at least one antagonist.
  • the anti-viral therapy is administered before the administration of the at least one antagonist. In some embodiments, the anti-viral therapy is administered simultaneously with the administration of the at least one antagonist.
  • the at least one mobilizing agent is chosen from G-CSF, anti- CXCR4, and anti-VLA-4 regimes.
  • the at least one mobilizing agent is administered before the administration of the at least one selectin antagonist.
  • the at least one mobilizing agent is administered after the administration of the at least one selectin antagonist.
  • the at least one mobilizing agent is administered simultaneously with the administration of the at least one selectin antagonist.
  • the at least one selectin antagonist is chosen from E-selectin antagonists.
  • the E-seiectin antagonist is a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the T-cells are collected from the blood of the mammal.
  • the at least one mobilizing agent is administered 0 to 3 days prior to collecting the T-cells, and/or the at least one selectin antagonist is administered 0, 6, 12, 24, 48, and/or 72 hours prior to collecting the T-cells.
  • the mammal is a mouse.
  • the mammal is a human.
  • the collected T-cells are CD8 r .
  • the collected T-cells have increased reconstitution potential compared to T-cells collected from a mammal wherein the at least one mobilizing agent and/or the at least one selectin antagonist is not administered.
  • Fig. 1 is a diagram illustrating the synthesis of compound A14.
  • Fig. 2 is a diagram illustrating the synthesis of compound A37.
  • Fig. 3 is a diagram illustrating the synthesis of compound A44.
  • Fig. 4 is a diagram illustrating the synthesis of compound A49.
  • Fig. 5 is a diagram illustrating the synthesis of compound A51.
  • Fig. 6 is a diagram illustrating the synthesis of compound A87.
  • Fig. 7 is a diagram illustrating the synthesis of compound A83.
  • Fig. 8 is a diagram illustrating the synthesis of compound A86.
  • Fig. 9 is a diagram illustrating the synthesis of compound 11.
  • Fig. 10 is a diagram illustrating the synthesis of compound 14.
  • Fig. 11 is a diagram illustrating the synthesis of compound 22.
  • Fig. 12 is a diagram illustrating the synthesis of compound 37.
  • Fig. 13 is a diagram illustrating the synthesis of compound 46.
  • Fig. 14 is a diagram illustrating the synthesis of compound 56.
  • Fig. 16 is a diagram illustrating the synthesis of compound 65.
  • Fig. 17 is a diagram illustrating the synthesis of compound 68.
  • Fig. 18 is a diagram illustrating the synthesis of compound 73.
  • Fig. 19 is a diagram illustrating the synthesis of compound 78.
  • Fig. 20 is a diagram illustrating the synthesis of compound 87.
  • Fig. 21 is a diagram illustrating the synthesis of compound 95.
  • Fig. 22 is a diagram illustrating the synthesis of compound 146.
  • Fig. 23 is a diagram illustrating the synthesis of compound 197.
  • Fig. 24 is a diagram illustrating the synthesis of compound 205.
  • Fig. 25 is a diagram illustrating the synthesis of compound 206.
  • Fig. 26 is a diagram illustrating the synthesis of compound 214.
  • Fig. 27 is a diagram illustrating the synthesis of compound 220.
  • Fig. 28 is a diagram illustrating the synthesis of compound 224.
  • Fig. 29 is a diagram illustrating the synthesis of compound 237.
  • Fig. 30 is a diagram illustrating the synthesis of compound
  • Fig. 31 is a diagram illustrating the synthesis of compound 245.
  • Fig. 32 is a diagram illustrating the synthesis of compound 257.
  • Fig. 33 is a diagram illustrating the synthesis of compound 263.
  • Fig. 34 is a diagram illustrating the synthesis of compound 276.
  • Fig. 35 is a diagram illustrating the synthesis of compound 291.
  • Fig. 36 is a diagram illustrating the synthesis of compound 295.
  • Fig. 37 is a diagram illustrating the synthesis of compound 307.
  • Fig. 38 is a diagram illustrating the synthesis of compound 316.
  • Fig. 39 is a diagram illustrating the synthesis of compound 318.
  • Fig. 40 is a diagram illustrating the synthesis of compound 145.
  • Fig. 41 is a diagram illustrating the synthesis of compound 332.
  • Figs. 42A-42C depicts the effects of G-CSF administration on the mobilization of CD8 + T-cells from the bone marrow into the bloodstream.
  • Fig. 42A shows CD8 + T-celi mobilization from the bone marrow before and after G-CSF administration.
  • Fig. 42B shows CD8 ⁇ T-celi mobilization into the bloodstream before and after G-CSF administration.
  • Fig. 42C shows CD 8 T-celi mobilization into the lymph nodes before and after G-CSF administration.
  • Figs. 43A-43B depicts the effects of co-administration of Compound A on G-CSF- mediated mobilization of T-cells.
  • Fig. 43 A shows total leukocy te counts per mL blood.
  • Fig. 43B shows total CD62L hs CD44 hi CD8 + T-cell counts per m ⁇ blood.
  • Fig. 44 depicts numbers of donor TCM CD8 + cells per niL of recipient blood in untreated, G-CSF alone, and G-CSF and Compound A co-administration treated donor mice.
  • Figs. 45A-45B depicts mobilization of donor TCM CDS ” cells.
  • Fig. 45A depicts numbers of donor TCM CD8 + cells per mL of recipient blood in G-CSF and G-CSF + Compound A treatment groups.
  • Fig. 45B depicts numbers of donor TCM CDS ” cells per mL of recipient blood m mobilizing agent alone and mobilizing agent + Compound A administration treatment groups.
  • Fig. 46 depicts results showing the percentage of CD62L hlgh CD8 + T-eeils in the blood of mice at 20 weeks post- transplant with G-CSF alone and G-CSF and Compound A.
  • Fig. 47 depicts results showing the reconstitution units in mice at 20 weeks post transplant with administration of G-CSF alone and G-CSF and Compound A.
  • Fig. 48 depicts mobilization kinetics of MV4.11 following administration of AMD-3100, Compound A, or Compound B.
  • E-seleetin ligand refers to a carbohydrate structure that contains the epitope shared by sialyl Le a and sialyl Le x .
  • Carbohydrates are secondary gene products synthesized by enzymes known as glycosyltransferases which are the primary gene products coded for by DNA. Each gfycosyltransferase adds a specific monosaccharide in a specific stereochemical linkage to a specific donor carbohydrate chain.
  • treatment is defined as the application or administration of a therapeutic agent to a subject, who has a disease, a symptom of disease or a
  • predisposition toward a disease with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease, one or more symptoms of the disease, or the predisposition toward the disease.
  • the compositions of the disclosure either alone or m combination with another therapeutic agent cure, heal, alleviate, relive, alter, remedy, ameliorate, improve or affect at least one symptom of HI V and/or AIDS, as compared to that symptom in the absence of treatment, the result should be considered a treatment of the underlying disorder regardless of whether all the symptoms of the disorder are cured, healed, alleviated, relieved, altered, remedied, ameliorated, improved or affected or not.
  • Treatment may be achieved using an“effective amount” of a therapeutic agent, which shall be understood to embrace partial and complete treatment, e.g., partial or complete curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease, one or more symptoms of the disease, or the predisposition toward the disease.
  • An“effective amount” of may be determined empirically.
  • a“therapeutically effective amount” is a concentration or which is effective for achieving a stated therapeutic effect.
  • pharmaceutically acceptable salts includes sodium, potassium, lithium, ammonium (substituted and unsubstituted), calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Pharmaceutically acceptable salts may, for example, be obtained using standard procedures well known in the field of pharmaceuticals.
  • prodrug as used herein, is defined to include a compound that when administered to a primate host generates an active compound as a result of a spontaneous reaction under physiological conditions, enzymatic catalysis, metabolic clearance, or combinations thereof.
  • At least one antagonist chosen from selectm antagonists, galectin antagonists, and Siglee antagonists.
  • the at least one antagonist is chosen from selectm antagonists.
  • Selectins are a group of structurally similar cell surface receptors important for mediating leukocyte binding to endothelial cells. These proteins are type 1 membrane proteins and are composed of an amino terminal lectin domain, an epidermal growth factor (EGF)-like domain, a variable number of complement receptor related repeats, a hydrophobic domain spanning region and a cytoplasmic domain. The binding interactions appear to be mediated by contact of the lectin domain of the selectins and various carbohydrate ligands.
  • EGF epidermal growth factor
  • E-selectin is found on the surface of activated endothelial cells and binds to the carbohydrate sialyi- Lewis x (SLe x ) which is presented as a glycoprotein or giycolipid on the surface of certain leukocytes (monocytes and neutrophils) and helps these cells adhere to capillary walls in areas where surrounding tissue is infected or damaged.
  • SLe x carbohydrate sialyi- Lewis x
  • E-selectin also binds to sialyl- Lewis' 1 (SLe a ) which is expressed on many tumor cells.
  • P-selectin is expressed on inflamed endothelium and platelets and also recognizes SLe x and SLe a but also contains a second site that interacts with sulfated tyrosine.
  • the expression of E-selectin and P ⁇ selectm is generally increased when the tissue adjacent to a capillary is infected or damaged.
  • L-selectin is expressed on leukocytes.
  • the selectm antagonists suitable for the disclosed compounds and methods include pan selectm antagonists.
  • suitable selectin antagonists include small molecules, such as nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, glycomimetics, antibodies, aptamers, lipids or other organic (carbon containing) or inorganic molecules.
  • the selectin antagonist is selected from antigen-binding molecules that are immuno-interactive with a selectin, peptides that bind to the selectin and that block cell cell adhesion, and carbohydrate or peptide mimetics of selectin ligands.
  • the selectin antagonist reduces the expression of a selectin gene or the level or functional activity of an expression product of that gene.
  • the selectin antagonist may antagonize the function of the selectin, including reducing or abrogating the activity of at least one of its ligand-binding sites.
  • the antagonist is an E-selectin antagonist, which is an agent that inhibits an activity of E-selectin or inhibits the binding of E-selectin to one or more E- selectin ligands (which in turn may inhibit a biological activity of E-selectin).
  • E-selectin antagonist includes antagonists of E-selectin only, as well as antagonists of E-selectin and either P-selectin or L-selectin, and antagonists of E-selectin, P-selectin, and L-selectin.
  • E-selectin antagonists include the glycomimetic compounds described herein. E-selectin antagonists also include antibodies, polypeptides, peptides, peptidomimetics, and aptamers which bind at or near the binding site on E-selectin to inhibit E-selectin interaction with sialyl Le a (sLe a ) or sialyl Le x (sLe x ).
  • the selectin antagonist is an E-selectin antagonist. Further disclosure regarding E-selectin antagonists suitable for the disclosed methods and compounds may be found in U.S. Patent No. 9,254,322, issued Feb 9, 2016; U S Patent No. 9,486,497, issued Nov. 8, 2016, which are hereby incorporated by reference. In some embodiments, the selectin antagonist is chosen from E-selectin antagonists disclosed in U.S. Patent No. 9,109,002, issued Aug. 18, 2015, which is hereby incorporated by reference. In some embodiments, the selectin antagonist is chosen from
  • the at least one antagonist is chosen from E-selectin antagonists.
  • the E-selectin antagonists are chosen from compounds of Formula
  • R 1 is chosen from Ci-Cs alkyl, C C -C B alkenyl, Ci-Cg alkynyl, Ci-Cg haloalkyl, C2- C B haloalkenyl, and C2-C8 haloalkynyl groups;
  • R 2 is chosen from H, -M, and -L-M;
  • Y 1 is chosen from Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, Ci-s haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, Ce-is aryl, and Ci-33 heteroaryl groups
  • R 4 is chosen from -OH and -NZ l Z groups, wherein Z and Z 2 , which may be identical or different, are each independently chosen from H, Ci-Cg alkyl, C 2 ⁇ Cg alkenyl, C 2 -Cg alkynyl, Ci-Cg haloalkyi, C 2 -Cs haloalkenyl, and C 2 -Cg haloalkynyl groups, wherein Z 5 and Z may together form a ring;
  • R 5 is chosen from Ci-Cg cycloalkyl groups
  • R 6 is chosen from -OH, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -C 8 alkynyl, Ci-C 8 haloalkyi, C 2 -Cg haloalkenyl, and C 2 -Cg haloalkynyl groups;
  • R 7 is chosen from -CH2OH, Ci-Cg alkyl, Ci-Cg alkenyl, C'2-Cg alkynyl, Ci-Cg haloalkyi, C 2 -Cg haloalkenyl, and C 2 ⁇ Cg haloalkynyl groups;
  • R 8 is chosen from Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, Ci-Cg haloalkyi, C 2 - Cg haloalkenyl, and C 2 -Cg haloalkynyl groups;
  • L is chosen from linker groups
  • the E-se!ectin antagonist is chosen from compounds of Formula (I), wherein the non-glycomimetic moiety comprises polyethylene glycol.
  • the E-selectin antagonist is chosen from compounds of Formula (la):
  • n is chosen from integers ranging from 1 to 100. In some embodiments, n is chosen from 4, 8, 12, 16, 20, 24, and 28. In some embodiments n is 12
  • the E-selectin antagonist is chosen from Compound A:
  • the E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (II):
  • R 1 is chosen from H, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, Ci-g haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups;
  • R 2 is chosen from -OH, M l'. -0C(-0)Y f , M 1(4 ())Y : . and
  • Y 1 is chosen from Cns alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Ci-g haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, Ce-is aryl, and Ci-13 heteroaryl groups;
  • R 4 is chosen from C3-8 cycloalkyl groups
  • R 3 is independently chosen from H, halo, Ci-s alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Ci- 8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; n is chosen from integers ranging from 1 to 4; and Linker is chosen from linker groups.
  • the E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (Ila):
  • linker groups of Formula I and/or Formula II are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • spacer groups independently chosen from groups comprising spacer groups, such spacer groups as, for example, -(Ctfc and -0(CH 2 )p-, wherein p is chosen from integers ranging from 1 to 30. In some embodiments, p is chosen from integers ranging from 1 to 20.
  • spacer groups include carbonyl groups and carbonyl- containing groups such as, for example, amide groups.
  • a non-limiting example of a spacer group is
  • the linker groups are independently chosen from
  • linker groups such as, for example, polyethylene glycols (PEGs)
  • At least one linker group is
  • At least one linker group is
  • At least one linker group is chosen from
  • the E-selectm antagonist is chosen from Compound B:
  • the at least one antagonist is chosen from E-selectin antagonists.
  • the E-selectin antagonists are chosen from compounds of Formula (III):
  • each Y 1 and each Y 2 which may be identical or different, are independently chosen from H, Ci-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1.12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, Ce-is aryl, and Ci-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 3 , which may be identical or different, is independently chosen from
  • each R 6 which may be identical or different, is independently chosen from H, Ci-12 alkyl and Ci-12 haloalkyl groups, and wherein each R', which may be identical or different, is independently chosen from C 3-8 alkyl, C 2-8 alkenyl, C 2 - 8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , -NHCN, and --NU ⁇ 4 groups, wherein each Y and each Y 4 , winch may be identical or different, are independently chosen from H, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, Ci-s haloalkyl, C2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN, Ci 4 alkyl, and C14
  • L is chosen from linker groups.
  • the E-selectin antagonist is chosen from compounds of Formula (IV):
  • each R 6 which may be identical or different, is independently chosen from H, C M2 alkyl and Ci- 12 haloaikyl groups, and wherein each R', which may be identical or different, is independently chosen from C 3-8 alkyl, C 2-8 alkenyl, C 2 - 8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , -NHCN, and -NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , w nch may be identical or different, are independently chosen from H, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, Ci-s haloaikyl, C2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN
  • Q is chosen from wherein R s is chosen from H, Ci- 8 alkyl, Cs-is aryl, CVis arylalkyf, and C M 3 heteroaryl groups and each p, which may be identical or different, is independently chosen from integers ranging from 0 to 250.
  • the E-selectin antagonist of Formula III or Formula IV is chosen from compounds of the following Formula (Illa/IVa) (see definitions of L and m for Formula (III) or (IV) above):
  • the E-selectin antagonist of Formula III or Formula IV is chosen from compounds of the following Formula (Illb/IVb) (see definitions of I and m for Formula ( III ) or (IV) above):
  • the E-selectin antagonist is Compound C:
  • the at least one antagonist is chosen from selectm antagonists.
  • the selectin antagonists are heterobifunctional inhibitors of E-selectin and ga!ectm-3, chosen from compounds of Formula (V):
  • R 1 is chosen from H, Ci-s alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Ci-g haloalkyl, C 2-8 haloalkenyl, C2-8 haloalkynyl,
  • n is chosen from integers ranging from 0 to 2
  • R 4 is chosen from H, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, Cj-s haloalkyl, C2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, and Ce-is aryd groups;
  • R 5 is chosen from -CN, Ci- 8 alkyl, and C M haloalkyl groups
  • the seiectin antagonist is chosen from compounds having the following Formulae:
  • the selectin antagonist is chosen from compounds having the following Formulae:
  • the antagonist is Compound D:
  • the selectin antagonist is chosen from compounds of Formula
  • R 1 is chosen from H, Ci- 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyi, Ci-g haloalkyl, C 2-8 haloalkenyl, C2-8 haloalkynyl,
  • R 2 is chosen from -OH, -OY 5 , halo,
  • Y 1 and Y 2 which may be the same or different, are independently chosen from Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyi, C4- 16 cyeloalkylalkyl, C2-12 heterocyclyi, Ce-is aryl, and Ci-13 heteroaryl groups, or Y 1 and Y 2 join together along with the nitrogen atom to winch they are atached to form a ring;
  • R 4 is chosen from H, Ci- 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Ci-s haloalkyl, C 2-8 haloalkenyl, C2-8 haloalkynyl, C 4 -16 cycioalkylalkyl, and Ck-ts aryl groups;
  • R 5 is chosen from -CN, Cs-s alkyl, and C 1-4 haloalkyl groups
  • X is chosen from -0-, -S-, -C-, and -N(R 10 )-, wherein R 10 is chosen from H, Ci -s alkyl, C2-8 alkenyl, C2-8 alkynyl, Cj-s haloalkyl, C2-8
  • Q is chosen from H, halo, and -O Z 3 groups, wherein Z 3 is chosen from H and Ci - 8 alkyl groups,
  • R 8 is chosen from H, Ci-g alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Ci-s haloalkyl, C 2-8 haloalkenyl, C2-8 haloalkynyl, C 4 -16 cycioalkylalkyl, C0-1S aryl, Ci-13 heteroaryl, C7-19 arylalkyl, and C2-14 heteroarylalkyl groups, wherein the Ci-8 alkyl, C2-8 alkenyl, C 2-8 alkynyl, Ci-s haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycioalkylalkyl, C &-18 aryl, C 3-13 heteroaryl, C7- 39 arylalkyl, and C 2-14
  • L is chosen from linker groups.
  • M is chosen from
  • M is chosen from
  • linker groups may be chosen from groups comprising spacer groups, such spacer groups as, for example, -(CFbV and -OiCFbV, wherein t is chosen from integers ranging from 1 to 20.
  • spacer groups include carbonyl groups and carbonyl-containing groups such as, for example, amide groups.
  • a non-limiting example of a spacer group is
  • the linker group is chosen from
  • the linker group is chosen from polyethylene glycols
  • v is chosen from integers ranging from 2 to 20. In some embodiments, v is chosen from integers ranging from 2 to 4. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments of Formula (VI), the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • the linker group is
  • Compound A2 Compound A1 (1.5 g, 4.02 mmoles) was dissolved in DCM (30 mL). Thiophenoi (0.9 g, 0.82 mL, 8.04 mmoles) was added followed by dropwise addition of boron trifluonde diethyl etherate (1.79 g, 1.49 mL, 12.06 mmoles). The reaction mixture w3 ⁇ 4s stirred at room temperature for 2 days. The reaction quenched by addition of aqueous saturated NaHCCL, transferred to a separatory funnel, and extracted 3 times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated.
  • Compound A3 Compound A2 (1 1 g, 2.60 mmoles) was dissolved in methanol (25 mL) at room temperature. Sodium methoxide (0.1 mL, 25% sol in MeOH) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture neutralized by the addition of Amberlyst acidic resin, filtered and concentrated to give crude 3, which was used for the next step without further purification.
  • Compound A6 Compound AS (1.8 g, 2.49 mmol) was dissolved in acetone (20 niL) and water (2 niL) and cooled on an ice bath. Trichloroisocyanuric acid (637 mg, 2.74 mmoles) was added and the reaction mixture stirred on the ice bath for 3 h. The acetone was removed in vacuo and the residue was diluted with DCM, transferred to a separatory funnel, and washed with saturated aqueous NaHCOs. The organic phase was
  • Compound A9 Compound A8 (5.0 g, 7.13 mmol) was azeotroped with toluene two times under reduced pressure, and then dried under high vacuum for 2 hours. It was then dissolved in anhydrous CH2CI2 (125 mL) and cooled on an ice bath while stirring under an atmosphere of argon. Tributyltin hydride (15.1 mL, 56.1 mmol) was added dropwise and the solution was allowed to stir for 25 minutes on the ice bath. Trimethylsi!yl inflate (2.1 mL, 11.6 mmol) dissolved in 20 mL of anhydrous CH2G2 w3 ⁇ 4s then added dropwase over the course of 5 minutes.
  • reaction was slowly warmed to ambient temperature and stirred for 16 hours.
  • the reaction mixture was then diluted with CH2G2 (50 mL), transferred to a separatory' funnel, and washed with saturated aqueous NaHCO:, (50 mL).
  • the aqueous phase was separated and extracted with CH2G2 (50 mL x 2).
  • the combined organic phases were washed with saturated aqueous NaHCCb (50 mL), dried over NaiSCE, filtered, and concentrated.
  • the residue was purified by flash chromatography (hexanes to 40% EtOAc in hexanes, gradient) to afford compound A9 (2.65 g, 48%).
  • Compound A11 Compound A10 (1 09 g, 2.5 mmol) and CSA (0.1 15 g, 0.49 mmol) were suspended in anhydrous MeCN (80 mL) under an argon atmosphere. Benzaldehyde dimethyl acetal (0.45 mL, 2.99 mmol) was added dropwise. The reaction mixture was allowed to stir for 16 hours at ambient temperature, during which time it became a homogenous solution. The reaction mixture was then neutralized with a few drops of EtiN, and concentrated. The residue was purified via flash chromatography (CH2G2 to 10% MeOH in CH2CI2, gradient) to afford compound All (978 mg, 75%).
  • Compound A12 Compound All (25.2 mg, 0.048 mmol) was azeotroped with toluene 2 times under reduced pressure, dried under high vacuum for 2 hours, then dissolved in anhydrous DMF (2 mL) and cooled on an ice bath. Benzyl bromide (6 uL, 0.05 mmol) dissolved in 0.5 mL of anhydrous DMF was added and the reaction and was stirred under an atmosphere of argon for 30 minutes at 0 °C. Sodium hydride (2 mg, 0.05 mmol, 60%) was added and the reaction was allowed to gradually warm to ambient temperature while stirring for 16 hours.
  • Compound A13 Compound A12 (6.3 mg, 0.01 mmol) was dissolved in anhydrous MeOH (1 mL) containing CSA (0.26 mg, 0.001 mmol). The reaction mixture was heated to 76 °C in a screw-cap scintillation vial while stirring. After 2 hours, an additional 0.13 mg of CSA in 0.5 mL of MeGH was added. The reaction mixture was stirred at 76 °C for 16 hours. The reaction mixture concentrated under reduced pressure. The residue was purified via preparative TLC (10% MeOH in CH2CI2) to afford compound A13 (4.2 mg, 80%).
  • Compound A15 is prepared according to Figure 1 by substituting 2-methyl benzyl bromide for benzyl bromide in step k.
  • Compound A16 is prepared according to Figure 1 by substituting 3 -methyl benzyl bromide for benzyl bromide m step k.
  • Compound A17 is prepared according to Figure 1 by substituting 4-methyl benzyl bromide for benzyl bromide in step k.
  • Compound A 19 is prepared according to Figure 1 by substituting 3-fluoro benzyl bromide for benzyl bromide in step k.
  • Compound A20 is prepared according to Figure 1 by substituting 4-fluoro benzyl bromide for benzyl bromide in step k.
  • Compound A21 is prepared according to Figure 1 by substituting 2-chloro benzyl bromide for benzyl bromide in step k.
  • Compound A23 is prepared according to Figure 1 by substituting 4-chloro benzyl bromide for benzyl bromide in step k.
  • Compound A24 is prepared according to Figure 1 by substituting 2-methoxy benzyl bromide for benzyl bromide in step k.
  • Compound A25 is prepared according to Figure 1 by substituting 3-methoxy benzyl bromide for benzyl bromide in step k.
  • Compound A26 is prepared according to Figure 1 by substituting 4-methoxy benzyl chloride for benzyl bromide in step k.
  • Compound A27 is prepared according to Figure 1 by substituting 2-picolyl bromide for benzyl bromide in step k.
  • Compound A28 is prepared according to Figure 1 by- substituting 3-pieolyl bromide for benzyl bromide in step k.
  • Compound A31 is prepared according to Figure 1 by substituting 3-fluoro, 4-chloro benzyl bromide for benzyl bromide in step k.
  • Compound A32 is prepared according to Figure 1 by substituting 3-chloro, 4-fluoro benzyl bromide for benzyl bromide in step k.
  • Compound A33 is prepared according to Figure I by substituting phenyl acetylene for 3, 4, 5-trifluorophenyl-l -acetylene in step d.
  • Compound A34 is prepared according to Figure 1 by substituting 3 -fluorophenyl acetylene for 3, 4, 5-trifluorophenyl-l -acetylene in step d.
  • Compound A35 is prepared according to Figure 1 by substituting 3,4-dif!uorophenyi-l -acetylene for 3, 4, 5-trifluorophenyl-l -acetylene in step d.
  • Compound A75 is prepared from compound A5Q using the procedures outlined for compound A51 and in Figures 1, 2, and 3.
  • Compound A77 is prepared from compound A50 using the procedures outlined for compound A51 and m Figures 1 , 2, and 3.
  • Compound A82 Compound A81 is dissolved in ethylenediamine (10 equivalents) under an atmosphere of argon and stirred at 70 °C until the reaction is complete. The reaction mixture is cooled to room temperature then co-evaporated with methanol and toluene.
  • E-selectm/Ig chimera is immobilized in 96 well microtiter plates by incubation at 37°C for 2 hours. To reduce nonspecific binding, bovine serum albumin is added to each well and incubated at room temperature for 2 hours. The plate is washed and serial dilutions of the test compounds are added to the wells in the presence of conjugates of biotinylated, sLe a polyacrylamide with streptavidin/horseradish peroxidase and incubated for 2 hours at room temperature.
  • the peroxidase substrate 3, 3', 5,5 * tetramethylbenzidme (TMB) is added. After 3 minutes, the enzyme reaction is stopped by the addition of H3PO4, and the absorbance of light at a wavelength of 450 nm is determined. The concentration of test compound required to inhibit binding by 50% is determined.
  • Galectin-3 antagonists is evaluated for their ability to inhibit binding of galectin-3 to a Gai i -SGlcNAc carbohydrate structure.
  • the detailed protocol is as follows. A 1 ug/rnL suspension of a Galpi-3GicNAepl -3Ga3pl ⁇ 4GlcNAcp-PA ⁇ biGtin polymer (Giycotech, catalog number 01-096) is prepared. A 100 uL aliquot of the polymer is added to the wells of a 96- well streptavidin-coated plate (R&D Systems, catalog number CP004).
  • a 100 uL aliquot of 1 X Tris Buffered Saline (TBS, Sigma, catalog number T5912 - 1 OX) is added to control wells.
  • the polymer is allowed to bind to the streptavidin-coated wells for 1.5 hours at room temperature.
  • the contents of the wells is discarded and 200 uL of I X TBS containing 1% bovine serum albumin (BSA) is added to each well as a blocking reagent and the plate is kept at room temperature for 30 minutes.
  • the wells are washed three times with IX TBS containing 0.1% BSA.
  • a serial dilution of test compounds is prepared in a separate V-bottom plate (Coming, catalog number 3897).
  • a 75 uL aliquot of the highest concentration of the compound to be tested is added to the first well in a column of the V-bottom plate then 15 ul are serially transferred into 60 uL IX TBS through the remaining wells in the column to generate a 1 to 5 serial dilution.
  • a 60 uL aliquot of 2 ug/rnL gaJectin-3 (IBL, catalog number IBATGP0414) is added to each well in the V-bottom plate.
  • a 100 uL aliquot of the gaiectin-3/test compound mixture is transferred from the V-bottom plate into the assay plate containing the Gai i-3GlcNAc polymer.
  • control wells in the assay plate are prepared m duplicate containing 1) both Gai i-3GlcNAc polymer and galectin-3, 2) neither the polymer nor galectin-3, 3) galeetin-3 only, no polymer, or 4) polymer only, no galectin-3.
  • the plate is gently rocked for 1.5 hours at room temperature.
  • the wells are washed four times with
  • TBS/0.1%BSA A 100 uL aliquot of anti-galectm-3 antibody conjugated to horse radish peroxidase (R&D Systems, from DGAL30 kit) is added to each w r eli and the plate is kept at room temperature for 1 hour. The wells are washed four times with TBS/0.1%BSA. A 100 uL aliquot of TMB substrate solution is added to each well.
  • the TMB substrate solution is prepared by making a 1 : 1 mixture of TMB Peroxidase Substrate (KPL, catalog number 5120-0048) and Peroxidase Substrate Solution B (KPL, catalog number 5120- 0037). The plate is kept at room temperature for 10 to 20 minutes. The color development is stopped by adding 100 uL 10% phosphoric acid (RICCA Chemical Co., catalog number 5850-16). The absorbance at 450 nm (A4 50 ) is measured using a
  • the selectin antagonist is a multimeric inhibitor of E-selectin, galectin-3, and/or CXCR4, chosen from compounds of Formula (VII):
  • each R 1 which may be identical or different, is independently chosen from H, Cu 12 alkyl, C2-J2 alkenyl, €2-52 alkynyl, Ci-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl,
  • Ci-s alkyl independently chosen from H, Ci-s alkyl, C2-8 alkenyl, C2-8 aikynyl, Ci-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; m is chosen from integers ranging from 2 to 256; and
  • L is independently chosen from linker groups.
  • At least one linker groups is chosen from groups comprising spacer groups, such spacer groups as, for example, -(Ohj z - and -0(CH 2 ) Z -, wherein z is chosen from integers rajiging from 1 to 250.
  • spacer groups include carbonyl groups and carbonyl-containing groups such as, for example, amide groups.
  • a non-limiting example of a spacer group is
  • At least one linker group is chosen from
  • At least one linker group is
  • At least one linker group is
  • At least one linker group is chosen from
  • I is chosen from dendrimers.
  • L is chosen from polyamidoamme (“PAMAM”) dendrimers.
  • PAMAM polyamidoamme
  • L is chosen from PAMAM dendrimers comprising succinamic.
  • L is PAMAM GO generating a tetramer.
  • L is PAMAM G1 generating an octamer.
  • L is PAMAM G2 generating a 16-mer.
  • L is PAMAM G3 generating a 32-mer.
  • L is PAMAM G4 generating a 64-mer.
  • L is PAMAM G5 generating a 128-mer.
  • m is 2 and L is chosen from
  • R 14 is chosen from H, Ci-s alkyl, Ce-is aryl, Cr- y aryla!kyl, and C3 -13 heteroaryl groups and each y, which may be identical or different, is
  • R 14 is chosen from Ci-g alkyl. In some embodiments of Formula (VII), R 14 is chosen from Cr-ig ary!alkyl. In some embodiments of Formula (VII), R 1 is H. In some embodiments of Formula (VII), R 14 is benzyl.
  • L is chosen from
  • y is chosen from integers ranging from 0 to 250.
  • L is chosen from groups. wherein y is chosen from integers ranging from 0 to 250.
  • L is
  • L is chosen from
  • y is chosen from integers ranging from 0 to 250
  • L is chosen from
  • y is chosen from integers ranging from 0 to 250.
  • L is
  • L is chosen from groups, wherein y is chosen from integers ranging from 0 to 250.
  • L is
  • L is
  • L is chosen from
  • L is
  • L is chosen from
  • each y which may be identical or different, is independently chosen from integers ranging from 0 to 250.
  • L is chosen from
  • each y which may be identical or different, is independently chosen from integers ranging from 0 to 250.
  • L is chosen from
  • At least one compound is chosen from compounds of Formula (VIE), wherein each R 1 is identical, each R 2 is identical, each R 3 is identical, each R 4 is identical, each R 3 is identical, and each X is identical. In some embodiments, at least one compound is chosen from compounds of Formula (VIT), wherein said compound is symmetrical.
  • Compound 4 Compound 3 is dissolved in methanol at room temperature. A solution of sodium methoxide in methanol (0.1 eq) is added and the reaction mixture stirred overnight at room temperature. The reaction mixture is quenched by the addition of acetic acid. The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 2 times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is separated by flash chromatography to afford compound 4.
  • Compound 10 Compound 9 is dissolved in methanol and degassed. To this solution is added Pd(01T) 2 /C. The reaction mixture is vigorously stirred under a hydrogen atmosphere for 12 hours. The reaction mixture is filtered through a Celite pad. The filtrate is concentrated under reduced pressure to give compound 10.
  • Compound 11 Compound 10 is dissolved in methanol at room temperature. A solution of sodium methoxide in methanol (1.1 eq) is added and the reaction mixture stirred overnight at room temperature. The reaction mixture is quenched by the addition of acetic acid. The reaction mixture is concentrated. The residue is separated by C-18 reverse phase chromatography to afford compound 11.
  • Compound 12 can be prepared in an analogous fashion to Figure 9 by substituting (acetylthio)acetyl chloride for N-trifluoroacetyi glycine anhydride in step e.
  • Compound 14 Compound 13 is dissolved in methanol at room temperature. A solution of sodium methoxide in methanol (0.3 eq) is added and the reaction mixture stirred overnight at room temperature. The reaction mixture is quenched by the addition of acetic acid. The reaction mixture is concentrated. The residue is separated by C-18 reverse phase chromatography to afford compound 14.
  • Compound 15 can be prepared in an analogous fashion to Figure 10 by using methylamme in place of azetidine in step a.
  • Compound 16 can be prepared in an analogous fashion to Figure 10 by using dimethylamme in place of azetidine in step a.
  • Compound 17 can be prepared in an analogous fashion to Figure 10 by using 2-methoxyethylamine in place of azetidine in step a.
  • Compound 18 can be prepared m an analogous fashion to Figure 10 by using piperidine in place of azetidine in step a.
  • Compound 19 can be prepared in an analogous fashion to Figure 10 by using morpholine in place of azetidme in step a.
  • Compound 21 A solution of compound 20 (0.4 eq) in DMSG is added to a solution of compound 11 (1 eq) and DIPEA (10 eq) in anhydrous DMSQ at room temperature. The resulting solution is stirred overnight. The solution is dialyzed against distilled water for 3 days with dialysis tube MWCO 1000 while distilled water is changed ever ⁇ 12 hours. The solution in the tube is lyophilized to give compound 21.
  • Compound 23 can be prepared in an analogous fashion to Figure 11 by replacing compound 20 with PEG-1 1 diaeetic acid di-NHS ester in step a.
  • Compound 24 can be prepared in an analogous fashion to Figure 11 by replacing compound 20 with PEG-15 diaeetic acid di-NHS ester in step a.
  • Compound 25 can be prepared in an analogous fashion to Figure 11 by replacing compound 20 with ethylene glycol diacetic acid di-NHS ester in step a.
  • Compound 26 can be prepared in an analogous fashion to Figure 11 by replacing compound 20 with 3,3'-[[2,2-bis[[3-[(2,5-dioxo-l-pyrrolidinyl)oxy]-3- oxopropoxy]metiiyl]-L3-propanediyl]bis(oxy)]bis-, l,r-bis(2,5-dioxo-l-pyrrolidinyl)- propanoic acid ester in step a.
  • Compound 27 can be prepared in an analogous fashion to Figure 1 1 by replacing ethylenediamine with 2-armnoethyl ether in step b.
  • Compound 28 can be prepared in an analogous fashion to Figure 11 by replacing ethylenediamine with 1,5-diammopentane in step b.
  • Compound 29 can be prepared in an analogous fashion to Figure 11 by replacing ethylenediamine with l,2-bis(2-aminoethoxy)ethane in step b.
  • Compound 30 can be prepared in an analogous fashion to Figure 11 by replacing compound 11 with compound 14 and compound 20 with PEG- 11 diacetic acid di-NHS ester m step a.
  • Compound 32 can be prepared in an analogous fashion to Figure 11 by replacing compound 11 with compound 17 and compound 20 with PEG- 15 diacetic acid di-NHS ester in step a.
  • Compound 33 can be prepared in an analogous fashion to Figure 11 by replacing compound 11 with compound 16 and compound 20 with ethylene glycol diacetic acid di-NHS ester m step a.
  • Compound 34 can be prepared in an analogous fashion to Figure 11 by replacing compound 11 with compound 18 in step a and replacing ethylenediamme with 2-aminoethyi ether in step b.
  • Compound 37 Compound 36 is dissolved in ethyienediamine and the reaction mixture is stirred overnight at 70 °C. The reaction mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography to give compound 37.
  • Compound 38 can be prepared in an analogous fashion to Figure 12 by substituting PEG-6-bis maleimidoylpropionamide for compound 35 in step a.
  • Compound 39 can be prepared in an analogous fashion to Figure 12 by substituting compound 35 for, l,r-[[2,2-bis[[3-(2,5-dihydro-2,5-dioxo-lH-pyrrol-l-yl) propoxy]methyl]-L3 propanediyl]bis(oxy ⁇ 3,l propanediyl)]bis-lii-pyrrole ⁇ 2,5-dioiie in step a.
  • Compound 40 can be prepared in an analogous fashion to Figure 12 by substituting propylenediamine for ethyienediamine in step b.
  • Compound 44 A solution of bispropagyi PEG- 5 (compound 43) and compound 42 (2.4 eq) in MeOH is degassed at room temperature. A solution of CuSOi/THPTA in distilled water (0.04 M) (0.2 eq) and sodium ascorbate (0.2 eq) are added successively and the resulting solution is stirred 12 hrs at 70 °C. The solution is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 45 Compound 45: Compound 44 is dissolved in MeOH/z-PrOH (2/1) and hydrogenated in the presence of Pd(OH)2 (20 wt %) at 1 atm of 3 ⁇ 4 gas pressure for 24 hrs at room temperature. The solution is filtered through a Celite pad. The filtrate is concentrated to give compound 45.
  • Compound 46 Compound 45 is dissolved in ethylenediamine and stirred for 12 hrs at 70 °C. The reaction mixture is concentrated under reduced pressure. The crude product is purified by C-18 column chromatography followed by lyophilization to give a compound 46.
  • Compound 47 can be prepared in an analogous fashion to Figure 13 using 3 -azi dopropanoi c anhydride (Yang, C et. ai JACS, (2013) 135(21), 7791-7794) in place of azidoacetic anhydride in step b.
  • Compound 48 can be prepared in an analogous fashion to Figure 13 using 4-azidobutanoic anhydride (Yang, C. et. al. JACS, (2013) 135(21), 7791-7794) in place of azidoacetic anhydride in step b.
  • Compound 49 can be prepared in an analogous fashion to Figure 13 using 4-azidobutanoic anhydride (Yang, C. el. ah JACS, (2013) 135(21), 7791 -7794) in place of azidoacetic anhydride in step b and using l ,2-bis(2-propynyloxy) ethane in place of compound 43 in step c.
  • 4-azidobutanoic anhydride Yang, C. el. ah JACS, (2013) 135(21), 7791 -7794
  • l ,2-bis(2-propynyloxy) ethane in place of compound 43 in step c.
  • Compound 50 can be prepared in an analogous fashion to Figure 13 using 4, 7, 10, 13, 16,19,22,25,28,31 -decaoxatetratriaconta- 1 , 33-diyne in place of compound 43 step c.
  • Compound 51 can be prepared in an analogous fashion to Figure 13 using 3,3 ! -[] 2-hisi ( 2-propyn-l-yloxy)meihyl]-l,3-propanediyi]bis(oxy)]bis-l-propyne in place of compound 43 in step c.
  • Compound 52 can be prepared in an analogous fashion to Figure 13 using 3,3’-[oxybis[[2,2-bis[(2-propyn-l -yloxy)methyl]-3,l-propanediyl]oxy]]bis-l - propyne in place of compound 43 in step c.
  • Compound 53 can be prepared in an analogous fashion to Figure 13 using butylenediamine in place of ethylenedianune in step e.
  • Compound 54 can be prepared in an analogous fashion to Figure 13 using 4-azidobutanoic anhydride (Yang, C. et. al. JACS, (2013) 135(21), 7791-7794) in place of azidoacetic anhydride in step b and using l ,2-bis(2-propynyloxy) ethane in place of compound 43 in step c and using 2-aminoethyi ether in step e.
  • 4-azidobutanoic anhydride Yang, C. et. al. JACS, (2013) 135(21), 7791-7794
  • l ,2-bis(2-propynyloxy) ethane in place of compound 43 in step c and using 2-aminoethyi ether in step e.
  • Compound 55 Compound 54 is dissolved in DMF and cooled on an ice bath.
  • Compound 56 Compound 55 is dissolved in ethylenediamine and stirred for 12 hrs at 70 °C The reaction mixture is concentrated under reduced pressure. The crude product is purified by C- 18 column chromatography followed by lyophilization to give a compound 56.
  • Compound 57 can be prepared in an analogous fashion to Figure 14 using ethyiamine in place of azetidme in step a.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 58 Compound 58 can be prepared in an analogous fashion to Figure 14 using dimethylamine in place of azetidine in step a.
  • Compound 59 can be prepared in an analogous fashion to Figure 14 using L2 ⁇ bis(2 ⁇ aminoethoxy)ethane in place of ethyienediamine m step b.
  • Compound 64 Activated powdered 4k molecular sieves are added to a solution of compound 60 and compound 63 (2 eq) in dry DCM under argon. The mixture is stirred for 2 hours at room temperature. Solid DMTST (1.5 eq) is added in 4 portions over 1.5 hours. The reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered through Celite, transferred to a separatory funnel and washed two times with half saturated sodium bicarbonate and two times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by flash chromatography to afford compound 64.
  • Compound 65 Compound 64 is dissolved m DMF. Sodium azide (1.5 eq) is added and the reaction mixture is stirred at 50°C until completion. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and transferred to a separatory funnel. The organic phase is washed 4 times with water then dried over sodium sulfate and concentrated. The residue is separated by column chromatography to afford compound
  • Compound 66 A solution of bispropagyl PEG-5 (compound 43) and compound 65 (2.4 eq) in MeOH is degassed at room temperature. A solution of CuSCVTHPTA m distilled water (0.04 M) (0 2 eq) and sodium ascorbate (0.2 eq) are added successively and the resulting solution is stirred 12 hrs at 50°C. The solution is concentrated under reduced pressure. The crude product is purified by chromatography to give a compound 66.
  • Compound 69 can be prepared in an analogous fashion to Figure 17 by replacing compound 43 with PEG-8 bis propargyl ether in step a.
  • Compound 70 can be prepared in an analogous fashion to Figure 17 by replacing compound 43 with ethylene glycol bis propargyl ether in step a.
  • Compound 71 can be prepared in an analogous fashion to Figure 17 using 3 ,3 ⁇ [[2 , 2 bis[(2 ⁇ propyn ⁇ l ⁇ yloxy)methyl] ⁇ l ,3-propanediyi]bisioxy)]bis ⁇ 1 -propyne in place of compound 43 m step a.
  • Compound 72 Compound 67 is dissolved in DMF and cooled on an ice bath.
  • Compound 73 Compound 72 is dissolved in ethylenediamine and stirred for 12 hrs at 70 °C. The reaction mixture is concentrated under reduced pressure. The crude product is purified by C-18 column chromatography followed by lyophilization to afford compound 73.
  • Compound 76 A solution of bispropargyl PEG-5 (compound 43, 27 mg, 0.1 mmole) and compound 75 (0.33 g, 0.24 mmole, 2.4 eq) in a mixed solution (MeOH/1,4 dioxane, 2/1, v/v, 12 mL) was degassed at room temperature. A solution of CuSC THPTA in distilled water (0.04 M) (0.5 mL, 20 pmole, 0.2 eq) and sodium ascorbate (4.0 mg, 20 pinole, 0.2 eq) were added successively and the resulting solution was stirred 12 hrs at 70 °C. The solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by combi-flash (EtOAc/MeOH, EtO Ac only - 4/1 , v/v) to give a compound 76 as a white foam (0.23 g, 70%).
  • Compound 77 A solution of compound 76 (0.23 g, 0.76 gmole) in solution of MeOH//- PrOH (2/1, v/v, 12 mL) was hydrogenated in the presence of Pd(OH)2 (0.2 g) and 1 atm of Hi gas pressure for 24 hrs at room temperature. The solution was filtered through a Celite pad and the cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The crude product was washed with hexane and dried under high vacuum to give compound 77 as a white solid (0.14 g, quantitative). MS: Calculated (CgoHisoNsCbs, 1762.8), ES- positive (1785.4, M+Na), ES - Negative (1761.5, M-l, 879.8).
  • Compound 78 Compound 77 (60 mg, 34.0 gmole) was dissolved in ethyienedi amine (3 mL) and the homogeneous solution was stirred for 12 hrs at 70 °C. The reaction mixture was concentrated under reduced pressure and the residue was dialyzed against distilled water with MWCO 500 dialysis tube. The crude product was further purified by C-18 column chromatography with water/MeOH (9/1 - 1/9, v/v) followed by lyophilization to give a compound 78 as a white solid (39 mg, 63%).
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 79 Compound 79 can be prepared in an analogous fashion to Figure 19 using 3-azidopropanoic anhydride (Yang, C. et. al. JACS, (2013) 135(21), 7791 -7794) in place of azidoacetic anhydride in step a.
  • Compound 80 can be prepared in an analogous fashion to Figure 19 using 4-azidobutanoic anhydride (Yang, C et. al. JACS, (2013) 135(21), 7791-7794) in place of azidoacetic anhydride in step a.
  • Compound 81 can be prepared in an analogous fashion to Figure 19 using 4-azidobutanoic anhydride (Yang, C. et. al. JACS, (2013) 135(21), 7791-7794) in place of azidoacetic anhydride in step a and using l,2-bi(2-propynyloxy) ethane in place of compound 43 m step b.
  • Compound 82 can be prepared in an analogous fashion to Figure 19 using 4,7,10,13,16,19,22,25,28,31-decaoxatetratriaconta-l, 33-diyne in place of compound 43 in step b.
  • Compound 83 can be prepared in an analogous fashion to Figure 19 using 2-ammoethyiether in place of ethyienediamine in step d.
  • Compound 84 can be prepared in an analogous fashion to Figure 19 using l ,2-bi(2-propynyloxy) ethane in place of compound 43 in step b.
  • Compound 85 can be prepared in an analogous fashion to Figure 19 using PEG-8 dipropargyi ether in place of compound 43 in step b and 1 ,5- diaminopentane m place of ethyl enediamine in step d.
  • Compound 88 can be prepared in an analogous fashion to Figure 20 using 2-aminoethyiether m place of ethyl enediamine in step b.
  • Compound 89 can be prepared in an analogous fashion to Figure 20 using dimethylamine in place of azetidme in step a and 2-aminoethylether in place of ethylenediamine in step b.
  • Compound 90 can be prepared in an analogous fashion to Figure 20 using piperidine in place of azetidine in step a.
  • Compound 92 can be prepared in an analogous fashion to Figures 11 and 12 using l,2-bi(2-propynyloxy) ethane in place of compound 43 in step b in Scheme 11
  • Compound 93 can be prepared in an analogous fashion to Figures 11 and 12 using l,2-bi(2-propynyloxy) ethane in place of compound 43 in step b in Scheme 11 and using 2-aminoethyi ether in place of ethyienediamine in step b of Scheme 12.
  • Compound 95 Compound 22 and compound 94 (5 eq)(preparation described in WO/2017089872) is co-evaporated 3 times from methanol and stored under vacuum for 1 hour. The mixture is dissolved in methanol under an argon atmosphere and stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (15 eq) is added and the reaction mixture is stirred overnight at room temperature. The solvent is removed and the residue is separated by C-18 reverse phase chromatography.
  • the purified material is dissolved in methanol at room temperature.
  • the pH is adjusted to 12 with IN NaOH.
  • the reaction mixture is stirred at room temperature until completion.
  • the pH is adjusted to 9.
  • the solvent is removed under vacuum and the residue is separated by C-18 reverse phase chromatography to afford compound 95.
  • Compound 96 can be prepared in an analogous fashion to Figure 21 by replacing compound 2:2 with compound 23 in step a.
  • Compound 98 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 25 m step a.
  • Compound 99 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 26 in step a.
  • Compound 100 can be prepared m an analogous fashion to Figure 21 by replacing compound 22 with compound 27 in step a. 100
  • Compound 101 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 28 in step a.
  • Compound 102 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 29 in step a.
  • Compound 103 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 30 in step a.
  • Compound 104 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 31 in step a.
  • Compound 105 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 32 in step a.
  • Compound 106 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 33 in step a.
  • Compound 107 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 34 in step a.
  • Compound 108 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 37 in step a.
  • Compound 109 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 38 in step a.
  • Compound 110 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 39 in step a.
  • Compound 111 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 40 in step a.
  • Compound 112 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 46 in step a.
  • Compound 113 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 47 in step a.
  • Compound 114 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 48 in step a.
  • Compound 115 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 49 in step a.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 116 Compound 116 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 50 in step a.
  • Compound 117 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 51 in step a.
  • Compound 118 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 52 in step a.
  • Compound 119 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound S3 in step a.
  • Compound 120 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 54 in step a.
  • Compound 121 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 56 in step a.
  • Compound 122 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 57 in step a.
  • Compound 123 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 58 in step a.
  • Compound 124 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 59 in step a.
  • Compound 125 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 68 in step a.
  • Compound 126 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 69 in step a.
  • Compound 127 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 70 in step a.
  • Compound 128 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 71 in step a.
  • Compound 129 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 73 in step a.
  • Compound 130 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 78 in step a.
  • Compound 132 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 80 in step a.
  • Compound 133 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 81 in step a.
  • Compound 134 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 82 in step a.
  • Compound 135 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 83 in step a.
  • Compound 136 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 84 in step a.
  • Compound 137 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 85 in step a.
  • Compound 138 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 87 in step a.
  • Compound 139 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 88 in step a.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 140 Compound 140 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 89 in step a.
  • Compound 141 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 90 in step a.
  • Compound 142 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 91 in step a.
  • Compound 143 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 92 in step a.
  • Compound 144 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 93 in step a.
  • Compound 147 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 23.
  • Compound 148 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 24.
  • Compound 149 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 25.
  • Compound 150 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 26.
  • Compound 151 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 27.
  • Compound 152 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 28.
  • Compound 153 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 29.
  • Compound 154 can be prepared m an analogous fashion to Figure 22 by replacing compound 22 with compound 30.
  • Compound 155 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 31.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 156 Compound 156; Compound 156 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 32.
  • Compound 157 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 33.
  • Compound 158 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 34.
  • Compound 159 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 37.
  • Compound 160 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 38.
  • Compound 161 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 39.
  • Compound 162 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 40.
  • Compound 163 Compound 163 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 46.
  • Compound 164 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 47.
  • Compound 165 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 48.
  • Compound 166 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 49.
  • Compound 168 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 51.
  • Compound 169 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 52.
  • Compound 170 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound S3.
  • Compound 171 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 54.
  • Compound 172 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 56.
  • Compound 173 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 57.
  • Compound 174 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 58.
  • Compound 175 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 59.
  • Compound 176 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 68.
  • Compound 177 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 69.
  • Compound 178 can be prepared m an analogous fashion to Figure 22 by replacing compound 22 with compound 70.
  • Compound 179 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 71.
  • Compound 180 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 73.
  • Compound 181 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 78.
  • Compound 182 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 79.
  • Compound 183 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 80.
  • Compound 186 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 83.
  • Compound 187 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 84.
  • Compound 188 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 85.
  • Compound 189 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 87.
  • Compound 190 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 88.
  • Compound 191 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 89.
  • Compound 192 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 90.
  • Compound 194 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 92.
  • Compound 195 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 93.
  • Compound 198 can be prepared in an analogous fashion to Figure 23 by replacing compound 196 with NPIS-methoxy acetate.
  • Compound 199 can be prepared in an analogous fashion to Figure 23 by replacing compound 196 with PEG- 12 propionic acid NHS ester.
  • Compound 200 can be prepared in an analogous fashion to Figure 23 by replacing compound 22 with compound 78.
  • Compound 201 can be prepared in an analogous fashion to Figure 23 by replacing compound 22 with compound 78 and replacing compound 196 with NHS- methoxyacetate.
  • Compound 202 can be prepared in an analogous fashion to Figure 23 by replacing compound 22 with compound 78 and replacing compound 196 with PEG-12 propionic acid NHS ester.
  • Compound 203 can be prepared in an analogous fashion to Figure 23 by replacing compound 22 with compound 78.
  • Compound 207 can be prepared in an analogous fashion to Figure 25 by replacing compound 78 with compound 22.

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Abstract

L'invention concerne des procédés et des composés pour le traitement du VIH et/ou du SIDA à l'aide d'antagonistes de sélectine, d'antagonistes de galectine-9 et/ou d'antagonistes de Siglec-7. Les procédés et les composés décrits utilisent les antagonistes décrits pour cibler et éliminer des réservoirs quiescents de cellules infectées pour traiter et/ou soigner cette infection.
EP19828513.2A 2018-12-10 2019-12-10 Procédés pour traitement du vih et du sida et élimination de réservoirs latents d'une infection par le vih à l'aide d'antagonistes de la sélectine, de la galectine et de siglec Withdrawn EP3893936A2 (fr)

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US8410066B2 (en) 2009-05-01 2013-04-02 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
EP2794626B3 (fr) 2011-12-22 2020-08-05 GlycoMimetics, Inc. Composés antagonistes de la sélectine e
US9867841B2 (en) * 2012-12-07 2018-01-16 Glycomimetics, Inc. Compounds, compositions and methods using E-selectin antagonists for mobilization of hematopoietic cells
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US11433086B2 (en) * 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
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