EP3911307A1 - Antagonistes de la sélectine ou de la galectine pour le traitement du syndrome de libération de la cytokine et de la neurotoxicité induite par le crs - Google Patents

Antagonistes de la sélectine ou de la galectine pour le traitement du syndrome de libération de la cytokine et de la neurotoxicité induite par le crs

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Publication number
EP3911307A1
EP3911307A1 EP20710319.3A EP20710319A EP3911307A1 EP 3911307 A1 EP3911307 A1 EP 3911307A1 EP 20710319 A EP20710319 A EP 20710319A EP 3911307 A1 EP3911307 A1 EP 3911307A1
Authority
EP
European Patent Office
Prior art keywords
compound
chosen
groups
alkyl
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
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EP20710319.3A
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German (de)
English (en)
Inventor
John L. Magnani
William E. Fogler
Ingrid G. Winkler
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Glycomimetics Inc
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Glycomimetics Inc
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Publication date
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Publication of EP3911307A1 publication Critical patent/EP3911307A1/fr
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    • 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
    • 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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Immunotherapy of cancer has recently made great strides with therapies reported for a number of different cancers resulting in new FDA-approved drugs.
  • the general concept behind many of these advances is to augment and activate the patient’s own immune system to combat the patient’s cancer.
  • Examples include engineered cytotoxic T-cells that are directed to the tumor (CAR T-cells) as well as bispecific antibodies that bind both T-cells and tumor cells together to enhance T -cell killing of the tumor cells.
  • CAR T-cells engineered cytotoxic T-cells that are directed to the tumor
  • bispecific antibodies that bind both T-cells and tumor cells together to enhance T -cell killing of the tumor cells.
  • These therapies also rely on the activation of the patient’s own immune system to aid in the killing of the tumor cells.
  • CRS cytokine release syndrome
  • CRS may be caused by many different stimuli, not only from drugs, but also from bacterial and viral infections. It has also been described as a“cytokine storm” that arises from massive overproduction of cytokines not only from T-cell stimulation but also from stimulation of bystander immune cells such as monocytes and macrophages (10,1 1) as well as non-immune cells such as endothelial cells. In fact, a hallmark of the severe form of CRS has been described as the activation of endothelial cells (1). Cytokines that may be elevated in CRS include: IL-6, TNFa, IFNg, IL-8, IL-10, MCP-1, MIR-Ib, and GM-CSF (12,13).
  • CRS Creactive protein suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression suppression s.
  • Tocilizumab an antibody directed to IL-6
  • CAR-T cell-induced severe or life-threatening CRS 15
  • IL-6 is a major cytokine that is elevated, it is only one of many deleterious cytokines expressed during CRS.
  • CRS-induced neurotoxicity is associated with a breakdown of the blood brain barrier through endothelial activation resulting in CAR-T cells and high levels of cytokines entering the brain.
  • E-selectin is also a biomarker of endothelial activation (19).
  • the selectin antagonists may be heterobifunctional antagonists that inhibit both a selectin (one or more of E-, L-, and P-selectin) and, for example, CXCR4 chemokine receptors or Galectin-3.
  • the selectin antagonists may be multimeric antagonists that inhibit a selectin (one or more of E-, L-, and P-selectin) and optionally, for example, CXCR4 chemokine receptors and/or Galectin-3.
  • the present disclosure provides methods for treating and/or preventing cytokine release syndrome and/or a cytokine release syndrome-induced neurotoxicity comprising administering to a subject in need thereof an effective amount of at least one antagonist chosen from selectin antagonists and galectin antagonists.
  • the at least one antagonist is chosen from selectin antagonists.
  • the selectin 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 a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the selectin 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 cytokine expression comprising administering to a subject in need thereof an effective amount of at least one antagonist chosen from selectin antagonists and galectin antagonists.
  • the at least one antagonist is chosen from selectin antagonists.
  • the selectin 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 a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the selectin 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 cytokine is chosen from TNF a , IFN-b, IFN-g, IL-23, IL-Ib, IL-6, IL-8, IL-10, MCP-1, MIP- 1 b, and GM-CSF.
  • Also disclosed herein are methods of reducing and/or eliminating endothelial activation comprising administering to a subject in need thereof an effective amount of at least one antagonist chosen from selectin antagonists and galectin antagonists.
  • the at least one antagonist is chosen from selectin antagonists.
  • the selectin 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 a small molecule, nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, glycomimetic, lipid, antibody, or an aptamer.
  • the selectin 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 subject has Acute Myeloid Leukemia (AML).
  • the method further comprises administering to the subject at least one cancer therapy.
  • the at least one cancer therapy is chemotherapy.
  • the at least one cancer therapy is administered simultaneously with the administration of the at least one antagonist.
  • the at least one cancer therapy is administered before the at least one antagonist.
  • the at least one cancer therapy is administered after the at least one antagonist.
  • 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. 15 is a diagram illustrating the synthesis of compound 60.
  • 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 241.
  • 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-D depict the change in biomarker levels of Ang2 and von Willebrand Factor (VWF) during endothelial activation.
  • Fig. 42A shows the fold change over normal of VWF antigen in Grade 0, Grade 1-3, and Grade 4-5 CRS patients.
  • Fig. 42B shows the Ang-2:Ang- 1 ratio during endothelial activation.
  • Fig. 42C shows the Ang-2:Ang-l ratio during endothelial activation.
  • Fig. 42D shows fold change over normal of VWF antigen during endothelial activation.
  • Fig. 43 depicts sE-Selectin levels (ng/mL) in plasma of AML patients treated with Compound A.
  • Figs. 44A-D depict the effects of administration of Compound A on cytokine expression in mice.
  • Fig. 44A shows TNF-a (pg/mL bone marrow fluid) levels in control and G-CSF treated mice with and without Compound A administration.
  • Fig. 44B shows IFN-b (pg/mL bone marrow fluid) levels in control and G-CSF treated mice with and without Compound A administration.
  • Fig. 44C shows IL-23 (pg/mL bone marrow fluid) levels in control and G- CSF treated mice with and without Compound A administration.
  • Fig. 44D shows IL-Ib (pg/mL bone marrow fluid) levels in control and G-CSF treated mice with and without Compound A administration.
  • E-selectin 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 glycosyltransferase 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.
  • compositions of the disclosure either alone or in combination with another therapeutic agent cure, heal, alleviate, relive, alter, remedy, ameliorate, improve or affect at least one symptom of cytokine release syndrome (CRS) and/or a cytokine release syndrome-induced neurotoxicity, 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.
  • CRS cytokine release syndrome
  • 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 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, as well as salts of amines.
  • 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 selectin antagonists and galectin antagonists comprising the use of at least one antagonist chosen from selectin antagonists and galectin antagonists.
  • the at least one antagonist is chosen from selectin 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 sialyl-Lewis x (SLe x ) which is presented as a glycoprotein or glycolipid 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 sialyl-Lewis x
  • E-selectin also binds to sialyl-Lewis a (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-selectin is generally increased when the tissue adjacent to a capillary is infected or damaged.
  • L-selectin is expressed on leukocytes.
  • selectin antagonists suitable for the disclosed methods include pan selectin antagonists.
  • any method of inhibiting E-selectin may be used to treat and/or prevent CRS and/or CRS-related conditions. Inhibition can be by any means, for example, antibody, small molecule, biologic, inhibitors of gene expression, etc.
  • selectin antagonists include small molecules, such as nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, 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 their entirety.
  • 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 its entirety.
  • the selectin antagonist is chosen from heterobifunctional antagonists disclosed in U.S. Patent No. 8,410,066, issued Apr. 2, 2013, and US Publication No.
  • E-selectin Antagonists (Formula I) and Heterobifunctional E-selectin and CXCR4 Antagonists (Formula II)
  • the at least one antagonist is chosen from E-selectin antagonists.
  • the E-selectin antagonist is chosen from compounds of Formula (I):
  • R 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups;
  • R 2 is chosen from H, -M, and -L-M;
  • Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1 -13 heteroaryl groups;
  • R 4 is chosen from -OH and -NZ'Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are each independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Z 1 and Z 2 may join together along with the nitrogen atom to which they are attached to form a ring;
  • R 5 is chosen from C 3-8 cycloalkyl groups
  • R 6 is chosen from -OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups;
  • R 7 is chosen from -CH 2 OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups;
  • R 8 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups;
  • L is chosen from linker groups
  • the E-selectin 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 to E- selectin and CXCR4 chosen from compounds of Formula (II):
  • R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups;
  • Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
  • R 4 is chosen from C 3-8 cycloalkyl groups
  • R 5 is independently chosen from H, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; n is chosen from integers ranging from 1 to 4; and
  • L is chosen from linker groups.
  • the E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (Ila): and pharmaceutically acceptable salts thereof.
  • the linker groups of Formula I and/or Formula II are independently chosen from groups comprising spacer groups, such spacer groups as, for example, -(CH 2 )p- 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-selectin antagonist is chosen form Compound B:
  • the at least one antagonist is chosen from E-selectin antagonists.
  • the E-selectin antagonist is chosen from compounds of Formula (III):
  • each R 6 which may be identical or different, is independently chosen from H, C 1-12 alkyl and C 1-12 haloalkyl groups
  • each R 7 which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , -NHCN, and -NY 3 Y 4 groups
  • each Y 3 and each Y 4 which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 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, C 1-4 al
  • the E-se lectin antagonist is chosen from compounds of Formula (IV):
  • each R 6 which may be identical or different, is independently chosen from H, C 1-12 alkyl and C 1-12 haloalkyl groups
  • each R 7 which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , -NHCN, and -NY 3 Y 4 groups
  • each Y 3 and each Y 4 which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 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, C 1-4 al
  • R 8 is chosen from H, C 1-8 alkyl, C 6-18 aryl, C 7-19 arylalkyl, and C 1-13 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 L and m for Formula (III) or (IV) above):
  • the E-selectin antagonist is Compound C:
  • the at least one antagonist is chosen from selectin antagonists.
  • the selectin antagonist is a heterobifunctional inhibitor of E-selectin and Galectin-3, chosen from compounds of Formula (V):
  • R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl,
  • R 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4 -16 cycloalkylalkyl, and C 6-18 aryl groups;
  • R 5 is chosen from -CN, C 1-8 alkyl, and C 1 -4 haloalkyl groups
  • L is chosen from linker groups.
  • the selectin 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: d D
  • the selectin antagonist is chosen from compounds of Formula (VI):
  • R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl,
  • R 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, and C 6-18 aryl groups;
  • R 5 is chosen from -CN, C 1-8 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, C1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Cus haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups,
  • Q is chosen from H, halo, and -OZ 3 groups, wherein Z 3 is chosen from H and C 1-8 alkyl groups,
  • R 8 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, C1-13 heteroaryl, C7-19 arylalkyl, and C 2.14 heteroarylalkyl groups, wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C4- 16 cycloalkylalkyl, C6-18 aryl, C1- 13 heteroaryl, C 7-19 arylalkyl, and C2-14 heteroarylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C 1-8 alkyl, C 1-8 hydroxyalky
  • M is chosen from
  • M is chosen from
  • linker groups may be chosen from groups comprising spacer groups, such spacer groups as, for example, -(CH 2 ) t - and -0(CH 2 )r, 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
  • 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.
  • 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).
  • 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 A5 Compound A4 (1.2 g, 2.65 mmoles) was dissolved in DMF (15 mL) and cooled on an ice bath. Sodium hydride (60% oil dispersion, 477 mg, 11.93 mmoles) was added and the mixture stirred for 30 minutes. Benzyl bromide (1.42 mL, 1 1.93 mmoles) was added and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride solution, transferred to a separatory funnel and extracted 3 times with ether. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated.
  • 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. Trimethylsilyl triflate (2.1 mL, 11.6 mmol) dissolved in 20 mL of anhydrous CH2CI2 was then added dropwise over the course of 5 minutes. The reaction was slowly warmed to ambient temperature and stirred for 16 hours.
  • reaction mixture was then diluted with CH2CI2 (50 mL), transferred to a separatory funnel, and washed with saturated aqueous NaHCCL (50 mL).
  • the aqueous phase was separated and extracted with CH2CI2 (50 mL x 2).
  • the combined organic phases were washed with saturated aqueous NaHCO 3 (50 mL), dried over Na2SO 4 , 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 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 MeOH 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 A19 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 A30 is prepared according to Figure 1 by substituting 3,4-difluoro benzyl 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 1 by substituting phenyl acetylene for 3, 4, 5 -trifluorophenyl-1 -acetylene in step d.
  • Compound A34 is prepared according to Figure 1 by substituting 3 -fluorophenyl acetylene for 3, 4, 5 -trifluorophenyl-1 -acetylene in step d.
  • Compound A35 is prepared according to Figure 1 by substituting 3, 4-difluorophenyl-l -acetylene for 3, 4, 5 -trifluorophenyl-1 -acetylene in step d.
  • Compound A76 is prepared according to Figure 1 by substituting 2-naphthyl bromide for benzyl bromide in step k.
  • the reaction mixture can be stirred at ambient temperature until completion.
  • the reaction mixture can be concentrated in vacuo and the residue purified by HPLC to afford compound A51.
  • Compound A74 is prepared from compound A50 using the procedures outlined for compound A51 and in Figures 1, 2, and 3.
  • Compound A75 is prepared from compound A50 using the procedures outlined for compound A51 and in 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. The residue is purified by HPLC to give compound A82.
  • E-selectin/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' tetramethylbenzidine (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 Galbl- 3GlcNAc carbohydrate structure.
  • the detailed protocol is as follows. A 1 ug/mL suspension of a Galbl-3GlcNAcpi-3Galbl-4GlcNAcP-PA-biotin polymer (Glycotech, 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 IX Tris Buffered Saline (TBS, Sigma, catalog number T5912 - 10X) is added to control wells.
  • TBS 96-well streptavidin-coated plate
  • 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 IX 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 (Corning, 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/mL galectin-3 (IBL, catalog number IBATGP0414) is added to each well in the V-bottom plate.
  • a 100 uL aliquot of the galectin- 3/test compound mixture is transferred from the V-bottom plate into the assay plate containing the Galbl-3GlcNAc polymer.
  • control wells in the assay plate are prepared in duplicate containing 1) both Galbl-3GlcNAc polymer and galectin-3, 2) neither the polymer nor galectin-3, 3) galectin-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-galectin-3 antibody conjugated to horse radish peroxidase (R&D Systems, from DGAL30 kit) is added to each well and the plate is kept at room temperature for 1 hour.
  • the wells are washed four times with TBS/0.1%BSA.
  • TMB substrate solution 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).
  • KPL TMB Peroxidase Substrate
  • KPL Peroxidase Substrate Solution B
  • 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 (A450) is measured using a FlexStation 3 plate reader (Molecular Devices). Plots of A450 versus test compound concentration and IC50
  • the selectin antagonist is a multimeric inhibitor of E-selectin, Galectin-3, and/or CXCR4, chosen from compounds of Formula (VII): prodrugs of Formula (VII), and pharmaceutically acceptable salts of any of the foregoing, wherein each R 1 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl,
  • each Y 1 which may be identical or different, is independently chosen from Ci -4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl groups and wherein each R 8 , which may be identical or different, is independently chosen from C 1-12 alkyl groups substituted with at least one substituent chosen from -OH, -OSO3Q, -OPO3Q2, -CO2Q, and -SO3Q groups and C 2-12 alkenyl groups substituted with at least one substituent chosen from -OH, -OSO 3 Q, -OPO 3 Q 2 , -CO2Q, and -SO3Q groups, wherein each Q, which may be identical or different, is independently chosen from H and pharmaceutically acceptable cations;
  • 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, -(CFfeV and -0(CH2)z-, wherein z is chosen from integers ranging 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
  • PEGs polyethylene glycols
  • z is chosen from integers ranging from 1 to 250
  • at least one linker group is
  • At least one linker group is
  • L is chosen from dendrimers. In some embodiments of Formula (VII), L is chosen from polyamidoamine (“PAMAM”) dendrimers. In some embodiments of Formula (VII), L is chosen from PAMAM dendrimers comprising succinamic. In some embodiments of Formula (VII), L is PAMAM GO generating a tetramer. In some embodiments of Formula (VII), L is PAMAM G1 generating an octamer. In some embodiments of Formula (VII), L is PAMAM G2 generating a 16-mer. In some embodiments of Formula (VII), L is PAMAM G3 generating a 32-mer. In some embodiments of Formula (VII), L is chosen from dendrimers. In some embodiments of Formula (VII), L is chosen from polyamidoamine (“PAMAM”) dendrimers. In some embodiments of Formula (VII), L is chosen from PAMAM dendrimers comprising succinamic. In some embodiments of Formula (VII),
  • 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, C 1-8 alkyl, C 6-18 aryl, C7.19 arylalkyl, and C1-13 heteroaryl groups and each y, which may be identical or different, is independently chosen from integers ranging from 0 to 250.
  • R 14 is chosen from C 1-8 alkyl.
  • R 14 is chosen from C 7 - 19 arylalkyl.
  • R 14 is H.
  • 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 chosen from
  • L is
  • L is chosen from groups, wherein y is chosen from integers ranging from 0 to 250.
  • L is
  • 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 (VII), wherein each R 1 is identical, each R 2 is identical, each R 3 is identical, each R 4 is identical, each R 5 is identical, and each X is identical. In some embodiments, at least one compound is chosen from compounds of Formula (VII), 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(OH)2/C. The reaction mixture is vigorously stirred under a hydrogen atmosphere for 12 hours. The reaction mixture is fdtered 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-trifluoroacetyl glycine anhydride in step e.
  • Compound 13 Compound 10 is dissolved in DMF and cooled on an ice bath.
  • 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 methylamine in place of azetidine in step a.
  • Compound 16 can be prepared in an analogous fashion to Figure 10 by using dimethylamine 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 in 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 azetidine in step a.
  • Compound 21 A solution of compound 20 (0.4 eq) in DMSO is added to a solution of compound 11 (1 eq) and DIPEA (10 eq) in anhydrous DMSO 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 every 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-11 diacetic 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 diacetic 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-pyrrolidinyI)oxy]-3-oxopropoxy] methyl]-l,3-propanediyl]bis(oxy)]bis-, l,l'-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-aminoethyl ether in step b.
  • Compound 28 can be prepared in an analogous fashion to Figure 11 by replacing ethylenediamine with 1,5-diaminopentane 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-1 1 diacetic acid di- NHS ester in step a.
  • Compound 31 can be prepared in an analogous fashion to Figure 11 by replacing compound 11 with compound 15 in 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 in 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 ethylenediamine with 2- aminoethyl ether in step b.
  • Compound 37 Compound 36 is dissolved in ethylenediamine 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,l'-[[2,2-bis[[3-(2,5-dihydro-2,5-dioxo-H-pyrrol-l-yl) propoxy]methyl]-l ,3-propanediyl]bis(oxy-3,l-propanediyl)]bis-l H-pyrrole-2, 5 ' dione in step a.
  • Compound 40 can be prepared in an analogous fashion to Figure 12 by substituting propylenediamine for ethylenediamine in step b.
  • Compound 44 A solution of bispropagyl PEG-5 (compound 43) and compound 42 (2.4 eq) in MeOH is degassed at room temperature. A solution of CuSCVTHPTA 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 chromatography to give compound 44.
  • Compound 45 Compound 44 is dissolved in MeOH/i-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
  • Compound 46 Compound 45 is dissolved in ethyienediamine 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.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 47 Compound 47 can be prepared in an analogous fashion to Figure 13 using 3- azidopropanoic anhydride (Yang, C. et. al. 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. 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.
  • Compound 50 can be prepared in an analogous fashion to Figure 13 using 4,7, 10, 13, 16, 19,22,25,28,31-decaoxatetratriaconta-l, 33-diyne in place of compound 43 in step c.
  • Compound 51 can be prepared in an analogous fashion to Figure 13 using 3, 3'-[[2.2-bis[(2-propyn- 1 -yloxy)methyl]- 1 ,3-propanediyl]bis(oxy)]bis- 1 -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 ethylenediamine 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-aminoethyl 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-aminoethyl ether in step e.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 55 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 ethylamine in place of azetidine in step a.
  • 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 1 ,2-bis(2-aminoethoxy)ethane in place of ethylenediamine in step b.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 66 Compound 60: To a stirred solution of compound 1 in DCM/MeOH (25/1) at room temperature is added orotic acid chloride (5 eq) and triphenylphosphine (5 eq). The reaction mixture is stirred 24 hours. The solvent is removed and the residue is separated by column chromatography to afford compound 60.
  • Compound 62 Compound 61 is dissolved in acetonitrile at room temperature.
  • Compound 63 Compound 62 is dissolved in pyridine at room temperature.
  • Compound 64 Activated powdered 4A 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 in 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 65.
  • 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 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 50°C. The solution is concentrated under reduced pressure. The crude product is purified by chromatography to give a compound 66.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 68 Compound 68: Compound 67 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 68.
  • 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]-1,3-propanediyl]bis(oxy)]bis-l-propyne in place of compound 43 in 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 CuSCVTHPTA in distilled water (0.04 M) (0.5 mL, 20 mmole, 0.2 eq) and sodium ascorbate (4.0 mg, 20 mmole, 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, EtOAc 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 mmole) in solution of MeOH/i- PrOH (2/1, v/v, 12 mL) was hydrogenated in the presence of Pd(OH)2 (0.2 g) and 1 atm of 3 ⁇ 4 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 (C80H130N8O35, 1762.8), ES- positive (1785.4, M+Na), ES - Negative (1761.5, M-l, 879.8).
  • Compound 78 Compound 77 (60 mg, 34.0 mmole) was dissolved in ethylenediamine (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%).
  • 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 in 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- aminoethylether in place of ethylenediamine 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 dipropargyl ether in place of compound 43 in step b and 1,5-diaminopentane in place of ethylenediamine in step d.
  • Compound 86 Compound 77 is dissolved in DMF and cooled on an ice bath.
  • Compound 87 Compound 86 is dissolved in ethylenediamine stirred for 12 hrs at 70 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by C-18 column chromatography followed by lyophilization to give a compound 87.
  • Compound 88 can be prepared in an analogous fashion to Figure 20 using 2- aminoethylether in place of ethylenediamine in step b.
  • Compound 89 can be prepared in an analogous fashion to Figure 20 using dimethylamine in place of azetidine 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 91 can be prepared in an analogous fashion to Figures 11 and 12 using in PEG-9 bis-propargyl ether in place of compound 43 in step b of Scheme 11.
  • 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-aminoethyl ether in place of ethylenediamine in step b of Scheme 12.
  • 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 22 with compound 23 in step a.
  • Compound 97 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 24 in step a.
  • Compound 100 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 27 in step a.
  • Compound 101 can be prepared in an analogous fashion to Figure 21 by replacing compound 22 with compound 28 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.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 106 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 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.
  • 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 53 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 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.
  • 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 154 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 30.
  • 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 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 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 46.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 164 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 167 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 50.
  • 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 53.
  • Compound 171 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 54.
  • 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 in 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.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 182 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 184 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 81.
  • Compound 185 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 82.
  • 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 193 can be prepared in an analogous fashion to Figure 22 by replacing compound 22 with compound 91.
  • 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.
  • PROPHETIC SYNTHESIS OF MULTIMERIC COMPOUND 198 Compound 198 can be prepared in an analogous fashion to Figure 23 by replacing compound 196 with NHS-methoxyacetate.
  • 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 PEGG2 propionic acid NHS ester.
  • Compound 203 can be prepared in an analogous fashion to Figure 23 by replacing compound 22 with compound 78.
  • Compound 205 A solution of compound 204 (synthesis described in Mead, G. et. al, Bioconj. Chem., 2015, 25, 1444 - 1452) (0.25 g, 0.53 mmole) and propiolic acid (0.33 mL, 5.30 mmole, 10 eq) in distilled water (1.5 mL) was degassed. A solution of CUSO4/THPTA in distilled water (0.04 M) (1.3 mL, 53 mmole, 0.1 eq) and sodium ascorbate (21 mg, 0.11 mmole, 0.2 eq) were added successively and the resulting solution was stirred 3 hrs at room temperature.
  • Compound 207 can be prepared in an analogous fashion to Figure 25 by replacing compound 78 with compound 22.
  • Compound 208 can be prepared in an analogous fashion to Figure 25 using compound 83 in place of compound 78.
  • Compound 209 can be prepared in an analogous fashion to Figure 25 using compound 87 in place of compound 78.
  • Compound 210 can be prepared in an analogous fashion to Figure 25 using compound 93 in place of compound 78.
  • Compound 211 can be prepared in an analogous fashion to Figure 25 using compound 37 in place of compound 78.
  • Compound 214 Compound 213 (500 mg, 1 mmol) was dissolved in 9 mL acetonitrile. Potassium hydroxide (1 mL of a 2M solution) was added and the reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous phase was extracted 3 times with dichloromethane. The aqueous phase was acidified with IN HC1 until pH ⁇ 1 and extracted 3 times with dichloromethane. The combined dichloromethane extracts from after acidification of the aqueous phase were concentrated in vacuo to give compound 214 as a yellow oil (406 mg).
  • Compound 219 Compound 218 is dissolved in methanol and degassed. To this solution is added Pd(OH)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 219.
  • Compound 221 can be prepared in an analogous fashion to Figure 27 by replacing compound 214 with compound 215.
  • Compound 222 can be prepared in an analogous fashion to Figure 27 by replacing compound 214 with compound 216.
  • Compound 223 can be prepared in an analogous fashion to Figure 27 by replacing compound 214 with compound 217.
  • Compound 225 can be prepared in an analogous fashion to Figure 28 substituting glutaric anhydride for succinic anhydride.
  • Compound 226 can be prepared in an analogous fashion to Figure 28 substituting compound 87 for compound 78.
  • Compound 227 can be prepared in an analogous fashion to Figure 28 substituting phthalic anhydride for succinic anhydride.
  • Compound 228 can be prepared in an analogous fashion to Figure 28 using compound 83 in place of compound 78.
  • Compound 229 can be prepared in an analogous fashion to Figure 28 using compound 87 in place of compound 78.
  • Compound 232 Compound 231 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 232.
  • Compound 236 Compound 235 is dissolved in methanol and degassed. To this solution is added Pd(OH)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 236.
  • Compound 237 Compound 236 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-l 8 reverse phase chromatography to afford compound 237.
  • Compound 238 can be prepared in an analogous fashion to Figure 29 by substituting (acetylthio)acetyl chloride for N-trifluoroacetyl glycine anhydride in step e.
  • Compound 239 can be prepared in an analogous fashion to Figure 29 by substituting the vinylcyclohexyl analog of compound 230 (preparation described in Schwizer, et. al, Chem. Eur. 2012, 18, 1342) for compound 230 in step a.
  • Compound 240 Compound 236 is dissolved in DMF and cooled on an ice bath.
  • Compound 241 Compound 240 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

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Abstract

L'invention concerne des procédés et des composés pour le traitement et/ou la prévention du CRS et de neurotoxicités induites par le CRS à l'aide d'au moins un antagoniste de sélectine. Les procédés et les composés de l'invention utilisent au moins l'un des antagonistes décrits pour cibler et réduire l'expression de la cytokine et/ou l'activation endothéliale pour traiter et/ou prévenir le CRS ou des états liés au CRS tels que les neurotoxicités induites par le CRS.
EP20710319.3A 2019-01-14 2020-01-14 Antagonistes de la sélectine ou de la galectine pour le traitement du syndrome de libération de la cytokine et de la neurotoxicité induite par le crs Withdrawn EP3911307A1 (fr)

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EP2679595B1 (fr) 2008-05-16 2016-12-28 Galecto Biotech AB Dérivés de di-(3-deoxy-3-1H-1,2,3-triazol-1-yl)-beta-D-galacto-pyranosyl)sulfane en tant qu'inhibiteurs de la galectine-3
AU2010241807B2 (en) 2009-05-01 2014-08-14 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US9109002B2 (en) 2011-12-22 2015-08-18 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
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