WO2019084030A1 - Composés de (4-hydroxypyrrolidin-2-yl)-hydroxamate et leurs procédés d'utilisation - Google Patents

Composés de (4-hydroxypyrrolidin-2-yl)-hydroxamate et leurs procédés d'utilisation

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Publication number
WO2019084030A1
WO2019084030A1 PCT/US2018/057139 US2018057139W WO2019084030A1 WO 2019084030 A1 WO2019084030 A1 WO 2019084030A1 US 2018057139 W US2018057139 W US 2018057139W WO 2019084030 A1 WO2019084030 A1 WO 2019084030A1
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Prior art keywords
substituted
unsubstituted
group
syndrome
compound
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PCT/US2018/057139
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English (en)
Inventor
Peter Dragovich
Lewis J. Gazzard
Thomas Pillow
Jack SADOWSKY
Steven T. STABEN
John Sui-Man WAI
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Genentech, Inc.
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Publication date
Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Publication of WO2019084030A1 publication Critical patent/WO2019084030A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/16—Peri-condensed systems

Definitions

  • the present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination.
  • the present disclosure is directed to compounds that contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated.
  • the present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of targeted proteins/polypeptides.
  • ubiquitin- proteasome system One of the cell's major degradation pathways is known as the ubiquitin- proteasome system.
  • a protein is marked for degradation by the proteasome by ubiquitinating the protein.
  • the ubiqitinization of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein.
  • the E3 ubiquitin ligase is part of a pathway that includes El and E2 ubiquitin ligases, which make ubiquitin available to the E3 ubiquitin ligase to add to the protein.
  • PROTACs bring together an E3 ubiquitin ligase with a protein that is to be targeted for degradation.
  • the PROTAC is comprised of a group that binds to an E3 ubiquitin ligase and a group that binds to the protein one wishes to degrade. These groups are typically connected with a linker. This molecular construct can bring the E3 ubiquitin ligase in proximity with the protein so that it is ubiquitinated and marked for degradation.
  • VHL von Hippel-Lindau
  • VCB the substrate recognition subunit of the E3 ligase complex
  • the primary substrate of VHL is Hypoxia Inducible Factor l a (HIF-l a), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell inducing cytokine erythropoietin in response to low oxygen levels.
  • HIF-la is constitutively expressed, its intracellular levels are kept very low under normoxic conditions via its hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent VHL-mediated ubiquitination.
  • PLD prolyl hydroxylase domain
  • VHL Von Hippel Lindau
  • VCB an important target in cancer, chronic anemia and ischemia
  • the present disclosure is directed to a compound of Formula (I), or a tautomer thereof:
  • R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl;
  • R 3 is substituted or unsubstituted alkyl, or R 3 is taken together with R 6 , when present, and the atoms to which they are attached, to form a substituted or unsubstituted heterocyclylene;
  • Y is selected from the group consisting of substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, O, S, -N(R 6 )-, -N(R 6 )-C(0)-, and - N(R 6 )-S0 2 -;
  • R 6 is selected from the group consisting of H and substituted
  • the present disclosure is directed to a compound of Formula (la), or a tautomer thereof:
  • R 1 , R 3 , Y, and D are defined the same as in Formula (I).
  • the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or (la), or a salt (e.g., a pharmaceutically acceptable salt) thereof, and one or more pharmaceutically acceptable excipients.
  • the present disclosure is directed to a method of treating a disease or disorder in a human in need thereof, comprising administering to said human an effective amount of a compound of Formula (I) or (la) or a salt (e.g, a pharmaceutically acceptable salt) thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (la).
  • the present disclosure is directed to a method of degrading a target protein in a cell comprising exposing the cell to a composition comprising an effective amount of the compound of Formula (I) or (la) or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein the compound effectuates the degradation of the target protein.
  • the present disclosure is directed to a compound of Formula (II), or a tautomer thereof:
  • R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl
  • R 3 is substituted or unsubstituted alkyl, or R 3 is taken together with R 6 , when present, and the atoms to which they are attached, to form a substituted or unsubstituted heterocyclylene
  • Z is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -N(R 6 )R 6a , -OR 6a , -SR 6a , and -N(R 6 )-S0 2 - R 6b
  • R 6 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstit
  • the present disclosure is directed to compounds that bind an E3 ubiquitin ligase protein complex.
  • compounds are described that bind to Von Hippel-Lindau (VHL), the substrate recognition subunit of the E3 ligase complex VCB.
  • VHL Von Hippel-Lindau
  • the description provides bifunctional compounds and associated methods of use for effectuating the ubiquitination and/or degradation of a chosen target protein.
  • PROTAC refers to proteoly sis-targeting chimera molecules having generally three components, an E3 ubiquitin ligase binding moiety (E3LB), a linker (L), and a protein binding moiety (PB moiety, also referred to herein as "D").
  • E3LB E3 ubiquitin ligase binding moiety
  • L linker
  • D protein binding moiety
  • E3LB E3 ubiquitin ligase binding moiety
  • PB moiety protein binding moiety
  • the E3LB used herein is a VHL ligand moiety.
  • VHL ligand moiety in a PROTAC compound refers to a VHL ligand that is covalently linked to one or more groups such as a linker (L), which itself can be optionally further linked to another chemical component, such as a protein binding moiety (D).
  • L linker
  • D protein binding moiety
  • linker refers to a chemical bond formed by sharing of one or more pairs of electrons.
  • linker means a chemical moiety comprising a chain of atoms that covalently attaches a component of a PROTAC to another component of the PROTAC.
  • a "patient” or “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • the patient, individual, or subject is a human.
  • the patient may be a "cancer patient," i.e. one who is suffering or at risk for suffering from one or more symptoms of cancer.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer are provided elsewhere herein.
  • a "chemotherapeutic agent” or “anti-cancer agent” refers to a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic an
  • Chemotherapeutic agents as defined herein include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • the compounds and compositions of the subject matter described herein are used to delay development of a disease or to slow the progression of a disease.
  • treatment is performed for prophylaxis only. In another embodiment, treatment is performed during the course of clinical pathology only (i.e., not for prophylaxis). In another embodiment, treatment is performed both during the course of clinical pathology and for prophylaxis.
  • a drug that is administered "concurrently" with one or more other drugs is administered during the same treatment cycle, on the same day of treatment as the one or more other drugs, and, optionally, at the same time as the one or more other drugs. For instance, for cancer therapies given every 3 weeks, the concurrently administered drugs are each administered on day-1 of a 3-week cycle.
  • the term "effective" is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, achieves the desired therapeutic or prophylactic result.
  • the term effective subsumes other effective amount or effective concentration terms, which are otherwise described or used in the present application.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • therapeutically effective amounts of a PROTAC of the present disclosure, as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • pharmaceutical formulation or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a "pharmaceutically acceptable excipient” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable excipient includes, but is not limited to, a buffer, carrier, stabilizer, or preservative.
  • salts refers to pharmaceutically acceptable organic or inorganic salts of a molecule.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate, and pamoate (i.e., ⁇ , ⁇ -methylene bis-(2-hydroxy-3
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterion.
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds described herein and these should be considered to form a further aspect of the subject matter.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable salts.
  • a "small molecule” or “small molecular compound” generally refers to an organic molecule that is less than about 5 kilodaltons (Kd) in size. In some embodiments, the small molecule is less than about 4 Kd, 3 Kd, about 2 Kd, or about 1 Kd. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol.
  • Kd kilodaltons
  • small molecules are non- polymeric. Small molecules are not proteins, polypeptides, oligopeptides, peptides, polynucleotides, oligonucleotides, polysaccharides, glycoproteins, proteoglycans, etc.
  • a derivative of a small molecule refers to a molecule that shares the same structural core as the original small molecule, but which can be prepared by a series of chemical reactions from the original small molecule.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of any length from one to twelve carbon atoms (C1-C12), wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • an alkyl radical is one to eight carbon atoms (Ci-Cg), or one to six carbon atoms (Ci-Ce), or one to four carbon atoms (C1-C4), or one to three carbon atoms (C1-C3).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i- propyl, isopropyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (i- Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t- Bu, t-butyl, tert-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH2
  • alkylene refers to a saturated linear or branched-chain divalent hydrocarbon radical of any length from one to twelve carbon atoms (C1-C12), wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein.
  • an alkylene radical is one to eight carbon atoms (Ci- Cg), one to six carbon atoms (Ci-Ce), or one to four carbon atoms (C1-C4).
  • alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH2CH2CH2-), and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of any length from two to twelve carbon atoms (C 2 -C 12 ) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (propargyl, -CH 2 C ⁇ CH), and the like.
  • alkynylene refers to a linear or branched divalent hydrocarbon radical of any length from two to twelve carbon atoms (C 2 -C 12 ) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C ⁇ C-), propynylene (propargylene, -CH 2 C ⁇ C-), and the like.
  • carrier refers to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C3-C12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
  • Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Spiro moieties are also included within the scope of this definition.
  • Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • Carbocyclyl groups are optionally substituted independently with one or more substituents described herein.
  • cycloalkylene refer to a divalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C 3 -C 12 ) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
  • Bicyclic cycloalkylenes having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic cycloalkylenes having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Spiro moieties are also included within the scope of this definition.
  • Examples of monocyclic cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-l-enylene, 1- cyclopent-2-enylene, l-cyclopent-3-enylene, cyclohexylene, 1-cyclohex-l-enylene, 1-cyclohex- 2-enylene, l-cyclohex-3-enylene, cyclohexadienylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, cycloundecylene, cyclododecylene, and the like. Cycloalkylene groups are optionally substituted independently with one or more substituents described herein.
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C2 0 ) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar”. Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.
  • Aryl groups are optionally substituted independently with one or more substituents described herein.
  • Arylene means a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C2 0 ) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some arylene groups are represented in the exemplary structures as "Ar”. Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring.
  • Typical arylene groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4- tetrahydronaphthyl, and the like.
  • Arylene groups are optionally substituted with one or more substituents described herein.
  • heterocycle refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described herein.
  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A.
  • Heterocyclyl also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholin-4-yl, piperidin-l-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-l-yl, thiomorpholin-4-yl, S- dioxothiomorpholin-4-yl, azocan-l-yl, azetidin-l-yl, octahydropyrido[l,2-a]pyrazin-2-yl, [l,4]diazepan-l-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperaz
  • Spiro moieties are also included within the scope of this definition.
  • the heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
  • heterocyclylene refers to a divalent saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described herein.
  • a heterocyclylene may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modem Heterocyclic Chemistry" (W.A.
  • Heterocyclylene also includes divalent radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • heterocyclylenes include, but are not limited to, morpholin-4- ylene, piperidin-l -ylene, piperazinylene, piperazin-4-ylene-2-one, piperazin-4-ylene-3-one, pyrrolidin-l-ylene, thiomorpholin-4-ylene, S-dioxothiomorpholin-4-ylene, azocan-l -ylene, azetidin-l -ylene, octahydropyrido[l,2-a]pyrazin-2-ylene, [l,4]diazepan-l -ylene, pyrrolidinylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothienylene, tetrahydropyranylene, dihydropyranylene, tetrahydrothiopyranylene, piperidino, mo holino, thiomorpholino, thioxanylene, piperid
  • Spiro moieties are also included within the scope of this definition.
  • the heterocyclylene groups herein are optionally substituted independently with one or more substituents described herein.
  • heteroaryl refers to a monovalent aromatic radical of 5-, 6-, or 7- membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups are pyridinyl (including, for example, 2- hydroxypyridinyl), imidazolyl, imidazopyridinyl, l -methyl-lH-benzo[d]imidazole, [l,2,4]triazolo[l ,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,
  • Heteroaryl groups are optionally substituted independently with one or more substituents described herein.
  • heteroarylene refers to a divalent aromatic radical of 5-, 6-, or 7- membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroarylene groups are pyridinylene (including, for example, 2- hydroxypyridinylene), imidazolylene, imidazopyridinylene, l-methyl-lH-benzo[d]imidazole, [l,2,4]triazolo[l ,5-a]pyridine, pyrimidinylene (including, for example, 4- hydroxypyrimidinylene), pyrazolylene, triazolylene, pyrazinylene, tetrazolylene, furylene, thienylene, isoxazolylene, thiazolylene, oxadiazolylene, oxazolylene, isothiazolylene, pyrrolylene, quinolinylene, isoquinolinylene, tetrahydroisoquinolinylene, indolylene, benzimidazolylene, benzofuranylene, cinnolinylene, indazolylene, indolizinylene, phthalazinylene
  • the heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible.
  • carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1
  • nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ - carboline.
  • acyl refers to both substituted and unsubstituted acyl.
  • an “acyl” may be -C(0)-R 16 , wherein R 16 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. In one particular embodiment, it is a substituted C1-C3 alkyl.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • co-administration and “co-administering” or “combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
  • one or more of the present compounds described herein are coadministered in combination with at least one additional bioactive agent, especially including an anticancer agent.
  • the co-administration of compounds results in synergistic activity and/or therapy, including anticancer activity.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context.
  • compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder.
  • bond ⁇ is shown, both a double bond and single bond are represented within the context of the compound shown.
  • a crossed double bond (* ⁇ ) both the E and Z configurations are represented within the context of the compound shown; and the compound may contain the E isomer or the Z isomer or a mixture of both the E and Z isomers.
  • VLB E3 Ubiquitin Ligase Von Hippel-Lindau (or VHL) E3 Ubiquitin Ligase
  • VHL or “Ubiquitin Ligase”
  • VCB E3 is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome.
  • ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule.
  • Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.
  • different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
  • VHL ligand a moiety that binds the E3 VHL ubiquitin ligase or a component thereof, is referred to a VHL ligand.
  • PB protein binding moiety
  • D protein binding moiety
  • Hsp90 inhibitors Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among numerous others.
  • compositions described herein exemplify some of the members of these and other types of small molecule target proteins.
  • VHL ligand By coupling the VHL ligand to a protein binding moiety (PB), the target protein or polypeptide is ubiquitinated and/or degraded by the proteasome.
  • PB protein binding moiety
  • certain groups e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl
  • the "substituted" group may be substituted with 1 , 2, 3, 4, 5, or more substituents, as indicated herein.
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be substituted with one or more substituents independently selected from, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl heterocyclyl, aryl, heteroaryl, halo (i.e., halogen), haloalkyl, oxo, OH, CN, -O-alkyl, S-alkyl, NH-alkyl, N(alkyl) 2 , O-cycloalkyl, S-cycloalkyl, NH-cycloalkyl, N(cycloalkyl) 2 , N(cycloalkyl)(alkyl), NH 2 , SH, S0 2 - alkyl, P(0)(0-alkyl)(alkyl), P(0)(0-alkyl) 2 , Si(OH) 3 , Si(alkyl
  • transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of and “consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • the description relates to a bifunctional PROTAC compound that binds an E3 ubiquitin ligase protein, and specifically VHL, or component thereof and a target protein.
  • the E3 ubiquitin ligase protein ubiquitinates the target protein once it and the target protein are placed in proximity by the PROTAC compound. Accordingly, the description provides such compounds that bind to such E3 ubiquitin ligase proteins, as well as bifunctional PROTAC compounds comprising the same.
  • E3 ubiquitin ligases confer substrate specificity for ubiquitination. There are known ligands which bind to these ligases.
  • An E3 ubiquitin ligase binding group (E3LB) is a peptide or small molecule that can bind an E3 ubiquitin ligase.
  • a particular E3 ubiquitin ligase is von Hippel-Lindau (VHL) tumor suppressor, the substrate recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbxl.
  • VHL Hypoxia Inducible Factor la
  • VEGF vascular endothelial growth factor
  • cytokine erythropoietin a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell inducing cytokine erythropoietin in response to low oxygen levels.
  • the present disclosure is directed to proteolysis-targeting chimera (PROTAC) compounds that are useful for regulating protein activity, and specifically, for facilitating the degradation of target proteins.
  • PROTAC compounds of the present disclosure are bifunctional compounds that can be used as modulators of targeted ubiquitination.
  • the compounds comprise on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein, such that degradation of the target protein/polypeptide is effectuated.
  • the VHL ligand moiety is a small molecule (i.e., not peptide based).
  • the VHL ligand moiety is chemically linked, via a bond or through a chemical linker, to a protein binding (PB) moiety (or "D"), wherein the VHL ligand moiety recognizes a VHL E3 ubiquitin ligase and the protein binding moiety recognizes a target protein or polypeptide, and wherein the VHL ligand moiety is coupled to the PB moiety.
  • PB protein binding
  • the present disclosure is directed to a compound according to the structure: VHLM-L, where L is a linker group and VHLM is a VHL ligand moiety.
  • VHL ligand moiety is coupled directly or via a chemical linker to a protein binding (PB) moiety (or "D").
  • PB protein binding
  • the description provides compounds that comprise a protein binding group according to the general structure: VHLM-L-PB or VHLM-L-D, where VHLM is a VHL ligand moiety, PB or D is a chemical moiety (protein binding moiety), which binds to a target protein or polypeptide, which is ubiquitinated by an ubiquitin ligase, and is chemically linked directly to the VHL ligand moiety or through a linker moiety L, which can be a bond or a chemical linker.
  • VHLM is a VHL ligand moiety
  • PB or D is a chemical moiety (protein binding moiety), which binds to a target protein or polypeptide, which is ubiquitinated by an ubiquitin ligase, and is chemically linked directly to the VHL ligand moiety or through a linker moiety L, which can be a bond or a chemical linker.
  • the PB or D moiety is alternatively also a VHL E3 ubiquitin ligase binding moiety, which may be the same or different than the VHL ligand moiety and is linked to the VHL ligand moiety directly or through a linker or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.
  • the VHL ligand moiety is coupled to a PB or D moiety directly (via a bond) or via a chemical linker.
  • the compound resembles a dimeric compound where both ends of the compound comprise a VHL ubiquitin ligase binding moiety as otherwise described herein.
  • the VHL ligand moiety and PB or D moiety may be covalently linked to the linker group through any group which is appropriate and stable to the chemistry of the linker, in certain embodiments, and as detailed further below, the linker may be independently covalently bonded to the VHL ligand moiety and the PB or D moiety through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which groups may be inserted anywhere on the VHL ligand moiety and PB or D moiety to provide maximum binding of the VHL ligand moiety on the VHL ubiquitin ligase and the PB or D moiety on the target protein to be degraded.
  • the target protein for degradation may be the ubiquitin ligase itself).
  • the linker may be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, an aryl group or a heterocyclic group on the VHL ligand moiety and/or PB or D moiety.
  • the present disclosure is directed to a compound (e.g. a PROTAC) of Formula (I), or a tautomer thereof:
  • R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl;
  • R 3 is substituted or unsubstituted alkyl, or R 3 is taken together with R 6 , when present, and the atoms to which they are attached, to form a substituted or unsubstituted heterocyclylene;
  • Y is selected from the group consisting of substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, O, S, -N(R 6 )-, -N(R 6 )-C(0)-, and -N(R 6 )- S0 2 -;
  • R 6 is selected from the group consisting of H and substituted or unsubstituted alkyl; or R 6 is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene;
  • L is a linker moiety
  • D is a protein binding moiety
  • the compound e.g. a PROTAC
  • a PROTAC is a compound of Formula (la), or a tautomer thereof:
  • R 1 is -W-R 7
  • W is selected from the group consisting of substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, and substituted or unsubstituted cycloalkylene
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -OR , -N(R )R , -C
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or
  • 8 8s unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -OR°, -N(R M )R , and -S0 2 R 8c , wherein R 8 , R 8a , R 8b , and R 8c are as defined above.
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, and -S0 2 R 8c , wherein R 8c is as defined above.
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -C(0)R 8c , - C(0)N(R 8a )R 8b , -N(R 8a )C(0)R 8c , -S0 2 N(R 8a )R 8b , and -S0 2 R 8c , wherein R 8a , R 8b , and R 8c are as defined above.
  • R 7 is a haloalkyl, for example, a -CF 3 .
  • R 1 is -W-R 7 ; W is substituted or unsubstituted phenylene; and R 7 is as defined above. In one embodiment, R 1 is substituted or unsubstituted phenyl.
  • R 1 is m is 0, 1, 2,3, 4, or 5;
  • R 1 is ; R 7 is as defined above; and > «w is the point of attachment to the remaining structure of the compound.
  • R 7 is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl.
  • R 1 is selected from the group consisting of:
  • R 7a is halo or -CN; R 7 is as defined above; and is the point of attachment to the remaining structure of the compound.
  • R 1 is selected from the group consisting of: 5 5 and ; wherein R 7 is as defined above; and is the point of attachment to the remaining structure of the compound.
  • R 7 is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl.
  • R is as defined above; and is the point of attachment to the remaining structure of the compound.
  • n 0,
  • R is selected from the group consisting of oxo, alkyl, haloalkyl, cycloalkyl, halo, -CN, -NH 2 , and substituted or unsubstituted alkynyl; ⁇ ) when present, is the point of attachment to the remaining structure of the compound; R a , when present, is selected from the ggrroouupp ccoonnssiissttiinngg ooff HH aanndd RR 99 ;; oo:r R 9a is the point of attachment to the remaining structure of the compound and « ⁇ is absent.
  • R 7 include
  • R 9a is alkyl, and R 9 is selected from the group consisting of halo and -CN.
  • R 7 is chlorophenyl, chloro-thiazolyl or trifluoromethyl-thiazolyl.
  • R 7 is ; and R 9 is a substituted or unsubstituted alkynyl.
  • the alkynyl is substituted with a substituted or unsubstituted aryl, such as phenyl.
  • the aryl is phenyl, and the phenyl is substituted with at least one R 10 , wherein R 10 is halo.
  • R 7 is selected from the group consisting of a substituted or unsubstituted 5-membered heteroaryl, and a substituted or unsubstituted 5- membered heterocyclyl.
  • R 7 may be, for example, 1 -pyrrolidinyl or 1-pyrrolidonyl.
  • R 7 is methylthiazolyl.
  • R 1 is -W-R 7
  • W is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl
  • R 7 is independently selected from the group consisting of halo, -CN, and substituted or unsubstituted alkyl.
  • W is a substituted or unsubstituted phenylene.
  • R 1 is a substituted or unsubstituted alkyl. In one embodiment, R 1 is a C 1-4 alkyl. In one embodiment, R 1 is tert-butyl.
  • R 1 is selected from the group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl. Additional non-limiting
  • R 1 are selected from the group consisting of:
  • R 3 is a substituted or unsubstituted Ci-C alkyl. In certain embodiments, R 3 isopropyl or tert-butyl.
  • Y is selected from the group consisting of substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, O, S, -N(R 6 )-, - N(R 6 )-C(0)-, and -N(R 6 )-S02-.
  • Y is substituted or unsubstituted heteroarylene, or a substituted or unsubstituted heterocyclylene.
  • Y is a substituted or unsubstituted heteroarylene. Examples
  • Y is selected from the group consisting of -N(R )-, - N(R 6 )-C(0)-, and -N(R 6 )-S0 2 -; and R 6 is selected from the group consisting of H and substituted or unsubstituted alkyl.
  • Y is selected from the group consisting of -N(R 6 )-, - N(R 6 )-C(0)-, and -N(R 6 )-S0 2 -; and R 6 is selected from the group consisting of H and substituted or unsubstituted C1-C6 alkyl.
  • Y is -N(R 6 )-C(0)- and R 6 is H.
  • Y is -N(R 6 )-C(0)-, R 6 is H, and R 3 is substituted or unsubstituted alkyl. In one particular embodiment, Y is -N(R 6 )-C(0)-, R 6 is H, and R 3 is isopropyl or tert-butyl.
  • Y is selected from the group consisting of -N(R 6 )-, - N(R 6 )-C(0)-, and -N(R 6 )-S0 2 -; and R 6 is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene.
  • the heterocyclylene is substituted with -(R n ) p ; wherein p is 0, 1, 2, 3, or 4; R 11 is selected from the group consisting of substituted or unsubstituted C1-C3 alkyl, halo, -CN, and -OR l la ; and each R l la is independently selected from the group consisting of H and substituted or unsubstituted alkyl (e.g., a C1-C3 alkyl). In one embodiment, R 11 is -OR l la , and is selected from the group consisting of -OCH 3 , -OCF 3 , and -OH.
  • p is 1 and R 11 is selected from the group consisting of -OCH 3 , -OCF 3 , and -OH.
  • R 6 is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted 5- or 6- membered heterocyclylene.
  • the 5- or 6-membered heterocyclylene is substituted with an alkyl.
  • R 1 is selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
  • R 3 is a C1-C6 alkyl, such as isopropyl or tert-butyl; Y is -N(R 6 )-C(0)- or and R 6 is H.
  • R 1 is , 1, 2, 3, 4, or 5; R is a
  • C1-C6 alkyl such as isopropyl or tert-butyl
  • Y is - N(R°)-C(0)- or
  • R 6 is H
  • each R 7 is independently selected from the group consisting of -CN, halo, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 1 is phenyl
  • R 3 is a
  • Ci-C 6 alkyl such as isopropyl or tert-butyl
  • Y is H
  • R 7 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, -CN.
  • R 1 i is a C1-C6 alkyl, such as
  • the present disclosure is directed to a compou Formula (I) or
  • R 1 is ; R 3 is tert-butyl; Y is -N(R 6 )-C(0)-; R 6 is H; and R 7 is substituted or unsubstituted heteroaryl or halo.
  • R 7 is a substituted or unsubstituted 5- or 6-membered heteroaryl.
  • the present disclosure is directed to a compou Formula
  • R 3 is isopropyl; Y is ; and R 7 is substituted or unsubstituted heteroaryl or halo. In one such embodiment, R 7 is a substituted or unsubstituted 5- or 6-membered heteroaryl. In one such embodiment, R 7 is halo.
  • the PROTAC is a compound of Formula (I) or a tautomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and has a structure selected from the group consisting of those structures in Table 1, wherein R 1 , L, and D are as defined herein; p is 0, 1, 2, 3, or 4; R 11 is selected from the group consisting of substituted or unsubstituted C 1-C3 alkyl, halo, -CN, and -OR l la ; and R lla is selected from the group consisting of H and substituted or unsubstituted alkyl.
  • the PROTAC is a compound of Formula (I) or a tautomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and has a structure selected from the group consisting of those structures in Table 2, wherein R 3 , R 7 , Y, L, and D are as defined herein; R 10 is halo; and m is 0, 1, 2, 3, 4, or 5.
  • the PROTAC is a compound of Formula I-B-9 or a salt (e.g., a pharmaceutically acceptable salt) thereof, having the structure
  • the PROTAC is a compound of Formula I-B-9a or a salt (e.g., a pharmaceutically acceptable salt) thereof, having the structure
  • R 7 is as defined above.
  • the PROTAC is a compound of Formula I-B-10 or a salt a pharmaceutically acceptable salt) thereof, having the structure
  • R 7 is as defined above.
  • the PROTAC is a compound of Formula I-B-10a or a salt a pharmaceutically acceptable salt) thereof, having the structure
  • the PROTAC is a compound of Formula I-B-11 or a salt (e.g., a pharmaceutically acceptable salt) thereof, having the structure
  • R 7 is as defined above.
  • the PROTAC is a compound of Formula I-B-l la or a salt (e.g., a pharmaceutically acceptable salt) thereof, having the structure
  • the PROTAC is a compound selected from the group consisting of a compound of Formula I-A-1, a compound of Formula I-A-9, a compound of Formula I-B-9, a compound of Formula I-B-21, a compound of Formula I-B-22, a compound of Formula I-B-23, a compound of Formula I-B-24, a compound of Formula I-B-25, a compound of Formula I-B-26, and a compound of Formula I-B-27, or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 , R 3 , R 7 , Y, L, and D are as defined herein, and m is 0, 1, 2, 3, 4, or 5.
  • the PROTAC is a compound selected from the group consisting of a compound of Formula I-A-1, a compound of Formula I-A-9, and a compound of Formula I-B-9, or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 , R 3 , R 7 , Y, L, and D are as defined herein, and m is 0, 1, 2, 3, 4, or 5.
  • the PROTAC is a compound selected from the group consisting of a compound of Formula I-A-1 a, a compound of Formula I-A-9a, a compound of Formula I-B-9a, a compound of Formula I-B-21 a, a compound of Formula I-B-22a, a compound of Formula I-B-23a, a compound of Formula I-B-24a, a compound of Formula I-B-25a, a compound of Formula I-B-26a, and a compound of Formula I-B-27a, or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 , R 3 , R 7 , Y, L, and D are as defined herein, and m is 0, 1, 2, 3, 4, or 5.
  • a salt e.g., a pharmaceutically acceptable salt
  • the PROTAC is a compound selected from the group consisting of a compound of Formula I-A-1 a, a compound of Formula I-A-9a, and a compound of Formula I-B-9a, or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 , R 3 , R 7 , Y, L, and D are as defined herein, and m is 0, 1, 2, 3, 4, or 5.
  • the PROTAC is a compound of Formula (I) or (la) or a tautomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and has a structure selected from the group consisting of those structures in Table 3, wherein L and D are as defined herein. Table 3
  • the PROTAC is a compound of Formula (I) or (la) or a tautomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and is selected from the group consisting of those compounds in Table 4.
  • the PROTAC is a salt (e.g., a pharmaceutically acceptable salt) of a compound in Table 4.
  • the PROTAC is a formate salt of any one of compounds 104, 104a, or 104b.
  • PROTAC compound or a VHL ligand as described herein, these can exist in solid or liquid form.
  • the compound In the solid state, the compound may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds.
  • solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates. " Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs. " The subject matter disclosed herein includes such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • PROTACs and VHL ligands described herein or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the subject matter disclosed herein.
  • a compound or salt of Formulas (I) or (la) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the subject matter disclosed herein. It is to be understood that the subject matter disclosed herein includes combinations and subsets of the particular groups described herein.
  • the subject matter disclosed herein also includes isotopically-labelled forms of the compounds described herein, but for the fact 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 compounds described herein and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, H, n C, 1 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • PROTAC compounds and VHL ligands as disclosed herein and pharmaceutically acceptable salts thereof that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the subject matter disclosed herein.
  • Isotopically- labelled compounds are disclosed herein, for example those into which radioactive isotopes such as H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H, and carbon-14, i.e., 14 C, isotopes are commonly used for their ease of preparation and detectability.
  • n C and 18 F isotopes are useful in PET (positron emission tomography), and 125 I isotopes are useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labelled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the present disclosure is directed to VHL ligands, and specifically, VHL ligands that bind to a VHL E3 ubiquitin ligase.
  • the VHL ligands of the present disclosure may be derivatized, e.g., by coupling the VHL ligand directly or via a chemical linker to a protein binding moiety to form a PROTAC, as discussed elsewhere herein.
  • the VHL ligand is a compound of Formula (II) or a tautomer thereof:
  • R 1 and R 3 are as defined above;
  • Z is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -N(R 6 )R 6a , -OR 6a , -SR 6a , and -N(R 6 )-S0 2 -R 6b ;
  • R 6 is selected from the group consisting of H and substituted or unsubstituted alkyl; or R 6 , when present, is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene;
  • R 6a is selected from the group consisting of H, substituted or unsubstituted acyl, and substituted or unsubstituted alkyl;
  • R 6b is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted aryl.
  • the VHL ligand may be a compound of Formula (Ila) or a tautomer thereof:
  • R 1 is -W-R 7
  • W is selected from the group consisting of substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, and substituted or unsubstituted cycloalkylene
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -OR 8 , -N(R 8a )
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -OR 8 , -N(R 8a )R 8b , and -S0 2 R 8c , wherein R 8 , R 8a , R 8b , and R 8c are as defined above.
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, and -S0 2 R 8c , wherein R 8c is as defined above.
  • R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, oxo, -CN, -C(0)R c , - C(0)N(R 8a )R 8b , -N(R 8a )C(0)R 8c , -S0 2 N(R 8a )R 8b , and -S0 2 R 8c , wherein R 8a , R 8b , and R 8c are as defined above.
  • R 7 is a haloalkyl, for example, a -CF 3 .
  • R 1 is -W-R 7 ;
  • W is substituted or unsubstituted phenylene; and
  • R 7 is as defined above.
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is ; m is 0, 1, 2,3, 4, or 5; R 7 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halo, -CN, -OR 8 , -N(R 8a )R 8b , -C(0)R 8c , -C(0)N(R 8a )R 8b , -N(R 8a )C(0)R 8c , - S0 2 N(R 8a )R 8b , and -S0 2 R 8c ; R 8 , R 8a , and R 8b are independently selected from the group consisting of H and substituted
  • R is ; R 7 is as defined above; and w* is the point of attachment to the remaining structure of the compound.
  • R 7 is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl.
  • R 1 is selected from the group consisting of:
  • R 7a is halo or -CN; R 7 is as defined above; and - ⁇ is the point of attachment to the remaining structure of the compound.
  • R 1 is selected from the group consisting of: , and ; wherein R 7 is as defined above; and > ⁇ is the point of attachment to the remaining structure of the compound.
  • R 7 is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl.
  • R is ; wherein R is as defined above; and is the point of attachment to the remaining structure of the compound.
  • R 7 is selected from the group consisting of
  • R 9 is selected from the group consisting of oxo, alkyl, haloalkyl, cycloalkyl, halo, -CN, -NH 2 , and substituted or unsubstituted alkynyl; *sw > ⁇ r ⁇ when present, is the point of attachment to the remaining structure of the compound; R 9a , when present, is selected from the group consisting of H and R 9 ; or R 9a is the point of attachment to the remaining structure of the compound and »/v w* is absent.
  • R 9 is selected from the group consisting of halo and -CN.
  • R 7 chlorophenyl, chloro-thiazolyl or trifluoromethyl-thiazolyl.
  • R 7 is ; and R 9 is a substituted or unsubstituted alkynyl.
  • the alkynyl is substituted with a substituted or unsubstituted aryl, such as phenyl.
  • the aryl is phenyl, and the phenyl is substituted with at least one R 10 , wherein R 10 is halo.
  • R 7 is selected from the group consisting of a substituted or unsubstituted 5-membered heteroaryl, and a substituted or unsubstituted 5- membered heterocyclyl.
  • R 7 may be, for example, 1 -pyrrolidinyl or 1-pyrrolidonyl.
  • R 7 is methythiazole.
  • R 1 is -W-R 7
  • W is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl
  • R 7 is independently selected from the group consisting of halo, -CN, and substituted or unsubstituted alkyl.
  • W is a substituted or unsubstituted phenylene.
  • R 1 is a substituted or unsubstituted alkyl.
  • R 1 is a C 1-4 alkyl.
  • R 1 is tert-butyl.
  • R 1 is selected from the group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl. Additional non-limiting
  • R 1 are selected from the group consisting of:
  • R 3 is a substituted or unsubstituted Ci.Ce alkyl. In certain embodiments, R 3 isopropyl or tert-butyl.
  • Z is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -N(R 6 )R 6a , -OR 6a , -SR 6a , and -N(R 6 )-S0 2 -R 6b , wherein R 6 , R 6a , and R 6b are as defined above.
  • Z is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • Z may be a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • Z include, but are not limited to
  • ⁇ indicates the point of attachment to the remaining structure of the compound
  • r is 0, 1, 2, or 3
  • each R 13 is independently selected from the group consisting of -OR 1 a and substituted or unsubstituted alkyl
  • each R 14 is independently selected from the group consisting of H, substituted or unsubstituted alkyl, and the point of attachment to the remaining structure of the compound
  • each R a is independently selected from the group consisting of H and substituted or unsubstituted alkyl; wherein when R 14 is the point of attachment to the remaining structure of the compound, « ⁇ is absent.
  • r is 0, 1 , or 2. In one embodiment, r is 1.
  • R 13 is a C1-C3 alkyl. In one embodiment, r is 1 and R 13 is -CH 3 .
  • R 13 is -OR 1 a
  • R 1 a is selected from the group consisting of C1-C3 alkyl and H.
  • r is 1, R 13 is -OR 1 a , and R 1 a is -CH 3 or H.
  • Z is a 5- or 6-membered substituted or unsubstituted heteroaryl. In another embodiment, Z is a 5-membered substituted or unsubstituted heteroaryl.
  • R is selected from the group consisting of -OR 1 a and substituted or unsubstituted alkyl; R 14 is selected from the group consisting of H and substituted or unsubstituted alkyl; and R 1 a is selected from the group consisting of H and substituted or unsubstituted alkyl.
  • r is 1 and R is a C1-C3 alkyl. In one embodiment, r is 1 and R 13 is -CH 3 . In one embodiment, r is 0.
  • r is 1 ; R 13 is -OR 1 a ; and R 1 a is selected from the group consisting of C1-C3 alkyl and H. In one embodiment, r is 1, R 13 is -OR 1 a , and R 1 a is -CH 3 or H. [0156] In one specific embodiment, Z is
  • R 1 a is selected from the group
  • Z may be wherein R is selected from the group consisting of -CH 3 and -OR a , and R a is H or -CH 3 .
  • Z is selected from the group consisting of -N(R 6 )R 6a , -OR 6a , - SR 6a , and -N(R 6 )-S0 2 -R 6b ; wherein R 6 is selected from the group consisting of H and substituted or unsubstituted alkyl; or R 6 , when present, is taken together with R 3 and the atoms to which they are attached to form a substituted or unsubstituted heterocyclylene; R 6a is selected from the group consisting of H, substituted or unsubstituted acyl, and substituted or unsubstituted alkyl; and R 6b is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted aryl.
  • R 6 is selected from the group consisting of H and substituted or unsubstituted C 1 -C6 alkyl and R 6a is selected from the group consisting of H, substituted or unsubstituted C 1 -C6 acyl, and substituted or unsubstituted C 1 -C6 alkyl.
  • R 6a is -C(0)-R 16 , wherein R 16 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl.
  • R 6a is -C(0)-R 16 , wherein R 16 is a substituted C 1 -C3 alkyl.
  • Z is -N(R 6 )R 6a , and R 6 and R 6a are as defined above.
  • Z is -N(R 6 )R 6a , R 6 is H, and R 6a is a substituted or unsubstituted acyl (e.g., a substituted or unsubstituted C1-C6 acyl).
  • Z is - N(R 6 )R 6a , R 6 is H, and R 6a is -C(0)CH 3 .
  • any of the Z moieties detailed herein for the compound of Formula (II) or (Ila) may be combined with any of the R 1 and/or R 3 groups detailed herein, as if each and every combination has been individually described.
  • R is nsubstituted phenyl;
  • R 3 is a C1-C6 alkyl, such as
  • R 6a is substituted or unsubstituted acyl
  • R 7 is substituted or unsubstituted heteroaryl or halo
  • R 13 is selected from the group consisting of -OR 1 a and substituted or unsubstituted alkyl (e.g., a C1-C6 alkyl); and R 1 a is selected from the group consisting of H and substituted or unsubstituted alkyl (e.g., a C1-C6 alkyl).
  • the present disclosure is directed to a compound of Formula (II) or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 is selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted cycloalkyl, substituted or unsubstituted aryl, and subs or unsubstituted heteroaryl; R 3 is a C1-C6 alkyl, such as
  • R is -OR 1 a or a Ci-C 6 alkyl
  • R 1 a is H or a Ci-C 6 alkyl
  • the present disclosure is directed to a compound of Formula r a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 is
  • R 3 is a C1-C6 alkyl, such as isopropyl or tert-butyl; Z is ; R 13 is -OR 1 a or a Ci-C 6 alkyl; R 1 a is H or a Ci-C 6 alkyl; and each R 7 is independently selected from the group consisting of -CN, halo, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • the present disclosure is directed to a compound of Formula or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 is or unsubstituted phenyl; R 3 is a C1-C6 alkyl, such as isopropyl or tert-butyl; Z is ; R 13 is -OR 1 A or a Ci-C 6 alkyl; R 1 A is H or a Ci-C 6 alkyl; and R 7 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, or -CN.
  • R 1 is or unsubstituted phenyl
  • R 3 is a C1-C6 alkyl, such as isopropyl or tert-butyl
  • Z is ;
  • R 13 is -OR 1 A or a Ci-C 6 alkyl;
  • R 1 A is H or a Ci-C 6 alkyl; and
  • R 7 is substitute
  • the present disclosure is directed to a compound of Formula or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 is or unsubstituted phenyl; R 3 is tert-butyl; Z is -N(R 6 )R 6A ; R 6 is H; R 6A is substituted or unsubstituted C1-C6 acyl, and R 7 is substituted or unsubstituted heteroaryl or halo.
  • R 7 is a substituted or unsubstituted 5- or 6-membered heteroaryl, and R 6A is - C(0)CH3.
  • R 1 is unsubstituted phenyl, and R 6A is -C(0)CH 3 .
  • the present disclosure is directed to a compound of Formula (II) or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein R 1 is ; R 3 is isopropyl; Z is ; R 7 is substituted or unsubstituted heteroaryl or halo; R 13 is -OR 1 A or a C1-C6 alkyl; and R 1 A is H or a C1-C6 alkyl.
  • R 7 is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 13 is -CH 3 or -OR 1 A ; and R 1 A is H or -CH 3 .
  • R 7 is halo; R 13 is -CH 3 or -OR 1 A ; and R 1 A is H or -CH 3 .
  • the VHL ligand is a compound of Formula (II) or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, and has a structure selected from the group consisting of those structures in Table 5.
  • VHL ligands of the present disclosure may be derivatized, e.g., by coupling the VHL ligand directly or via a chemical linker to a protein binding moiety to form a PROTAC, as discussed elsewhere herein.
  • the VHL ligand and PB moiety may be covalently linked to one another and/or to the linker group through any group which is appropriate and stable to the chemistry of the linker.
  • the linker may be independently covalently bonded to the VHL ligand and the PB moiety through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, among others, each of which groups may be inserted anywhere on the VHL ligand and PB moiety to provide maximum binding of the VHL ligand on the VHL ubiquitin ligase and the PB moiety on the target protein to be degraded.
  • the linker may be linked to a substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted aryl group, or to a substituted or unsubstituted heterocyclic group on the VHL ligand and/or PB moiety.
  • a linker and PB moiety are linked to a VHL ligand of Formula (II) or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, through the Z substituent to form a PROTAC.
  • the resulting PROTAC has a structure of Formula (I) or (la) or a pharmaceutically acceptable salt thereof.
  • a linker and PB moiety are linked to a VHL ligand of Formula (II) or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, through the R 1 substituent to form a PROTAC.
  • R 1 may be an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl that is substituted with a substituent suitable for linker attachment.
  • the R 1 substituent may be further modified to introduce a substituent suitable for linker attachment (e.g., introducing a hydroxyl group to a phenyl).
  • VHL ligands of the present disclosure that may be derivatized at the R 1 position to attach a linker and PB moiety (“-L-D") include the following: 112
  • linker group L may be any linker group as described hereinafter.
  • PB moiety (“D") may be any protein binding moiety as described hereinafter.
  • the PB moiety is a group which binds to a target protein intended to be degraded.
  • the term "protein” includes oligopeptides and polypeptide sequences of sufficient length that they can bind to a PB moiety. Any protein in a eukaryotic system or a microbial system, including a virus, bacteria or fungus, as otherwise described herein, are targets for ubiquitination mediated by the compounds described herein.
  • the target protein may be a eukaryotic protein.
  • PB moieties include, for example, any moiety which binds to a protein specifically (binds to a target protein) and includes the following non-limiting examples of small molecule target protein moieties: heat shock protein 90 (Hsp90) inhibitors, kinase inhibitors and phosphatase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain- containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, RAS inhibitors, EGFR inhibitors, and BRM inhibitors, as well as compounds that bind to the aryl hydrocarbon receptor (AHR), RAF receptor kinase, FKBP, Androgen Receptor (AR), estrogen receptor (ER), thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, acyl-protein thioesterase-1 and -2 (APT1 and APT2), USP7, and BRG1, among numerous others
  • compositions described below exemplify some of the members of these types of small molecule target protein binding moieties.
  • small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest.
  • These protein binding moieties are linked to the VHL ligand moiety through a linker, in order to present a target protein (to which the protein binding moiety is bound) in proximity to the ubiquitin ligase for ubiquitination and degradation.
  • target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, proteins involved in aromatase activity, proteins involved in motor activity, proteins involved in helicase activity, proteins involved in metabolic processes (anabolism and catabolism), proteins involved in antioxidant activity, proteins involved in proteolysis, proteins involved in biosynthesis, proteins with kinase activity, proteins with oxidoreductase activity, proteins with transferase activity, proteins with hydrolase activity, proteins with lyase activity, proteins with isomerase activity, proteins with ligase activity, proteins with enzyme regulator activity, proteins with signal transducer activity, proteins with structural molecule activity, proteins with binding activity (protein, lipid carbohydrate), proteins with receptor activity, proteins with cell motility, membrane fusion proteins
  • Proteins of interest can include proteins from eukaryotes and prokaryotes including humans as targets for drug therapy, other animals, including domesticated animals, microbials for the determination of targets for antibiotics and other antimicrobials and plants, and even viruses, among numerous others.
  • the PB moiety of a PROTAC may be any peptide or small molecule that bind protein targets such as FoxOl, HDAC, DP-1, E2F, ABL, AMPK, BRK, BRSK I, BRSK2, BTK, CAMKK1, CAMKK alpha, CAMKK beta, Rb, Suv39HI, SCF, pl9INK4D, GSK-3, pi 8 INK4, myc, cyclin E, CDK2, CDK9, CDG4/6, Cycline D, pl6 INK4A, cdc25A, BMI1, Akt, CHKl/2, C 1 delta, CK1 gamma, C 2, CLK2, CSK, DDR2, DYRK1 A/2/3, EF2K, EPH-A2/A4/B1/B2/B3/B4, EIF2A 3, Smad2, Smad3, Smad4, Smad7, p53, p21 Cipl, PAX, Fyn,
  • protein targets include Ras proteins, P13K, Ral- GDS, H-Ras, N-Ras, KRas4A, K-Ras4B, BRG1, RAF, BRAF, CRAF, and BET.
  • the protein target is selected from the group consisting of EGRF, RAS, BRM, BRG1, MDM2, RAF (BRAF and CRAF), BET, and USP7.
  • a number of drug targets for human therapeutics also represent protein targets to which a protein binding moiety may be bound and incorporated into compounds according to the present disclosure. These include proteins which may be used to restore function in numerous polygenic diseases, including for example B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo- oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5- lipoxygenase, tryptase serine protease,
  • Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels. Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.
  • Haloalkane dehalogenase enzymes are another target of specific compounds according to the present disclosure.
  • Compounds according to the present disclosure which contain chloroalkane peptide binding moieties may be used to inhibit and/or degrade haloalkane dehalogenase enzymes which are used in fusion proteins or related dioagnostic proteins as described in WO 2012/078559, the contents of which is incorporated by reference herein.
  • the PB moiety is a haloalkyl group, wherein said alkyl group generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, often about 2 to 10 carbons in length, often about 3 carbons to about 8 carbons in length, more often about 4 carbons to about 6 carbons in length.
  • the haloalkyl groups are generally linear alkyl groups (although branched-chain alkyl groups may also be used) and are end-capped with at least one halogen group, preferably a single halogen group, often a single chloride group.
  • Haloalkyl PB moieties for use in the present disclosure may be represented by the chemical structure-(CH 2 ) v -Halo where v is any integer from 2 to about 12, often about 3 to about 8, more often about 4 to about 6. Halo may be any halogen, but is preferably CI or Br, more often CI. [0178] In still other embodiments, the PB moiety has the structure
  • This group binds selectively to estrogen receptors and is useful for treating diseases which are modulated through estrogen receptors, and in particular cancers, such as breast cancer, endometrial cancer, ovarian cancer and uterine cancer, among others.
  • compositions described below exemplify some of the members of these types of small molecule target protein binding moieties.
  • Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest. References which are cited hereinbelow are incorporated by reference herein in their entirety.
  • HSP90 inhibitors as used herein include, but are not limited to:
  • linker group L or a -L-(VHL ligand moiety) group is attached via the terminal acetylene group;
  • HSP90 inhibitors modified (modified) identified in Wright, et al, "Structure- Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms," Chem Biol. 2004 Jun; l l(6):775-85, including the HSP90 inhibitor PU3 having the structure: where a linker group L or -L-(VHL ligand moiety) is attached via the butyl group; and
  • 17-alkylamino-17-desmethoxy geldanamycin (“ 17- AAG”) or 17-(2-dimethylaminoethyl)amino-17-desmethoxy geldanamycin (“ 17-DMAG”)) (derivatized, where a linker group L or -L-(VHL ligand moiety) group is attached via the amide group).
  • Kinase inhibitors as used herein include, but are not limited to:
  • R is a linker group L or a -L-(VHL ligand moiety) group attached via the ether group; [0188] 2.
  • R is a linker group L or a -L-(VHL ligand moiety) group attached to the phenyl moiety
  • R is a linker group L or a -L-(VHL ligand moiety) group attached to the pyrimidine
  • the kinase inhibitor Afatinib (derivatized) (N-[4-[(3-Chloro-4- fluorophenyl)amino] -7- [ [(3 S)-tetrahy dro-3-furany 1] oxy ] -6-quinazoliny 1] -4(dimethy lamino)-2- butenamide) (derivatized where a linker group L or a-L-(VHL ligand moiety) group is attached preferably via the aliphatic amine group);
  • the kinase inhibitor Fostamatinib (derivatized) ([6-( ⁇ 5-fluoro-2-[(3,4,5- trimethoxyphenyl)amino]pyrirnidin-4-yl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H- pyrido[3,2-b]-l,4-oxazin-4-yl]methyl disodium phosphate hexahydrate) (derivatized where a linker group L or a -L-(VHL ligand moiety) group is attached preferably via a methoxy group);
  • kinase inhibitor Lenvatinib (derivatized) (4-[3-chloro-4- (cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivatized where a linker group L or a -L-(VHL ligand moiety) group is attached preferably via the cyclopropyl group);
  • Vandetanib (N-(4-bromo-2-fluorophenyl)- 6-methoxy-7-[(l -methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized where a linker group L or a -L-(VHL ligand moiety) group is attached preferably via the methoxy or hydroxyl group);
  • kinase inhibitor Vemurafenib (derivatized) (propane- 1 -sulfonic acid ⁇ 3- [5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide) (derivatized where a linker group L or a -L-(VHL ligand moiety) group is attached preferably via the sulfonyl propyl group);
  • R is a linker group L or a -L-(VHL ligand moiety) group preferably attached to the phenyl moiety or via the aniline amine group;
  • R is a linker group L or a -L-(VHL ligand moiety) group attached preferably to the phenyl moiety
  • R is a linker group L or a -L-(VHL ligand moiety) group attached preferably to the phenyl moiety or the aniline amine group
  • R is a linker group L or a -L-(VHL ligand moiety) group attached to the phenyl moiety or the diazole group
  • R is a linker group L or a -L-(VHL ligand moiety) group attached preferably to the phenyl moiety
  • R is a linker group L or a -L-(VHL ligand moiety) group attached to the phenyl moiety or a hydroxyl or ether group on the quinoline moiety;
  • MDM2 inhibitors as used herein include, but are not limited to:
  • Compounds targeting Human BET Bromodomain-containing proteins include, but are not limited to the compounds associated with the targets as described below, where "R” designates a site for linker group L or a -L-(VHL ligand moiety) group attachment.
  • R designates a site for linker group L or a -L-(VHL ligand moiety) group attachment.
  • HDAC Inhibitors include, but are not limited to:
  • Human Lysine Methyltransferase inhibitors include, but are not limited to:
  • Angiogenesis inhibitors include, but are not limited to:
  • Estradiol (derivatized), which may be bound to a linker group L or a -L-(VHL ligand moiety) group as is generally described in Rodriguez-Gonzalez, et al, "Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer," Oncogene (2008) 27, 7201-7211;
  • Estradiol, testosterone (derivatized) and related derivatives including but not limited to DHT and derivatives and analogs thereof, having the structure(s) and binding to a linker group L or a -L-(VHL ligand moiety) group as generally described in Sakamoto, et al, "Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation," Mol Cell Proteomics 2003 Dec; 2(12): 1350-8; and
  • Immunosuppressive compounds include, but are not limited to:
  • Glucocorticoids e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone
  • Glucocorticoids e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone
  • beclomethasone dipropionate derivatized where a linker group or a -L-(VHL ligand moiety) is bound, e.g. to a proprionate
  • Methotrexate (derivatized where a linker group or a-L-(VHL ligand moiety) group can be bound, e.g. to either of the terminal hydroxyls);
  • Ciclosporin (derivatized where a linker group or a-L-(VHL ligand moiety) group can be bound, e.g. at any of the butyl groups);
  • Compounds targeting the aryl hydrocarbon receptor include, but are not limited to:
  • Compounds targeting RAF Receptor include, but are not limited to: [0333] 1. PLX4032
  • RAF inhibitors described in WO 2015/075483 including but not limited to, the compounds having the structure set forth on page 31 of WO 2015/075483, as defined therein, (derivatized such that a linker group L or a -L-(VHL ligand moiety) is attached); and
  • Compounds targeting FKBP include, but are not limited to:
  • R designates a site for a linker group L or a -L-(VHL ligand moiety) group attachment
  • R designates a linker group L or a -L-(VHL ligand moiety) group
  • R designates a linker group L or a -L-(VHL ligand moiety) group
  • R designates a linker group L or a -L-(VHL ligand moiety)
  • ER Estrogen Receptor
  • R designates a site for linker group L or-L-(VHL ligand moiety) group attachment. See, Angew. Chem. Int. Ed. 2011, 50, 9838- 9842, where L is a linker group as otherwise described herein and said VHL ligand moiety is as otherwise described herein such that -L-(VHL ligand moiety) binds the VHL ligand moiety to a protein binding moiety as otherwise described herein.
  • RAS family inhibitors used herein include, but are not limited to:
  • EGFR family inhibitors used herein include, but are not limited to:
  • TKIs EGFR tyrosine kinase inhibitors identified in Jia et al "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors" Nature 2016, 534, 129-132, such as EAI045
  • TKIs EGFR tyrosine kinase inhibitors
  • BRM family inhibitors used herein include, but are not limited to, the BRM tyrosine kinase inhibitors (TKIs) inhibitors identified in Gerstenberger, BS. et al "Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit" J.
  • TKIs BRM tyrosine kinase inhibitors
  • BRG/BRG1 family inhibitors used herein include but are not limited to the BRG/BRG1 inhibitors described in WO 2016/138114A1 (e.g., in Formula (I) of WO 2016/138114A1) (derivatized such that a linker group L or a -L-(VHL ligand moiety) group is attached).
  • USP7 family inhibitors used herein include but are not limited to the USP7 inhibitors as defined in Formula (I) of US Patent Application No. 2016/0185785A1 (derivatized such that a linker group L or a -L-(VHL ligand moiety) groupis attached).
  • target protein is used to describe a protein or polypeptide, which is a target for binding to a compound according to the present disclosure and degradation by ubiquitin ligase hereunder.
  • target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest.
  • binding moieties are linked to VHL ligand moieties through linker groups L.
  • PB moieties may also be small molecule compounds such as those disclosed in US Patent Application No. 2014/0356322 and US Patent Application No. 2016/0045607.
  • Compounds disclosed therein can be classified as Heat Shock Protein 90 (HSP90) inhibitors, Kinase and Phosphatase inhibitors, MDM2 inhibitors, HDAC inhibitors, Human Lysine Methyltransferase Inhibitors, Angiogenesis inhibitors, Immunosuppressive compounds, as well as compounds that bind to: Human BET Bromodomain-containing proteins, the aryl hydrocarbon receptor (AHR), RAF receptor kinase, FKBP, Androgen Receptor (AR), Estrogen receptor (ER), Thyroid Hormone Receptor, HIV Protease, HIV Integrase, HCV Protease, Acyl-protein Thioesterase-1 and -2 (APT1 and APT2).
  • Other specific PB moieties may also be small molecule compounds such as those disclosed in US Patent Application No.
  • Target proteins and/or PB moieties are also described in: Holderfield, et al, "Targeting RAF kinases for cancer therapy: BRAF mutated melanoma and beyond," Nat. Rev. Cancer, 2014, 14, 455-467 (RAF); and Filippakoupoulos, et al, “Targeting bromodomains: epigenetic readers of lysine acetylation,” Nature Reviews Drug Discovery, 2014, 13, 337-356 (BET). 3.
  • the VHL ligand moiety and PB moiety (D) of PROTACs as described herein can be connected with a linker (L).
  • the linker group L is a group comprising one or more covalently connected structural units of A, wherein each A unit is a group coupled to at least one of a VHL ligand moiety, a PB moiety, another A unit, or a combination thereof.
  • an A unit links a VHL ligand moiety, a PB moiety, or a combination thereof directly to another VHL ligand, PB moiety, or combination thereof.
  • an A unit links a VHL ligand moiety, a PB moiety, or a combination thereof indirectly to another VHL ligand moiety, PB moiety, or combination thereof through one or more different A unit(s).
  • one or more covalently connected structural units of A may be coupled to the VHL ligand moiety of the PROTAC of the present disclosure at substituent Y.
  • the linker L may be coupled to Y, D, or combinations thereof.
  • one or more covalently connected structural units of A may be coupled to a PB moiety and also to a VHL ligand of the present disclosure at R 1 , R 2 , or Z, as described herein, to form a PROTAC.
  • q is an integer greater than or equal to 1.
  • q is greater than 2.
  • q is 2.
  • A is a group which is connected to a VHL ligand moiety and a PB moiety.
  • q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.
  • the linker is selected from the group consisting of:
  • the linker is selected from the group consisting of
  • the linker group is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units and 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms.
  • the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.
  • the linker may be asymmetric or symmetrical.
  • the linker group may be any suitable moiety as described herein.
  • the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.
  • the VHL ligand moiety and PB moiety may be covalently linked to the linker group through any group which is appropriate and stable to the chemistry of the linker.
  • the linker is independently covalently bonded to the VHL ligand moiety and the PB moiety preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which groups may be inserted anywhere on the VHL ligand moiety and PB moiety to provide maximum binding of the VHL ligand moiety on the ubiquitin ligase and the PB moiety on the target protein to be degraded.
  • the target protein for degradation may be the ubiquitin ligase itself.
  • the linker may be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, an aryl group or a heterocyclic group on the VHL ligand moiety and/or PB moiety. It is noted that a VHL ligand moiety or a PB moiety may need to be derivatized to make a chemical functional group that is reactive with a chemical functional group on the linker. Alternatively, the linker may need to be derivatized to include a chemical functional group that can react with a functional group found on the VHL ligand moiety and/or PB moiety.
  • the linker L can also be represented by the formula: where Q 1 is a group which links the VHL ligand moiety to Q 2 ; and Q 2 is a group linking Q 1 to the PB moiety.
  • Q 1 is absent (a bond), -(CH 2 )i-0, -(CHR 15 )i-0, - [C(R 15 ) 2 ]i-0, -(CH 2 )i-S, -(CH 2 )i-N-R 15 , -S, -S(O), -S(0) 2 , -OP(0)OR 15 , -Si(R 15 ) 2 , or a (CH 2 ) r Q Q 4 group wherein Q Q 4 forms an amide group, or a urethane group, ester or thioester group, or
  • each U is independently a bond, O, S or N-R 15 ; and each i is independently 0 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.
  • Q is a
  • each V is independently a bond (absent), -(CH 2 )i U C U (CH 2 ) j is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5;
  • k is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5; preferably k is 1, 2, 3, 4, or 5;
  • m' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, l to 10, l to 8, l to 6, 1, 2, 3, 4 or 5;
  • n' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, l to 8, l to 6, 1 , 2, 3, 4 or 5;
  • X 1 is O, S or N-R 15 , preferably O;
  • CON is a connector group (which may be a bond) which connects Q 1 to Q 2 , when present in the linker group.
  • CON is a bond (absent), a heterocycle including a water soluble heterocycle such as a piperazinyl or other group or a group,
  • X 2 is cycloalkyl, heterocyclyl, O, S, NR 12 , S(O), S(0) 2 , -S(0) 2 0, -OS(0) 2 , OP(0)OR 15 , Si(R 15 ) 2 , or OS(0) 2 0;
  • X 3 is O, S, CHR 12 , NR 12 ;
  • R 12 is H or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof;
  • R 15 is as defined above.
  • the linker group is a (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units and 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units.
  • the linker is optionally substituted; i.e., comprises chemical groups interdispersed within or on the PEG linker.
  • the PEG linker is substituted with an alkyl, alkylene, aromatic group, or aryl group, e.g., phenyl, benzyl, or heterocyclyl group, or amino acid side chain and is optionally interdispersed with optionally substituted O, N, S, P, or Si atoms.
  • CON is
  • the linker may be asymmetrical or symmetrical.
  • the VHL ligand moiety and PB moiety may be covalently linked to the linker group through any group which is appropriate and stable to the chemistry of the linker, in preferred aspects, the linker is independently covalently bonded to the VHL ligand moiety and the PB moiety through an amide, ester, thioester, keto group, carbamate (urethane) or ether, each of which groups may be inserted anywhere on the VHL ligand moiety and PB moiety to allow binding of the VHL ligand moiety to the ubiquitin ligase and the PB moiety to the target protein to be degraded.
  • the linker can be designed and connected to VHL ligand moiety and PB moiety to minimize, eliminate, or neutralize any impact its presence might have on the binding of VHL ligand moiety and PB moiety to their respective binding partners.
  • the targeted protein for degradation may be an ubiquitin ligase.
  • the linker may be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, an aryl group, or a heterocyclic group on the VHL ligand moiety and/or PB moiety.
  • the linker is connected to the VHL ligand moiety through substituent Y.
  • the description provides therapeutic or pharmaceutical compositions comprising an effective amount of at least one of the compounds as described herein, including, e.g., at least one VHL ligand, at least one PROTAC, and combinations thereof.
  • Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound according to the present disclosure, and optionally one or more of the compounds otherwise described herein, in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, and optionally an additional bioactive agent, represents a further aspect of the disclosure.
  • the compositions comprise pharmaceutically acceptable salts, in particular, acid or base addition salts of compounds as described herein.
  • the acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds include those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., l, l '-methylene-bis-(2- hydroxy-3 naphthoate)] salt
  • Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.
  • compositions as described herein may in certain embodiments be administered in single or divided unit doses by the oral, parenteral or topical routes.
  • Administration of the compounds may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, by inhalation spray, rectally, vaginally, or via an implanted reservoir, among other routes of administration.
  • Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration.
  • compositions comprising an effective amount of compound according to the present disclosure, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
  • Compounds according to the present disclosure may be administered in immediate release, intermediate release or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but may also be administered in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of compound at an injection site.
  • compositions of VHL ligands and/or PROTACs as described herein can be prepared for parenteral administration with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • a PROTAC having the desired degree of purity is optionally mixed with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation for reconstitution or an aqueous solution.
  • compositions of the present disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations.
  • the compounds of the disclosure can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a pharmaceutical composition comprising a PROTAC or VHL ligand in association with one or more pharmaceutically acceptable excipients.
  • a typical formulation is prepared by mixing the compounds of the disclosure with excipients, such as carriers and/or diluents.
  • excipients such as carriers and/or diluents.
  • Suitable carriers, diluents and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the particular carrier, diluent or other excipient used will depend upon the means and purpose for which the compound is being applied.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are nontoxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
  • Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine,
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the PROTAC or aid in the manufacturing of the pharmaceutical product.
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such 1,3-butanediol.
  • the sterile injectable preparation may also be prepared as a lyophilized powder.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables, as well as natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions as described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions as described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-acceptable transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the compounds may be coated onto a stent which is to be surgically implanted into a patient in order to inhibit or reduce the likelihood of occlusion occurring in the stent in the patient.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • PROTAC and VHL ligand compositions ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
  • compositions comprising a PROTAC or VHL ligand of the present disclosure can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "therapeutically effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to unwanted side effects.
  • the PROTAC can be formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.
  • a patient or subject in need of therapy using compounds according to the present disclosure can be treated by administering to the patient (subject) an effective amount of the compound according to the present disclosure including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known erythopoiesis stimulating agents as otherwise identified herein.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day.
  • One typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • a typical topical dosage will range from 0.01-5% wt/wt in a suitable carrier.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of about 25-250 mg is often convenient.
  • the active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001 -30 mM, preferably about 0.1-30 mM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, poly gly colic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U. S. Pat. No.4,522,81 1 (which is incorporated herein by reference in its entirety).
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphati
  • pharmaceutically acceptable salt is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds described herein which are presented to increase the solubility of the compound in the gastric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present disclosure.
  • pharmaceutically acceptable derivative is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide other prodrug group), which, upon administration to a patient, provides directly or indirectly the present compound or an active metabolite of the present compound.
  • the subject matter further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally or by any other desired route.
  • PROTACs disclosed herein may be used to treat various diseases or disorders.
  • exemplary hyperproliferative disorders include benign or malignant solid tumors and hematological disorders such as leukemia and lymphoid malignancies.
  • Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders.
  • the disease or disorder to be treated is a hyperproliferative disease such as cancer.
  • cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
  • lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
  • Autoimmune diseases for which the PROTAC may be used in treatment include rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as systemic lupus erythematosus (SLE) and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (such as, for example, ANCA-associated vasculitis, including Churg-Strauss vas
  • More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.
  • Other disease states or disorders which may be treated using compounds or compositions according to the present disclosure include, for example, asthma, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease (PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, and Turner syndrome.
  • PDD1 or 4 Polycystic kidney disease
  • Further diseases or disorders which may be treated by compounds or compositions according to the present disclosure include Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.
  • Alzheimer's disease Amyotrophic lateral
  • Still additional diseases or disorders which can be treated by compounds or compositions according to the present disclosure include acemloplasminemia, Achondrogenesis type H, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Adenomatous Polyposis Coli, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alkaptonuric ochronosis, alpha 1- antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, Amelogenesis imperfecta, Anders on-Fabry disease, Anemia, Angiokeratoma Corporis Diffusum, Angiomatosis retinae (von Hippel-Lindau disease) Apert syndrome, Arachnodactyly (Mar
  • cancer is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendroglio
  • Additional cancers which may be treated using compounds according to the present disclosure include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), Tlineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre B ALL, Pre- B Lymphomas, Large B ⁇ cell Lymphoma, Burkitts Lymphoma, B ⁇ cell ALL Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • T-ALL T-lineage Acute lymphoblastic Leukemia
  • T-LL Tlineage lymphoblastic Lymphoma
  • Peripheral T-cell lymphoma Peripheral T-cell lymphoma
  • Adult T-cell Leukemia Pre B ALL, Pre- B Lymphomas, Large B ⁇ cell Lymphoma, Burkitts Lymphoma
  • B ⁇ cell ALL Philadelphia chromosome positive ALL Philadelphia chromosome positive CML.
  • the present disclosure is directed to a method of treating a disease or disorder in a human in need thereof, comprising administering to the human an effective amount of a compound of the present disclosure (e.g., a PROTAC of Formula (I), (la), (II), or (Ila)), or a salt (e.g., a pharmaceutically acceptable salt) thereof, or a pharmaceutical composition of the present disclosure that comprises said PROTAC.
  • a compound of the present disclosure e.g., a PROTAC of Formula (I), (la), (II), or (Ila)
  • a salt e.g., a pharmaceutically acceptable salt
  • a PROTAC of the present disclosure is used in a method of treating solid tumor, e.g., ovarian.
  • a PROTAC of the present disclosure is used in a method of treating hematological malignancies such as non-Hodgkin's lymphoma (NHL), diffuse large hematopoietic lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia (AML), and myeloid cell leukemia (MCL), and including B-cell related cancers and proliferative disorders.
  • NHL non-Hodgkin's lymphoma
  • diffuse large hematopoietic lymphoma diffuse large hematopoietic lymphoma
  • follicular lymphoma mantle cell lymphoma
  • chronic lymphocytic leukemia multiple myeloma
  • AML acute myeloid leukemia
  • MCL myeloid cell leukemia
  • a PROTAC of the present disclosure is used in a method of treating ovarian, breast and pancreatic cancers.
  • the cancer may be associated with the expression or activity of a MUC16/CA125/0772P polypeptide. See, e.g., WO 2007/001851; US 7,989,595; US 8,449,883; US 7,723,485; Chen et al (2007) Cancer Res. 67(10): 4924-4932; Junutula, et al, (2008) Nature Biotech., 26(8):925-932.
  • a PROTAC of the present disclosure is used in a method of treating cancer, e.g., breast or gastric cancer, more specifically HER2 positive breast or gastric cancer, wherein the method comprises administering such PROTAC to a patient in need of such treatment.
  • cancer e.g., breast or gastric cancer, more specifically HER2 positive breast or gastric cancer
  • a PROTAC of the present disclosure may be administered by any route appropriate to the condition to be treated.
  • the PROTAC or VHL will typically be administered parenterally, i.e. infusion, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
  • a PROTAC can be used either alone or in combination with other agents in a therapy.
  • a PROTAC may be co-administered with at least one additional therapeutic agent.
  • Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the PROTAC can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent and/or adjuvant.
  • a PROTAC can also be used in combination with radiation therapy.
  • coadministration shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time.
  • compounds according to the present disclosure may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided that effective concentrations of coadministered compounds or compositions are found in the subject at a given time.
  • the description provides combination therapies comprising an effective amount of a compound as described herein in combination with an additional bioactive agent.
  • bioactive agent is used to describe an agent, other than a compound as described herein, which is used in combination with the present compounds as an agent with biological activity to assist in effecting an intended therapy, inhibition and/or prevention/prophylaxis for which the present compounds are used.
  • Preferred bioactive agents for use herein include those agents which have pharmacological activity similar to that for which the present compounds are used or administered and include for example, anti-cancer agents, antiviral agents, especially including anti-HIV agents and anti-HCV agents, antimicrobial agents, antifungal agents, etc.
  • the compound as described herein, the additional bioactive agent or both are present in an effective amount or, in certain embodiments, a synergistically effective amount.
  • additional anti-cancer agent is used to describe an anti-cancer agent, which may be combined with compounds according to the present disclosure to treat cancer.
  • these agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN- 101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bel -2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cd
  • anti-HIV agent or “additional anti-HIV agent” includes, for example, nucleoside reverse transcriptase inhibitors (NRTI), other non-nucloeoside reverse transcriptase inhibitors (i.e., those which are not representative of the present disclosure), protease inhibitors, fusion inhibitors, among others, exemplary compounds of which may include, for example, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddl (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (NRTI), other non-n
  • NNRTI's i.e., other than the NNRTI's according to the present disclosure
  • NNRTI's may be selected from the group consisting of nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro- 3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide), etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl 3',3'-
  • a PROTAC or VHL ligand can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.
  • the appropriate dosage of a PROTAC (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of PROTAC, the severity and course of the disease, whether the PROTAC is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the PROTAC, and the discretion of the attending physician.
  • the PROTAC is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 10 ng/kg to 300 mg/kg (e.g.
  • 0.1 mg/kg - 10 mg/kg) of a PROTAC can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
  • One typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment would generally be sustained until a desired suppression of disease symptoms occurs.
  • One exemplary dosage of a PROTAC would be in the range from about 0.05 mg/kg to about 10 mg/kg.
  • one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient.
  • Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the patient receives from about two to about twenty, or e.g. about six doses).
  • An initial higher loading dose, followed by one or more lower doses may be administered.
  • other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • present disclosure may be used to treat a number of disease states and/or disorders, including any disease state and/or disorder in which proteins are dysregulated and where a patient would benefit from the degradation of proteins.
  • the present disclosure relates to a method for treating a disease state by degrading a protein or polypeptide through which a disease or disorder is modulated comprising administering to said patient or subject an effective amount of at least one compound as described hereinabove, optionally in combination with an additional bioactive agent.
  • the method according to the present disclosure may be used to treat a large number of diseases or disorders including cancer, by virtue of the administration of effective amounts of at least one compound described herein.
  • the description provides a method of ubiquitinating/degrading a target protein in a cell.
  • the method comprises administering a bifunctional compound or a pharmaceutical composition comprising a bifunctional compound that comprises a VHL ligand moiety and a protein binding moiety, preferably linked through a linker moiety, as otherwise described herein, wherein the VHL ligand moiety is coupled to the protein binding moiety and wherein the VHL ligand moiety recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably a VHL E3 ubiquitin ligase) and the protein binding moiety recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation/inhibition of the effects of the target protein and the control of protein levels.
  • the control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target
  • the present disclosure is directed to a method of degrading a target protein in a cell comprising exposing the cell to a composition comprising an effective amount of a compound Formula (I), (II), (la), or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein the compound effectuates the degradation of the target protein.
  • a composition comprising an effective amount of a compound Formula (I), (II), (la), or (Ila), or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein the compound effectuates the degradation of the target protein.
  • the description provides a method of treating or preventing in a patient in need thereof a disease or disorder modulated through a protein where the degradation of that protein will produce a therapeutic effect in that patient, the method comprising administering to a patient in need an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.
  • the disease state or condition may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacteria, fungus, protozoa or other microbe or may be a disease state, which is caused by overexpression of a protein, which leads to a disease state and/or condition.
  • kits containing materials useful for the treatment of the diseases and disorders described above.
  • the kit comprises a container comprising a PROTAC.
  • the kit may further comprise a label or package insert, on or associated with the container.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
  • a "vial” is a container suitable for holding a liquid or lyophilized preparation.
  • the vial is a single-use vial, e.g. a 20-cc single-use vial with a stopper.
  • the container may be formed from a variety of materials such as glass or plastic.
  • the container may hold a PROTAC or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is a PROTAC of the present disclosure.
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.
  • the label or package insert may indicate that the patient to be treated is one having a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotraumatic disease or event.
  • the label or package inserts indicates that the composition comprising a PROTAC can be used to treat a disorder resulting from abnormal cell growth.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as phosphate-buffered saline, Ringer's solution and dextrose solution.
  • dextrose solution such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dext
  • the kit may further comprise directions for the administration of the PROTAC and, if present, the second pharmaceutical formulation.
  • the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
  • kits are suitable for the delivery of solid oral forms of a PROTAC, such as tablets or capsules.
  • a PROTAC such as tablets or capsules.
  • Such a kit preferably includes a number of unit dosages.
  • Such kits can include a card having the dosages oriented in the order of their intended use.
  • An example of such a kit is a "blister pack".
  • Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • a kit may comprise (a) a first container with a PROTAC contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound with anti-hyperproliferative activity.
  • the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet; however, the separate compositions may also be contained within a single, undivided container.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

Abstract

La présente invention concerne des composés bifonctionnels, qui peuvent être utilisés en tant que modulateurs de l'ubiquitination ciblée. En particulier, la présente invention concerne des composés qui contiennent sur une extrémité un fragment de ligand VHL, qui se lie à la ligase d'ubiquitine VHL E3, et, sur l'autre extrémité, une fraction qui se lie à une protéine cible de telle sorte que la dégradation de protéine/polypeptide cible est effectuée. L'invention concerne également des ligands VHL.
PCT/US2018/057139 2017-10-24 2018-10-23 Composés de (4-hydroxypyrrolidin-2-yl)-hydroxamate et leurs procédés d'utilisation WO2019084030A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CNPCT/CN2017/107447 2017-10-24
CN2017107447 2017-10-24
CN2018105403 2018-09-13
CNPCT/CN2018/105403 2018-09-13

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