WO2016115360A1 - Ligands c-myc capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci - Google Patents

Ligands c-myc capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci Download PDF

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WO2016115360A1
WO2016115360A1 PCT/US2016/013429 US2016013429W WO2016115360A1 WO 2016115360 A1 WO2016115360 A1 WO 2016115360A1 US 2016013429 W US2016013429 W US 2016013429W WO 2016115360 A1 WO2016115360 A1 WO 2016115360A1
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group
substituted
phenyl
alkyl
monomer
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PCT/US2016/013429
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English (en)
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Lee Daniel Arnold
Kenneth W. Foreman
Meizhong Jin
Jutta Wanner
Douglas S. Werner
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Coferon, Inc.
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Publication of WO2016115360A1 publication Critical patent/WO2016115360A1/fr

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    • 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
    • A61K47/555—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 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems

Definitions

  • Myc is overexpressed in a variety of cancers, including breast cancers, colon cancers, gynecological cancers, and hepatocellular cancers, and is implicated in the carcinogenesis process.
  • Numerous strategies have been explored for inhibiting the action of c-Myc, with the goal of developing a viable treatment for cancer.
  • nucleic acid-based strategies have been employed to interrupt c-Myc transcription or translation, or alternatively to interrupt transcription or translation of downstream c-Myc target genes.
  • such strategies have generally been hindered by low efficacy and/or difficulty in delivery of the therapeutic.
  • Max is another member of the bHLH-Zip family of transcription factors and can combine with c-Myc to form a heterodimer that binds to DNA, thereby activating genes that promote both cell proliferation and survival.
  • previous attempts to inhibit or disrupt the binding of c-Myc and Max have failed to reach the clinic. Accordingly, there exists a need for viable therapeutics that inhibit c-Myc.
  • such monomers may be capable of binding to another monomer in an aqueous media (e.g., in vivo) to form a multimer, (e.g., a dimer).
  • Contemplated monomers may include a ligand moiety (e.g., a pharmacophore for the target biomolecule), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • a ligand moiety e.g., a pharmacophore for the target biomolecule
  • linker element e.g., a pharmacophore for the target biomolecule
  • a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecule
  • a first monomer capable of forming a biologically useful multimer capable of modulating c-Myc when in contact with a second monomer in an aqueous media is provided.
  • Such a first monomer may be represented by the formula:
  • X 1 is a first ligand moiety capable of modulating a first binding site on said c-
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
  • Z 1 is a first linker capable of binding to the second monomer; and the second monomer is represented by the formula:
  • X 2 is a second ligand moiety capable of modulating a second binding site on said c-Myc;
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ;
  • Z 2 is a second linker capable of binding to the first monomer through Z 1 .
  • a therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer and a second monomer is provided.
  • a first monomer may be represented by:
  • X 1 is a first ligand moiety capable of modulating a first c-Myc binding site
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
  • Z 1 is a first linker capable of binding to Z 2 to form the multimer
  • X 2 is a second ligand moiety capable of modulating a second c-Myc binding site
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; and Z 2 is a boronic acid or oxaborale moiety capable of binding with the Z 1 moiety of Formula I to form the multimer; and
  • a first monomer is provided, wherein the first monomer is represented by the formula X -Y -Z (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites, tautomers, cocrystalates, solvates, and hydrates thereof, wherein X 3 is a first ligand moiety capable of modulating a c-Myc binding site;
  • Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ;
  • Z 3 is a linker capable of forming a therapeutic multimer with another monomer or other monomers of Formula III, wherein Z 3 is the same for the first monomer and other monomers of the multimer.
  • a method of treating a disease (e.g., cancer) associated with c-Myc in a patient in need thereof is provided.
  • a disease e.g., cancer
  • Such a disclosed method can include administering to said patient a first monomer represented by:
  • X ⁇ Y ⁇ Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, tautomers, cocrystalates, solvates, and hydrates thereof, wherein X 1 is a first ligand moiety capable of modulating a first c-Myc binding site; and administering to said patient a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), wherein X 2 is a second ligand moiety capable of modulating a second c-Myc binding site, wherein upon administration, said first monomer and said second monomer forms a multimer in vivo that binds to the first and the second c-Myc binding sites.
  • FIG. 1 shows a screenshot of a protein X-ray crystal structure in which the structures of I-BET762 and an isoxazole pharmacophore are overlaid, according to an embodiment.
  • FIG. 2 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment.
  • pharmacophores i.e., ligands
  • FIG 3. depicts (A) structures of COl and C02 (10074-G5 analog) and (B)
  • FIGs. 4A, 4B, and 4C depict structures of representative monomers.
  • FIG 5. shows results of combinations of disclosed monomers having synergistic activity in a cell proliferation assay.
  • 5A-C Dose-response curves for three different combinations, E07+N11 (A), E08+N11 (B), and E10+N11 (C) tested in the cell proliferation screen. In each case the dose-response curve for each individual monomer is plotted.
  • the dose- response curves for the predicted additive response (Bliss) and the combination experimental data are plotted with an increasing concentration of E07, E08 or E10 in the presence of Ni l (30 ⁇ ). The data is plotted as a mean ⁇ SEM from 3 independent experiments.
  • FIG. 6 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment.
  • pharmacophores i.e., ligands
  • such monomers may be capable of binding to another monomer in an aqueous media (e.g., in vivo) to form a multimer, (e.g., a dimer).
  • Contemplated monomers may include a ligand moiety (e.g., a pharmacophore moiety), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • a ligand moiety e.g., a pharmacophore moiety
  • linker element e.g., a pharmacophore moiety
  • a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g.
  • contemplated monomers may be separate or separable in a solid or in an aqueous media under one set of conditions, and when placed in an aqueous media having one or more biomolecules (e.g., under a different set of conditions) can 1) form a multimer with another monomer through the linker on each monomer; and either: 2a) bind to the biomolecule in two or more locations (e.g., protein binding sites) through each ligand moiety of the respective monomer or 2b) bind to two or more biomolecules through each ligand moiety of the respective monomer.
  • disclosed monomers may interact with another appropriate monomer (i.e.
  • a monomeric pair in an aqueous media (e.g., in vivo) to form a multimer (e.g., a dimer) that can bind to two separate target biomolecule binding sites (e.g., protein binding sites).
  • the two separate target binding sites can be proximal binding sites on the same target, for example, a first binding site on c-Myc and a second binding site on c-Myc.
  • the ligand moiety of a contemplated monomer may be a pharmacophore or a ligand moiety that is, e.g., capable of binding to and/or modulating a biomolecule, such as, for example, a protein, e.g., a specific protein binding site, a component of a biological cell, such as a ribosome (composed of proteins and nucleic acids) or an enzyme active site (e.g., a protease, such as tryptase).
  • the linker element comprises a functional group capable of forming a chemical bond with another linker element.
  • the linker moiety may also serve as a signaling entity or "reporter," and in some instances the assembly of two or more linkers can produce a fluorescent entity or fluorophore with properties distinct from the individual linker moiety.
  • a plurality of monomers, each comprising a linker element may react to form a multimer connected by the linker elements.
  • the multimer may be formed in vivo.
  • the multimer may have enhanced properties relative to the monomers that form the multimer. For example, in certain embodiments, the multimer may bind to a target with greater affinity than any of the monomers that form the multimer. Also described are methods of making the compositions and methods of administering the compositions.
  • the first ligand moiety and the second ligand moiety may each be capable of binding to a binding site of c-Myc.
  • X 1 , X 2 , X 3 and X 4 of Formulae I, II, III or IV may each be capable of binding to a binding site of a c-Myc.
  • a first ligand moiety may be capable of binding to a first binding pocket on c-Myc and a second ligand moiety may be capable of binding to a second binding pocket c-Myc.
  • a ligand moiety may bind to Max.
  • a plurality of monomers may assemble to form a multimer.
  • the multimer may be used for a variety of purposes. For example, in some instances, the multimer may be used to perturb a biological system. As described in more detail below, in some embodiments, the multimer may bind to or modulate a target
  • a contemplated multimer may be used as a pharmaceutical. Without wishing to be bound by any theory, it is believed that the contemplated multimers inhibit or disrupt the association of c-Myc with Max. Further, it is believed that inhibiting c-Myc can induce apoptosis in a cancer cell.
  • a multimer may form in vivo upon administration of suitable monomers to a subject.
  • the multimer may be capable of interacting with a relatively large target site as compared to the individual monomers that form the multimer.
  • a target may comprise, in some embodiments, two protein binding sites separated by a distance such that a multimer, but not a monomer, may be capable of binding to both binding sites essentially simultaneously.
  • contemplated multimers may bind to a target with greater affinity as compared to a monomer binding affinity alone.
  • a contemplated multimer may advantageously exhibit enhanced properties relative to the monomers that form the multimer.
  • a multimer may have improved binding properties as compared to the monomers alone.
  • a multimer may have improved signaling properties.
  • the fluorescent properties of a multimer may be different as compared to a monomer.
  • the fluorescent brightness of a multimer at a particular wavelength may be significantly different (e.g., greater) than the fluorescent brightness at the same wavelength of the monomers that form the multimer.
  • a difference in signaling properties between the multimer and the monomers that form the multimer may be used to detect formation of the multimer or map out a second binding site.
  • detection of the formation of the multimer may be used to screen monomers, as discussed in more detail below.
  • the multimers may be used for imaging or as diagnostic agents.
  • a contemplated multimer may comprise 2 to about 10 monomers, for example, a multimer may be a dimer, a trimer, a tetramer, or a pentamer.
  • a monomer may comprise a ligand moiety, a linker element, and a connector element that associates the ligand moiety with the linker element.
  • the linker element of a first monomer may combine with the linker element of a second monomer.
  • the linker element may comprise a functional group that can react with a functional group of another linker element to form a bond linking the monomers.
  • the linker element of a first monomer may be substantially the same as the linker element of a second monomer.
  • the linker element of a first monomer may be substantially different than the linker element of a second monomer.
  • the ligand moiety may be a pharmacophore.
  • the ligand moiety (e.g., a pharmacophore) may bind to a target molecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
  • a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
  • the IC5 0 of the first monomer against a first target binding site and the IC5 0 of the second monomer against a second target binding site may be greater than the apparent IC5 0 of a combination of the monomers against the first target binding site and the second target binding site.
  • the combination of monomers may be any suitable ratio.
  • the ratio of the first monomer to the second monomer may be between 10: 1 to 1 : 10, in some embodiments between 5: 1 and 1 :5, and in some embodiments between 2: 1 and 1 :2.
  • the ratio of the first monomer to the second monomer may be essentially 1 : 1.
  • the ratio of the smaller of the IC5 0 of the first monomer and the second monomer to the apparent IC5 0 of the multimer may be at least 3.0. In other instances, the ratio of the smaller IC5 0 of the first monomer or the second monomer to the apparent IC5 0 of the multimer may be at least 10.0. In some embodiments, the ratio of the smaller IC5 0 of the first monomer or the second monomer to the apparent IC5 0 of the multimer may be at least 30.0. [0027] For example, for disclosed monomers forming a heteromultimer, the apparent
  • IC5 0 resulting from an essentially equimolar combination of monomers against the first target binding site and the second target binding site may be, in some embodiments, at least about 3 to 10 fold lower, at least about 10 to 30 fold lower, at least about 30 fold lower, or at least about 40 to 50 fold lower than the lowest of the IC5 0 of the second monomer against the second target binding site or the IC50 of the first monomer against the first target binding site.
  • oligomer e.g., dimer
  • concentrations favoring greater extent of oligomer (e.g., dimer) formation As the binding of monomers to the target binding sites increases their proximity and effectively increases their local concentration on the target, the rate and extent of dimerization (oligomerization) is promoted when geometries are favorable. As a result, the occupancy of the target sites by favorable monomers may be nearly completely in the homodimeric (or oligomeric) state. In this manner the target, for example, may serve as a template for the dimerization (or oligomerization) of the monomers, significantly enhancing the extent and rate of dimerization.
  • the affinity of the multimer for the target biomolecule(s) are less than 1 ⁇ , in some embodiments, less than 1 nM, in some embodiments, less than 1 pM, in some embodiments, less than 1 fM, and in some
  • Affinities of individual heterodimerizing monomers for the target biomolecule can be assessed through the testing of the respective monomers in appropriate assays for the target activity or biology because they do not typically self-associate.
  • the testing of homodimerizing monomers may not, in some embodiments, afford an affinity for the monomeric or dimeric state, but rather the observed effect (e.g., IC5 0 ) is a result of the monomer-dimer dynamics and equilibrium, with the apparent binding affinity (or IC5 0 ) being, e.g., a weighted measure of the monomer and dimeric inhibitory effects upon the target.
  • the pH of the aqueous fluid in which the multimer forms may be between pH 1 and 9, in some embodiments, between pH 1 and 3, in some embodiments, between pH 3 and 5, in some embodiments, between pH 5 and 7, and in some embodiments, between pH 7 and 9.
  • the multimer may be stable in an aqueous solution having a pH between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
  • the aqueous solution may have a physiologically acceptable pH.
  • the ligand moiety may be capable of binding to a target and at least partially disrupting a biomolecule-biomolecule interaction (e.g., a protein-protein interaction). In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein subunit-subunit interaction. In some embodiments, the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.
  • the linker element may be capable of generating a signal.
  • the linker element may be capable of fluorescing.
  • the linker element may have greater fluorescence when the monomer to which it is attached is part of a multimer as compared to when the monomer to which it is attached is not part of a multimer.
  • the fluorescent brightness of a linker element may increase by at least 2-fold, in some embodiments, by at least 5 -fold, in some embodiments, by at least 10-fold, in some embodiments, by at least 50-fold, in some embodiments, by at least 100-fold, in some embodiments, by at least 1000-fold, and in some embodiments, by at least 10000-fold.
  • a linker element in a multimer may have a peak fluorescence that is red-shifted relative to the peak fluorescence of the linker element in a monomer. In other embodiments, a linker element may have a peak fluorescence that is blue-shifted relative to the peak fluorescence of a linker element in a monomer.
  • a first monomer may be capable of forming a biologically useful multimer capable of modulating c-Myc when in contact with a second monomer in an aqueous media.
  • a first monomer may be represented by the formula:
  • X 1 is a first ligand moiety capable of binding to or modulating a first binding site on said c-Myc;
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
  • Z 1 is a first linker capable of binding to the second monomer; and
  • a second monomer may be represented by the formula:
  • X 2 is a second ligand moiety capable of binding to a second binding site on said c-Myc;
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; and Z 2 is a second linker capable of binding to the first monomer through Z 1 .
  • the monomers when in contact in an aqueous solution each has a different linker, e.g., Z 1 and Z 2 are different, the monomers may be referred to as 'hetero' monomers.
  • a first and second monomer capable of forming a multimer when in contact in an aqueous solution each has the same linker, e.g., Z 1 and Z 2 are the same, the monomers may be referred to as 'homo' monomers.
  • X 1 and X 2 are different.
  • a monomer may be represented by the formula:
  • X 3 is a ligand moiety capable of binding to a binding site of c-Myc
  • Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ;
  • Z is a linker capable of binding to one or more Z moieties from other X -Y -Z monomers to form a biologically useful multimer.
  • a first monomer is capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media, wherein the first monomer is represented by the formula: X ⁇ Y ⁇ Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, tautomers, cocrystalates, solvates, and hydrates thereof, wherein
  • X 1 is a first ligand moiety capable of binding to a first binding site of c-Myc; Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ; Z 1 is a first linker capable of binding to the second monomer (e.g., in vivo); and the second monomer is represented by the formula:
  • X 4 is a second ligand moiety capable of binding to a second binding site of c- Myc, wherein the first binding site is e.g., within about 10, 20, 30, 40, 50, 60, 70, 80 or more A, e.g. within about 50 A of the second binding site;
  • Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 4 ; and Z 4 is a second linker capable of binding to the first monomer through Z 1 .
  • a first monomer may be capable of forming a biologically useful multimer when in contact with one, two, three or more monomers .
  • a first and second monomer may be represented by the formula:
  • X 3 is a first ligand moiety capable of binding to and modulating a first binding site of c- Myc;
  • Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ;
  • Z 3 is linker capable of forming a therapeutic multimer (e.g., dimer) with another monomer or other monomers of Formula III, wherein Z 3 is the same for the first and second monomer, as noted below.
  • a first and second monomer capable of forming a multimer e.g., dimer
  • the monomers may be referred to as 'homo' monomers.
  • the second binding site may be within 40 A of the first binding site, or in some embodiments within 30 A of the first binding site.
  • the maximum distance between the first ligand moiety (e.g., first binding site) and the second ligand moiety (e.g. , second binding site) in the biologically useful multimer is less than about 25 A, in some embodiments less than 20 A, and in some embodiments less than 15 A.
  • the connector moiety may have a length of less than about 30 A. In certain embodiments, the connector moiety may have a length of less than about 25 A. In certain embodiments, the connector moiety may have a length of less than about 15 A. In certain other embodiments, the connector moiety may have a length of less than about 10 A. In still other embodiments, the connector moiety may have a length of less than about 5 A. In certain embodiments, the connector moiety may have a length of between about 5 A and about 30 A.
  • a monomer may be selected from the group consisting of:
  • R is selected from the group consisting of:
  • X is independently selected for each occurrence from S, O, NH and N-Ci- 6 alkyl
  • Z is selected from the group consisting of H, halo, CF 3 , 0-Ci- 6 alkyl, hydroxyl, and Ci_ ealkyl;
  • Y is NR.” ', O or CR" i- 2 , wherein R" is independently selected from the group consisting of H, methyl, O, NH, and N-Ci- 6 alkyl; R' " is independently selected from the group consisting of H, Cl-6alkyl, phenyl, optionally substituted with 1-3 halogen, nitrile, Cl-3alkyl or haloalkyl; and
  • n 1, 2, or 3.
  • linker moieties Z 1 , Z 2 , Z 3 and Z 4 of Formulas I, II, III and IV may, in some embodiments, be the same or different.
  • linker moieties are independently contemplated herein.
  • the first monomer is represented by the formula
  • X ⁇ Y ⁇ Z 1 wherein Z 1 is a first linker that, for example, may form a dimer with a
  • Z 1 is a first linker selected from the group consisting of
  • Ai is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • a 2 independently for each occurrence, is (a) absent; or (b) selected from the group consisting of -N-, acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, provided that at least one of Ai and A 2 is present; or
  • Ai and A 2 together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;
  • a 3 is selected from the group consisting of -NHR', -SH, or -OH;
  • W is CR' or N
  • R' is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -N0 2 , -SH, or -OH;
  • n 1-6;
  • Ri is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -N0 2 , -SH, or -OH;
  • Qi is (a) absent; or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or
  • Ri and Qi together with the atoms to which they are attached form a substituted or unsubstituted 4-8 membered c cloalkyl or heterocyclic ring;
  • BB independently for each occurrence, is a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one or more groups represented by R 2 , wherein the two substituents comprising -OH have a 1,2 or 1,3 configuration;
  • each R 2 is independently selected from hydrogen, halogen, oxo, sulfonate, -N0 2 , -CN, - OH, -NH 2 , -SH, -COOH, -CONHR', -CONH-S0 2 -R', -S0 2 NH-CO-R', substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R 2 together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system;
  • Ai independently for each occurrence, is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • R' is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or na hthyl, substituted or unsubstituted heteroaryl, -NH 2 , -N0 2 , -SH, or -OH;
  • BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety;
  • a 3 independently for each occurrence, is selected from the group consisting of -NHR' or -OH;
  • R3 and R4 are independently selected from the group consisting of H, Ci- 4 alkyl, phenyl, or R 3 and R4 taken together from a 3-6 membered ring;
  • R5 and R6 are independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; Ci- 4 alkoxy; halogen; -OH; -CN; - COOH; -CONHR'; or R 5 and R6 taken together form phenyl or a 4-6 membered heterocycle; and
  • R' is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphth l, substituted or unsubstituted heteroaryl, -NH 2 , -N0 2 , -SH, or -OH;
  • Ai is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • a 3 is selected from the group consisting of -NHR' or -OH;
  • AR is a fused phenyl or 4-7 membered aromatic or partially aromatic heterocyclic ring, wherein AR is optionally substituted by oxo, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; d -4 alkoxy; -S- Ci -4 alkyl; halogen; -OH; -CN; -COOH; -CONHR';
  • R5 and R6 are independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; Ci-4alkoxy; halogen; -OH; -CN; - COOH; CONHR'; and
  • R' is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -N0 2 , -SH, or -OH;
  • Qi is selected from the group consisting of Ci- 4 alkyl, alkylene, or a bond; Ci_
  • Q 2 is selected from the group consisting of H, Ci_ 4 alkyl, alkylene, or a bond; Ci- 6 cycloalkyl; a 5-6 membered heterocyclic ring; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted phenyl or naphthyl; or substituted or unsubstituted heteroaryl;
  • a 3 independently for each occurrence, is selected from the group consisting of -NH 2 or
  • a 4 is selected from the group consisting of -NH- NH 2 ; -NHOH, -NH-OR", or -OH;
  • R" i selected from the group consisting of H or Ci- 4 alkyl
  • a 5 is selected from the group consisting of -OH, -NH 2 , -SH, -NHR' ";
  • R" ' is selected from -NH 2 ; -OH; phenoxy; heteroaryloxy; and Ci- 4 alkoxy;
  • R5 and R6 are independently selected from the group consisting of H, C h alky 1 optionally substituted by hydroxyl, amino, halo, or thio; Ci-4alkoxy; halogen; -OH; -CN; - COOH; -CONHR'; or R 5 and R6 taken together may form a 5-6 membered ring; R' is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -SH, or -OH.
  • Ai may be selected from the group consisting of Ci-
  • C 3 alkylene optionally substituted with one, two, or three halogens, or -C(O)-.
  • Z 1 may be wherein R 2 , independently for each occurrence, is selected from H, C 1-4 alkyl, or two Ri moieties taken together form a 5- or
  • Z 1 may be A 3 . In some cases, Z 1 may be
  • a 3 HO .
  • a 3" .
  • Z 1 may be HO' N
  • Z 1 may be a monosaccharide or a disaccharide.
  • Z may be selected from the group consisting of
  • X is selected from O, S, CH, NR', or when X is NR', N may be covalently bonded to Y of Formula I;
  • R' is selected from the group consisting of H, Ci- 4 alkyl;
  • R5, R6, and R7 are independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo, or thio;
  • AA is a 5-6 membered heterocyclic ring optionally substituted by Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; Ci-4alkoxy; halogen; -OH; -CN -COOH; -
  • Z may be In
  • Z may be be nitrogen.
  • Z 1 may be example, in some cases, the s, Z
  • 1 may be A 4 .
  • Z 1 may be OH .
  • Z 1 may be ome cases, Z may be . In some embodiments, Z may be
  • Z may be
  • Z 1 may be . In other embodiments, Z 1
  • the second monomer may be X 2 -Y 2 -Z 2 (Formula II), wherein Z 2 is a boronic acid or oxaborale moiety, and wherein X 2 is a second ligand capable of binding to a second target biomolecule segment (e.g. a segment of a fusion protein or a binding site of tandem binding sites), and Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 .
  • X 1 and X 2 may be the same. In other instances, X 1 and X 2 may be different.
  • the second monomer may be X 4 -Y 4 -Z 4 (Formula IV), wherein Z 4 is a boronic acid or oxaborale moiety, and wherein X 4 is a second ligand moiety capable of binding to a protein binding site, wherein the protein binding site is within e.g., about 50 A of the binding site (e.g., second binding site on same protein as first binding site, or a segment of a fusion protein or a second binding site of tandem binding sites), and Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 4 .
  • X 1 may be capable of binding to a first binding site
  • X 4 may be capable of binding to a second binding site, wherein the second binding site is within, e.g., about 50 A of the first binding site.
  • X 1 and X 4 may be the same. In other instances, X 1 and X 4 may be different.
  • the first target biomolecule and the second target biomolecule may be different. In other embodiments, the first target biomolecule and the second target biomolecule may be the same.
  • the linker of the second monomer for example, Z 2 or Z 4 _ may be selected from the group consisting of:
  • R 8 is selected from the group consisting of H, halogen, oxo, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C2- 4 alkenyl, Ci- 4 alkoxy; -S- Ci- 4 alkyl; -CN; - COOH; or -CONHR';
  • Ai is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
  • AA independently for each occurrence, is phenyl, naphthyl, or a 5-7 membered heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, Ci_ 4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C2- 4 alkenyl, Ci- 4 alkoxy; -S- Ci- 4 alkyl; -CN; -COOH; -CONHR'; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and R' is H or Ci- 4 alkyl.
  • Rg and the substituent comprising boronic acid may be ortho to each other, and Rg may be -CH 2 NH 2 .
  • the linker of the second monomer may be selected from
  • the linker of the second monomer may be selected from the group consisting of:
  • Rg is selected from the group consisting of H, halogen, oxo, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C2- 4 alkenyl, Ci- 4 alkoxy; -S- Ci- 4 alkyl; -CN; COOH: or -CONHR': AA, independently for each occurrence, is a 5-7 membered heterocyclic ring having one, two, or three heteroatoms, or phenyl, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halo, Ci- 4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C2- 4 alkenyl, Ci- 4 alkoxy; -S- Ci- 4 alkyl; -CN; -COOH; - CONHR'; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl
  • R' is H or Ci -4 alkyl.
  • a monomer may be represented by the formula:
  • a 3 is -OH, -SH, or -NHR';
  • R3 is selected from the group consisting of H, halo, Ci- 4 alkyl, C3- 6 cycloalkyl, and heterocycle, wherein Ci-4alkyl, C3-6cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; and
  • R4 is selected from the group consisting of H, halo, Ci- 4 alkyl, C3- 6 cycloalkyl, and heterocycle, wherein Ci- 4 alkyl, C3- 6 cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or
  • R 3 and R4 can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C3- 6 cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle;
  • R' is H or Ci- 4 alkyl
  • R' is Ci- 4 alkyl optionally substituted with hydroxyl; -NH 2 ; -OH; and Ci- 4 alkoxy;
  • R3 is selected from the group consisting of H, halo, Ci- 4 alkyl, C3- 6 cycloalkyl and heterocycle, wherein Ci- 4 alkyl, C3- 6 cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl;
  • R4 is selected from the group consisting of H, Ci- 4 alkyl, C3- 6 cycloalkyl and heterocycle, wherein Ci- 4 alkyl, C3- 6 cycloalkyl, or heterocycle may be optionally substituted by one, two or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or
  • R3 and R4 can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C3- 6 cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle; and
  • Z is a linker moiety capable of binding to one or more X -Y -Z 3 monomers to form a biologically useful multimer.
  • a monomer may be capable of reacting with one or more other monomers to form a multimer.
  • a first monomer may react with a second monomer to form a dimer.
  • a first monomer may react with a second monomer and a third monomer to form a trimer.
  • a first monomer may react with a second monomer, a third monomer, and a fourth monomer to form a tetramer.
  • each of the monomers that form a multimer may be essentially the same.
  • each of the monomers that form a multimer may be substantially different.
  • at least some of the monomers that form a multimer may be essentially the same or may be substantially different.
  • the linker element of a first monomer and the linker element of a second monomer may be substantially different.
  • a connector element of a first monomer and a connector element of a second monomer may be substantially different.
  • the ligand moiety (e.g., a pharmacophore) of a first monomer and the ligand moiety (e.g., a pharmacophore) of the second monomer may be substantially different.
  • formation of a multimer from a plurality of monomers may be irreversible. In some embodiments, formation of a multimer from a plurality of monomers may be reversible.
  • the multimer may have an oligomer or dimer dissociation constant between 10 mM and 1 nM, in some embodiments between 1 mM and 100 nM, in some embodiments between 1 mM and 1 ⁇ , and in some embodiments between 500 ⁇ and 1 ⁇ .
  • the multimer may have a dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 ⁇ , in some embodiments less than 100 ⁇ , in some embodiments less than 50 ⁇ , in some embodiments less than 1 ⁇ , in some embodiments less than 100 nM, and in some embodiments less than 1 nM.
  • ligand moieties X 1 , X 2 , X 3 and X 4 of Formulas I, II, III and IV may, in some embodiments, be different.
  • ligand moieties are independently contemplated herein.
  • the ligand moiety may be a pharmacophore.
  • pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects (e.g. , by targeting c-Myc).
  • identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
  • pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
  • monomers that include a pharmacophore may bind to a binding site on c-Myc.
  • monomers that include a pharmacophore may bind to a binding site on Max.
  • Such monomers may form a multimer, as disclosed herein, that may be capable of binding to a first binding site and a second binding site of c-Myc or a binding site of c-Myc and a binding site of Max.
  • a person skilled in the art may appreciate that additional pharmacophores may be discovered in the future and that the pharmacophores illustrated herein are not intended to limit in any way the claims.
  • a ligand e.g. , a pharmacophore
  • an attachment point on a pharmacophore may be chosen so as to preserve at least some ability of the pharmacophore to bind to a binding site of a protein (e.g., c-Myc).
  • preferred attachment points may be identified using X-ray crystallography. The following description of a non-limiting exemplary method illustrates how a preferred attachment point may generically be identified. For example, as shown in FIG.
  • a small molecule 110 (dark gray) labeled "EAM1" in the PDB file [also known as I-BET or IBET762] may be identified.
  • the I-BET triazolo ring (indicated by white circle 120) contains two adjacent nitrogen atoms in the 3 and 4 positions and a methyl group 130 bound to the adjacent carbon at the 5 position. Together, the nitrogen atoms and methyl group constitute an acetyl lysine mimetic. The corresponding acetyl lysine mimetic in the new pharmacophore 140 (light gray) should be aligned to these elements.
  • the final conformation and orientation of the newly aligned pharmacophore 140 in the site may be determined using a variety of approaches known to computational chemists, but can be done as simply as performing an energy minimization using a molecular mechanics forcefield.
  • the alphanumeric identifiers in FIG. 1 correspond to amino acid residues in the 3P50 structure, where the letter of the identifier is the one-letter amino acid symbol and the number of the identifier is the position of the amino acid residue in the primary sequence of the protein.
  • Attachment points 150 on the aligned pharmacophore which permit access to amino acid residues D96, Y139, N140, K141, D144, D145, M149, W81, or Q85 in the 3P50 structure are considered preferred attachment points for linkers. It should be apparent to those skilled in the art that overlays of the pharmacophore of interest with other alternate pharmacophores can be used to identify potential attachment points.
  • FIG. 2 provides a non-limiting set of pharmacophores (i.e., ligands) showing preferred attachment points (indicated by circled arrows) for connecting the pharmacophore to a linker.
  • pharmacophores i.e., ligands
  • preferred attachment points indicated by circled arrows
  • X 1 is a first ligand moiety capable of binding to a first binding site of c-Myc.
  • X 2 is a second ligand moiety capable of binding to a second binding site of c-Myc.
  • X 1 is a first ligand moiety capable of binding to a first binding site of Max.
  • the disclosed ligand moieties, X 1 , X 2 , X 3 and X 4 of Formulas I, II, III and IV may be or include binding site ligands as described herein. It will be appreciated that the ligands disclosed herein can be attached at any open site to a -Y-Z moiety (e.g., -Y ⁇ Z 1 ,
  • ligand moieties include those represented by the formulae:
  • X is O, S, NR. " , or CR" 2 ;
  • T is independently selected from the group consisting of N and CH;
  • R 1 is H, alkyl, phenyl, or a 5-10 membered heterocyclyl
  • R 2 is O or S
  • R 2 is NR", O, S, or a bond
  • R 3 is selected from the group consisting of phenyl, diphenyl, naphthyl, 5-10 membered heteroaryl, and cyclohexyl, wherein phenyl, diphenyl, naphthyl, heteroaryl, and cyclohexyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, nitro, cyano, acyl, carboxyl, S0 2 R", S0 2 N(R") 2 , C(0)-N(R") 2 , N(R")acyl, hydroxy, d -3 alkoxy, Ci- 4 alkyl, Ci- 4 alkenyl, and Ci- 4 alkynyl;
  • R 4 is nitro N(R")acyl, N(R") 2 , carboxyl, or -C(0)-N(R") 2 ;
  • R 5 is selected from the group consisting of phenyl, diphenyl, naphthyl, 5-11 membered heteroaryl, and cyclohexyl, wherein phenyl, diphenyl, naphthyl, heteroaryl, and cyclohexyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, nitro, cyano, acyl, carboxyl, S0 2 R", S0 2 N(R") 2 , C(0)-N(R") 2 , N(R")acyl, hydroxy, Ci -3 alkoxy, Ci- 4 alkyl, Ci- 4 alkenyl, and Ci- 4 alkynyl; and
  • R 6 is H, alkyl, C3-iocycloalkyl, phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
  • R 9 is selected from the group consisting of H, Ci- 6 alkyl, -CF 3 , Ci- 6 alkoxy, -CN, -N0 2 , and -COOH;
  • R 10 is selected from the group consisting of H, -CN, -COOH, -Ci- 6 alkyl, Ci- 6 cycloalkyl, -O-Ci-ealkyl, -OC(0)-Ci -6 alkyl, -OC(0)-NR' 2 , -NR'-C(0)-Ci- 6 alkyl, -NR'-C(0)-0-Ci -6 alkyl, - NR'-C(0)-NR' 2;
  • R 11 is selected from the group consisting of phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted;
  • R 12 is selected from the group consisting of -C(0)-Co- 6 alkyl-phenyl, -C(0)-Co- 6 alkyl- heteroaryl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted;
  • R is independently selected from the group consisting of -NH-Ci- 6 alkyl-phenyl, -NH- Ci- 6 alkyl-heteroaryl, -N(Ci- 6 alkyl)-Ci- 6 alkyl-phenyl, and piperazine, wherein the alkyl, phenyl, heteroaryl, and piperazine are optionally substituted;
  • R 14 is selected from the group consisting of halo, optionally substituted C h alky 1, optionally substituted and nitrile;
  • R 15 and R 16 are independently selected from the group consisting of H and optionally substituted Ci- 6 alkyl
  • R' is independently selected from the group consisting of H, Ci- 6 alkyl, and phenyl;
  • R" is selected from the group consisting of H and Ci- 4 alkyl; or two R" together with the carbon to which they are attached form a C3- 6 cycloalkyl.
  • X 1 may be:
  • X may be:
  • X 2 may be:
  • X 2 may be:
  • connector moieties Y 1 , Y 2 , Y 3 , and Y 4 of Formulas I, II, III and IV may, in some embodiments, be the same or different.
  • connector moieties are
  • a monomer may comprise a connector that joins the ligand moiety with the linker element.
  • such connectors do not have significant binding or other affinity to an intended target.
  • a connector may contribute to the affinity of a ligand moiety to a target.
  • a connector element may be used to connect the linker element to the ligand moiety.
  • a connector element may be used to adjust spacing between the linker element and the ligand moiety.
  • the connector element may be used to adjust the orientation of the linker element and the ligand moiety.
  • the spacing and/or orientation the linker element relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target.
  • connectors with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a multimer to its target biomolecule.
  • connectors with restricted degrees of freedom are preferred to promote cellular permeability of the monomer.
  • the connector element may be used for modular assembly of monomers.
  • a connector element may comprise a functional group formed from reaction of a first and second molecule.
  • a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a linker element.
  • the connector element may comprise a spacer having a first functional group that forms a bond with a ligand moiety and a second functional group that forms a bond with a linker element.
  • Contemplated connecters may be any acceptable (e.g., pharmaceutically and/or chemically acceptable) bivalent linker that, for example, does not interfere with
  • linkers may be substituted or unsubstituted Ci-Cio alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, acyl, sulfone, phosphate, ester, carbamate, or amide.
  • Conte connectors may include polymeric connectors, such a polyethylene glycol (e.g., , where n is 1 , 2, 3, 4, 5, 6, 7, 8, 9,
  • contemplated connectors may be a covending bond or a bivalent C 1-2 o saturated or unsaturated, straight or branched, hydrocarbon chain, wherem one, two, or three or four methylene units of the hydrocarbon chain are optionally and independently replaced by cyclopropylene, -NR-, - N(R)C(0)-, -C(0)N(R)-, - Ni R )S ⁇ -.
  • a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
  • a connector may have the following structure: , where:
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20;
  • R 1 and R 2 are, independently for each occurrence, selected from the group consisting of H, Ci- 6 alkyl, Ci- 6 heteroalkyl, phenyl, or heteroaryl, wherein alkyl, heteroalkyl, phenyl, and heteroaryl are optionally substituted with -OH, -NH 2 , -SH, -COOH, -C(0)NH 2 , halo, phenyl, and heteroaryl; or R 1 and R 2 , together with the atoms to which they are attached, form a heterocyclic structure optionally substituted with -OH, -NH 2 , -SH, -COOH, -C(0)NH 2 , halo, phenyl, and heteroaryl.
  • a connector may comprise a phenyl, naphthyl, or mono or bicyclic heteroaryl ring, each optionally substituted.
  • a connector may comprise one or more of the following aryl structures:
  • a connector may comprise a triazole ring having the following structure:
  • a monomer comprising a triazole-containing connector may have the following general structure: ⁇
  • Such triazole-joined compounds may be formed, e.g., as a result of a "click" type reaction (i.e., an azide-alkyne cycloaddition).
  • a first segment of a connector having a terminal alkyne and a second segment of a connector having a terminal azide may be joined by a "click" reaction to form a single connector joined by a triazole, as shown above.
  • the first connector and the second connector each are less than or equal to 20 atoms in length, or in some embodiments each are less than or equal to 12 atoms in length.
  • a connecter moiety may maximally span from about 5.4 to about 50A, in some embodiments about 5 A to about 25A, in some embodiments about 2 ⁇ to about 5()A, in some embodiments about 20A to about 30 A, and in some embodiments about 6A to about 1.5 A in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
  • a connecter moiety may maximally span from about 1 A to about 2 ⁇ , m some embodiments about 1 A to about lOA, in some embodiments about 1 A to about 5 A, and in some embodiments about 5 A to about 15A in length.
  • a connector moiety may maximally span about lA, about 3 A, about 5 A, about 7 A, about 9 A, about 1 1 A, about 13 A, about 15A, about 17A, or about 19A.
  • a connector may be selected from the group consisting of:
  • R 13 is selected from the group consisting of H and Ci- 6 alkyl
  • s is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and t is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.
  • R 13 may be H. In certain other embodiments, R 13 may be Ci-6alkyl. For example, in some embodiments, R 13 may be methyl.
  • a connector may be selected from the group consisting of:
  • a connector may be selected from the group consisting of:
  • R 13 is selected from the group consisting of H and Ci- 6 alkyl; and s is an integer from 1-15.
  • heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.
  • R 13 may be H. In certain other embodiments, R 13 may be Ci- 6 alkyl. For example, in some embodiments, R 13 may be methyl.
  • a connector may be selected from the group consisting of:
  • u is an integer from 6-15.
  • a connector may be selected from the group consisting of:
  • the synthetic route in Scheme Xa illustrates a general method for preparing ligand-connector derivatives. The method involves attaching the desired substituents to a carboxylic acid of the ligand.
  • the desired connector can be installed by reacting the ligand 1 with the appropriate nucleophile 2 to provide 3 (ligand-connector derivative).
  • Scheme Xa provides for a connector Y (e.g. Y 1 , Y 2 , Y 3 or Y 4 ).
  • the desired connector attached at the carbonyl substituent can be installed by reacting carboxylic acid 1 with common coupling reagents such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
  • ctor may be selected from the group consisting of:
  • n 1, 2, 3, 4 or 5.
  • any free amino group seen in the connector examples of Table A above may be functionalized further to include additional functional groups.
  • the attachment point on the ligand e.g., the carboxylic acid of 1 in Scheme Xa
  • the linker as represented by:
  • the connector-linker moiety (i.e., Y-Z) may be formed from direct attachment of the connector-linker to the ligand (as shown in Scheme Xa'), or the connector-linker moiety may be formed from the further functionalization of any functional group in the connector with the linker (e.g., a boronic acid linker).
  • a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
  • the connector-linker moiety may be: w here R 1 is H or -C 1-4 alkyl.
  • the connector-linker (i.e., Y-Z) moiety may be formed from direct attachment of Y-Z to the carbonyl, or the Y-Z moiety may be formed from the further functionalization of any free amino group seen in the -NH-R examples (i.e., Y examples) of Table A above to include the linker moiety (Z).
  • Examples of -NH-R-Z groups (e.g., Y-Z groups) having a boronic acid, diol or silanol linker (Z) can be found in Tables A', A", and A'", exemplified below. It is clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
  • the synthetic route in Scheme Xb illustrates another general method for preparing ligand-connector derivatives.
  • the method involves attaching the desired substituents for example to an -OH, or NH 2 group (e.g., a phenol group or amine) of the ligand.
  • an -OH, or NH 2 group e.g., a phenol group or amine
  • X Br, CI, I, O s or OTs
  • the connector (Y) may be selected from the group consisting of:
  • n 1, 2, 3, 4 or 5.
  • Any free amino group seen in the connector examples of Table B above may be functionalized further to include additional functional groups, e.g., a benzoyl group.
  • the connector-linker moiety (i.e., Y-Z) may be formed from direct attachment of the connector-linker to the ligand (as shown in Scheme Xb'), or the connector-linker moiety may be formed from the further functionahzation of any functional group in the connector with the linker (e.g., a boronic acid linker).
  • a boronic acid linker Examples of Y-Z groups having a boronic acid linker (Z) can be found in Table B', seen below. It should be clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
  • X Br, CI, I, OMs or OTs
  • the synthetic route in Scheme Xc illustrates another general method for preparing ligand-connector derivatives.
  • the method involves attaching the desired substituents to an aryl halide or heteroaryl halide using, e.g., a cross-coupling reaction.
  • X CI, Br, I, -O s, or -OTs
  • the connector (Y) may be selected from the group consisting of:
  • n may be 0, 1, 2, 3,4 or
  • the connector may generally be represented for example, by: where n may be 0, 1, 2, 3, 4, 5, or 6.
  • the connector may be:
  • the ligand may be further elaborated to incorporate not only a connector moiety, but also a linker, as e.g., represented by: SCHEME Xc'
  • X CI, Br, l, -OMs, or -OTs
  • the synthetic route in Scheme Xd illustrates a general method for preparing ligand-connector derivatives.
  • the method involves attaching the desired carbonyl substituents to the free amine to form an amide, urea, or carbamate.
  • the carbonyl group can be installed by reacting amine 12 (see Scheme Xd) with carboxylic acid 13 to provide 14 (ligand-connector derivative).
  • -C(0)-Connector i.e., -Y
  • -Y may be selected from the group consisting of:
  • a first monomer and a second monomer may form a dimer in aqueous solution.
  • the first monomer may form a biologically useful dimer with a second monomer in vivo.
  • molecular self- assembly may be directed through noncovalent interactions, e.g., hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, electrostatic, and/or electromagnetic interactions.
  • pi-pi and pi-cation interactions can be used to drive multimerization.
  • van der Waals and electromagnetic forces are other interactions that can help to drive multimerization.
  • acid/base pairs and donor-acceptor pairs e.g., amide and/or sulfonamide pairs, can be employed to help direct self- assembly.
  • use of hydrophobic interactions can be used for multimerization targeting a membrane-bound protein.
  • metal coordination might be used when the target itself incorporates the metal, but could also be used in other scenarios.
  • a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X ⁇ Y ⁇ Z 1 with a second monomer X 2 - Y 2 -Z 2 .
  • Z 1 is a first linker capable of binding to the second monomer
  • Z 2 is a second linker capable of binding to the first monomer through Z 1 .
  • Z 2 is a nucleophile moiety capable of binding with the Z 1 moiety of Formula I to form the multimer.
  • the first monomer forms a biologically useful dimer with a second monomer in vivo.
  • a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X ⁇ Y ⁇ Z 1 with a second monomer X 4 -Y 4 -Z 4 .
  • Z 1 is a first linker capable of binding to the second monomer
  • Z 4 is a second linker capable of binding to the first monomer through Z 1 .
  • the multimerization may be substantially irreversible in an aqueous media. In some instances, the multimer may be fluorescent.
  • the extent, probability and rate of the reverse reaction will depend heavily upon a range of conditions including temperature, concentration, solvent, catalysis, and binding to the target biomolecule.
  • the term "irreversible” typically refers to the low probability of the reverse reaction occurring to a significant extent in an aqueous media within the timeframe of associated biological, pharmacologic and metabolic events, e.g., tum-over or degradation of the target biomolecule, signal transduction responses, drug metabolism and clearance, etc.
  • the affinity of the "irreversible" multimeric assembly for the target biomolecule is at least an order of magnitude higher than that of its monomers, it is likely to persist on the target for a prolonged period and exhibit a very slow off-rate. Additionally, the binding of the
  • “irreversible” multimeric assembly is considered e.g., comparable to, or longer than the half- life for, the associated biological processes, with the potential to provide a relatively long duration of pharmacologic action.
  • X 1 and X 2 may be different. In some embodiments, X 1 and X 4 may be different.
  • contemplated monomers and multimers may be administered to a patient in need thereof.
  • a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof is provided.
  • the method comprises administering to the patient thereof an amount of the first monomer and an amount of a second monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.
  • a first monomer and a second monomer may be administered substantially sequentially. In other embodiments, the first monomer and the second monomer are administered substantially simultaneously. In some embodiments the monomers may be administered, sequentially or simultaneously, by different routes of administration or the same route of administration. In still further embodiments, a first monomer and a second monomer may be administered after forming a multimer.
  • a method of modulating two or more target biomolecule binding sites is provided, e.g., two binding sites of c-Myc.
  • a first ligand moiety e.g., bound to a first monomer
  • a second ligand moiety e.g., bound to a second monomer
  • a method of modulating two or more target biomolecule binding sites is provided, e.g., a binding site of c-Myc and a binding site of Max.
  • a first ligand moiety (e.g., bound to a first monomer) may bind to a binding site of c-Myc and a second ligand moiety (e.g., bound to a second monomer) may bind to a binding site of Max.
  • a multimer comprising the first and second ligand moieties may form prior to binding the first and second binding sites. In other embodiments, a multimer may form after one and/or two of the monomers bind the first and second binding sites.
  • a multimer contemplated herein may be used to inhibit or facilitate protein subunit-subunit interactions.
  • a multimer contemplated herein may be used to inhibit or facilitate protein-protein interactions.
  • a contemplated multimer may be capable of inactivating a signaling pathway (e.g., a c-Myc pathway).
  • a multimer may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the multimer does not bind the target protein.
  • monomers may be chosen such that a multimer formed from the monomers binds to at least two regions of a target molecule.
  • a contemplated multimer may be capable of binding to a first protein binding site and a second protein binding site, wherein the second protein binding site is, e.g. between about 5 A and about 30 A of the first protein binding site, or in some embodiments within about 40 A of the first protein binding site.
  • the compounds contemplated herein may be used in a method for treating diseases or conditions for which a c-Myc inhibitor is indicated, for example, a compound may be used for treating cancer.
  • a method of treating cancer in a patient in need thereof by administering to the patient a contemplated compound is a method of treating cancer in a patient in need thereof by administering to the patient a contemplated compound.
  • Contemplated herein are methods of treating cancers, e.g., cancers such as including hematological, epithelial including lung, breast and colon carcinomas, mesenchymal, hepatic, renal and neurological tumors, comprising administering a disclosed compound to a patient in need thereof.
  • contemplated herein is a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering two or more disclosed monomers such that the monomers form a multimer (e.g. dimer) in-vivo.
  • a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering two or more disclosed monomers such that the monomers form a multimer (e.g. dimer) in-vivo.
  • a compound in the manufacture of a medicament for the treatment of diseases or conditions for which a c-Myc inhibitor is indicated is indicated.
  • a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
  • the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
  • compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
  • Treatment can be continued for as long or as short a period as desired.
  • the compositions may be administered on a regimen of, for example, one to four or more times per day.
  • a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
  • a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
  • the present disclosure provides pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules and the like
  • the subject composition is mixed with one or more
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, acetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such a talc,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds may alternatively be administered by aerosol.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
  • enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising monomers, dimers, and/or multimers, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins
  • kits are provided containing one or more compositions each including the same or different monomers.
  • Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • Such kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • compositions that include a second active agent, or administering a second active agent.
  • the compounds, as described herein may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the term "substituted" is contemplated to include all permissible substituents of organic and inorganic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; phenyl; naphthyl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -CI; - Br; -I; -OH; -N0 2 ; -CN; -SCN; -SR X ; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2 CH 2 OH; - CH 2 NH 2 ; -CH 2 S0 2 CH 3 ; -OR x ,
  • R x independently is hydrogen, aliphatic, heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted.
  • the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • acyl refers to a moiety that includes a carbonyl group.
  • an acyl group may have a general formula selected from - C(0)R x ; -C0 2 (R x ); -C(0)N(R x ) 2 ; -OC(0)R x ; -OC0 2 R x ; and -OC(0)N(R x ) 2 ; wherein each occurrence of R x independently includes, but is not limited to, hydrogen, aliphatic,
  • heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or poly cyclic aliphatic
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
  • Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • aryl refers to stable mono- or poly cyclic, heterocyclic, poly cyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl or aromatic refers to a mono- or bi cyclic carbocyclic ring system having one or two aromatic rings selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • Heteroaryl moieties may be selected from: pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl, aromatic, heteroaryl, and heteroaromatic groups described herein can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with a group selected from: Ci- 6 alkyl; phenyl; heteroaryl; benzyl; heteroarylalkyl; Ci- 6 alkoxy; Ci- 6 cycloalkoxy; Ci_ 6heterocyclylalkoxy; Ci-6heterocyclyloxy; heterocyclyloxyalkyl; C2-6alkenyloxy; C 2-
  • heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
  • heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a poly cyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C2- 6 alkenyl, and C3-
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
  • exemplary alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C3_ 6 alkenyloxy.
  • alkenyloxy groups include, but are not limited to allyloxy, butenyloxy, etc.
  • alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O).
  • alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as Ci -6 alkoxy, and C 2 - Cealkoxy, respectively.
  • alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • alkoxy carbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-).
  • alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as Ci- 6 alkoxycarbonyl.
  • alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
  • alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
  • exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
  • alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci- 6 alkyl, Ci- 4 alkyl, and respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2- methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 3-methyl-2-butyl, 2,2-dimethy 1-1 -propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethy 1-1 -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkylene refers to a bivalent saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -Ci- 6 alkylene-, -C h alky lene-, and
  • alkylene has two open valences.
  • alkyl groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, 2-methyl-l -propylene, 2- methyl-2-propylene, 2-methyl-l -butylene, 3-methyl-l -butylene, 3-methyl-2-butylene, 2,2- dimethy 1-1 -propylene, 2-methyl-l -pentylene, 3 -methyl- 1-pentylene, 4-methyl-l-pentylene, 2- methyl-2-pentylene, 3-methyl-2-pentylene, 4-methyl-2-pentylene, 2,2-dimethy 1-1 -butylene, 3,3-dimethyl-l -butylene, 2-ethyl-l -butylene, butylene, isobutylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, etc.
  • alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-).
  • exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as Ci_
  • alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C2- 6 alkynyl, and C3- 6 alkynyl, respectively.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • carbonyl refers to the radical -C(O)-.
  • cyano refers to the radical -CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
  • cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C3- 6 cycloalkyl or C4- 6 cycloalkyl and derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
  • halo or halogen as used herein refer to F, CI, Br, or I.
  • heterocyclylalkoxy refers to a heterocyclyl- alkyl-O- group.
  • heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl- group.
  • heterocyclyloxy refers to a heterocyclyl-O- group.
  • heteroaryloxy refers to a heteroaryl-O- group.
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • connector refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a
  • Contemplated connectors are generally hydrolytically stable.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.
  • “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
  • the compounds are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, >-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers.
  • the enantiomers and diastereomers may be designated by the symbols "(+),” "(-).” " ?" or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds.
  • stereoisomers when used herein comprises all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 10 B, 2 H, H, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2 P, 5 S, 18 F, and 6 C1, respectively.
  • a compound may have one or more H atom replaced with deuterium.
  • isotopically -labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-8)alkyl, (C 2 -i 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxy methyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxycarbonyloxy )ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
  • di-N,N-(Ci-C 2 )alkylamino(C 2 -C 3 )alkyl such as ⁇ -dimethylaminoethyl
  • carbamoyl-(Ci-C 2 )alkyl N,N-di(Ci-C 2 )alkylcarbamoyl-(Ci-C
  • a prodrug can be formed by the replacement of the one or both hydrogen atoms of the alcohol groups with a group such as:
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci_ 6)alkanoyloxymethyl, l-((Ci-6)alkanoyloxy)ethyl, l-methyl-l-((Ci-6)alkanoyloxy)ethyl (Ci- 6)alkoxycarbonyloxymethyl, N-(Ci-6)alkoxycarbonylaminomethyl, succinoyl, (Ci-6)alkanoyl, a- amino(Ci-4)alkanoyl, arylacyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where each a- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci-C6)alkyl) 2 or glycosyl (the radical
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an
  • oxodioxolenyl (oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine.
  • a starting material or intermediate used in the synthesis of a contemplated compound may have an enantiomeric excess greater than 0, e.g. , greater than about 95%, greater than about 98%, greater than about 99%, or essentially 100%.
  • a starting material or intermediate may be essentially stereoisomerically pure.
  • partial or complete loss of chiral integrity may occur during the synthesis of the contemplated compound thereby reducing or eliminating the enantiomeric excess.
  • a stereoisomerically pure starting material or intermediate is used in a synthesis of a contemplated compound
  • partial or complete loss of chiral integrity results in a stereoisomeric mixture.
  • a stereoisomeric mixture may be partially or essentially completely resolved by subjecting the stereoisomeric mixture to a chiral purification technique (e.g. , chiral HPLC purification).
  • reaction mixture was partitioned between DCM (20 mL) and water (10 mL) and separated.
  • the aqueous layer was extracted with DCM (2 X 10 mL) and the combined organic layers were washed with water (2 X 20 mL) and dried over anhydrous
  • reaction mixture was partitioned between DCM (20 mL) and water (10 mL) and separated.
  • the aqueous layer was extracted with DCM (2 X 10 mL) and the combined organic layers were washed with water (2 X 20 mL) and dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC purification to afford 30 mg, 19% yield of the title compound as an orange solid.
  • Reagents are either purchased commercially or prepared according to previously described methods.
  • reaction mixture was diluted with H 2 0 (10 mL) and extracted with DCM (3 X 20 mL). The combined organic layers were dried over anhydrous Na 2 SC>4, filtered and concentrated in vacuo resulting in the crude compound which was purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in ft-hexane followed by preparative HPLC purification to afford 20 mg (9% yield) of title compound as yellow solid.
  • reaction mixture was diluted with H2O (30 mL), the solid precipitated was filtered and dried resulting in the crude compound which was purified by column chromatography on silica gel eluting with 0-10% ethyl acetate in «-hexane to afford (500 mg, 62% yield) of as off white solid.

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Abstract

L'invention concerne des monomères pouvant former un multimère biologiquement utile lorsqu'il entre en contact avec un, deux, trois autres monomères, voire plus, dans un milieu aqueux. Dans un aspect, de tels monomères peuvent se lier à un autre monomère dans un milieu aqueux, (par exemple, in vivo) pour former un multimère (par exemple, un dimère). Les monomères selon l'invention peuvent comprendre un fragment de ligand, un élément lieur et un élément connecteur qui relie le fragment de ligand et l'élément lieur. Dans un milieu aqueux, ces monomères peuvent se lier ensemble par l'intermédiaire de chaque élément lieur et peuvent donc moduler une ou plusieurs biomolécules presque simultanément, par exemple, moduler au moins deux ou plus de deux sites de liaison sur c-Myc.
PCT/US2016/013429 2015-01-14 2016-01-14 Ligands c-myc capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci WO2016115360A1 (fr)

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US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN113185425A (zh) * 2021-04-28 2021-07-30 中国船舶重工集团公司第七二五研究所 一种胺类仿生固化促进剂制备方法
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JP2021531253A (ja) * 2018-07-09 2021-11-18 ザ スクリプス リサーチ インスティテュート Ｍｙｃ阻害のための改良された化合物
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CN116554079A (zh) * 2023-07-11 2023-08-08 南京市鸿舜医药科技有限公司 一种组蛋白去乙酰化酶抑制剂及用途
WO2024209363A1 (fr) 2023-04-06 2024-10-10 Pfizer Inc. Composés dérivés d'acide indazole propionique substitués et leurs utilisations en tant qu'activateurs d'ampk

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11225481B2 (en) * 2015-12-29 2022-01-18 Centre National De La Recherche Scientifique Xanthine derivative inhibitors of BET proteins
JP2021531253A (ja) * 2018-07-09 2021-11-18 ザ スクリプス リサーチ インスティテュート Ｍｙｃ阻害のための改良された化合物
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
CN113185425A (zh) * 2021-04-28 2021-07-30 中国船舶重工集团公司第七二五研究所 一种胺类仿生固化促进剂制备方法
WO2024209363A1 (fr) 2023-04-06 2024-10-10 Pfizer Inc. Composés dérivés d'acide indazole propionique substitués et leurs utilisations en tant qu'activateurs d'ampk
CN116554079A (zh) * 2023-07-11 2023-08-08 南京市鸿舜医药科技有限公司 一种组蛋白去乙酰化酶抑制剂及用途
CN116554079B (zh) * 2023-07-11 2023-11-10 南京市鸿舜医药科技有限公司 一种组蛋白去乙酰化酶抑制剂及用途

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