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WO2024197219A1 - Agents de dégradation de mdm2 et leurs utilisations - Google Patents

Agents de dégradation de mdm2 et leurs utilisations Download PDF

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Publication number
WO2024197219A1
WO2024197219A1 PCT/US2024/021049 US2024021049W WO2024197219A1 WO 2024197219 A1 WO2024197219 A1 WO 2024197219A1 US 2024021049 W US2024021049 W US 2024021049W WO 2024197219 A1 WO2024197219 A1 WO 2024197219A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
composition
compound
impurity
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English (en)
Inventor
Jianfeng QI
Christopher P. Hencken
John Traverse
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Kymera Therapeutics Inc
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Kymera Therapeutics Inc
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Publication of WO2024197219A1 publication Critical patent/WO2024197219A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention provides compounds and methods useful for the modulation of murine double minute 2 (MDM2) protein via ubiquitination and/or degradation by compounds according to the present invention.
  • MDM2 murine double minute 2
  • the invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • Ubiquitin-Proteasome Pathway or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins.
  • UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases.
  • the covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • the murine double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades the tumor-suppressor p53.
  • Reversible small molecule inhibitors (SMIs) of the MDM2/p53 interaction have been developed to stabilize p53 and to induce apoptosis in wildtype p53 tumors.
  • MDM2 SMIs induce a p53/MDM2 feedback loop, resulting in upregulation of MDM2 protein levels and p53 pathway inhibition thus drastically limiting their biological activity and clinical application.
  • MDM2 targeted protein degradation suppresses p53-dependent MDM2 protein feedback upregulation and is therefore expected to lead to a superior response compared to MDM2 SMIs.
  • MDM2 degraders including (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N- (( 1 R,4R)-4-(4-( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl-2-oxo-2,3 -dihydro- 1 H-benzo[d] imidazol-5 - yl)piperidine-l-carbonyl)cyclohexyl)-2"-oxodispiro[cyclohexane-l,2'-pyrrolidine-3',3"-indoline]-5'- carboxamide, have been described previously, for example, in WO 2021/188948, the contents of which are incorporated herein by reference in their entireties.
  • the present invention addresses the need for new compositions of MDM2 degraders and provides additional advantages.
  • 3',3"-indoline]-5'-carboxamide (compound 1-1 herein) or a pharmaceutically acceptable salt thereof may contain a number of impurities.
  • the present invention provides a composition comprising compound 1-1 and one or more impurity compounds selected from the group consisting of:
  • a solid cancer or hematological malignancy is acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt lymphoma/leukemia, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • LGL-L large granular lymphocytic leukemia
  • AML acute myeloid leuk
  • impurity profde of an active pharmaceutical agent (“API” or “drug substance”) is an important aspect of any pharmaceutical drug product.
  • API active pharmaceutical agent
  • drug substance drug substance
  • compositions comprising compound I- 1:
  • impurity compounds i.e., impurities
  • Compound 1-1 is a potent and highly selective heterobifunctional small molecule therapeutic targeting MDM2 and the E3 ligase CRBN to mediate the selective degradation of MDM2 via the ubiquitin- proteasome system.
  • the present invention provides methods for treating a solid cancer or hematological malignancy in a patient comprising administering to the patient a pharmaceutical composition comprising compound 1-1 as described herein.
  • the composition comprises compound 1-1, and one or more impurities selected from the group consisting of 1-2, 1-3, and I- 4, or a pharmaceutically acceptable salt thereof, as described herein.
  • phannaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Phannaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Phannaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N fC’i ialkyl) i salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • the terms “about” or “approximately” have the meaning of within 20% of a given value or range.
  • the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • the temr “patient” or “subject” means a mammal, preferably a human.
  • a “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, condition, or disorder, to treat, diagnose, prevent, and/or delay the onset of the disease, condition, or disorder.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, condition, or disorder is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, condition, or disorder.
  • a “therapeutically effective amount” is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms associated with autoimmune/autoinflammatory disease in a patient.
  • treat refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder.
  • treatment refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the tenn “treating” includes preventing relapse or recurrence of a disease or disorder.
  • unit dosage form refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. Hie specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of tire disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • an area percent of the UPLC, or an area percentage UPLC, of compound 1-1 refers to the area of the compound I- 1 peak(s) relative to the total area of the compound 1-1 and impurity compounds peaks in the composition in a UPLC chromatogram.
  • an area percent of the UPLC, or an area percentage UPLC, of an impurity compound refers to the area of the impurity compound peak(s) relative to the total area of the compound 1-1 and impurity compounds peaks in the composition in a UPLC chromatogram.
  • an area percent of the UPLC, or an area percentage UPLC, of total impurity compounds refers to the area of all impurity compounds peak(s) relative to the total area of the compound 1-1 and impurity compounds peaks in the composition in a UPLC chromatogram.
  • an area percentage is relative to the area of compound 1-1 in a UPLC chromatogram.
  • a UPLC method is as described in the examples, e.g., Column: InfmityLab Poroshell 120 EC-C18, 2.1x150 mm. 1.9 pm at 25 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in CAN; Detection: 225 nm; Gradient: 10% B to 28 min: 95% B to 31 min; 10% B to 36 min; and Flow rate: 0.4 mL/min.
  • Tire tenn “weight percent” or “wt%” as used herein refers to the weight percentage of a component calculated based on the non-salt form.
  • a weight percentage of compound 1-1 refers to the weight percent of compound 1-1 relative to the total weight of a composition.
  • a weight percentage of an impurity, or total organic impurities refers to the weight percent of the impurity, or total organic impurities, relative to the total weight of a composition.
  • a weight percentage of an impurity, or total organic impurities refers to the weight percent of the impurity, or total organic impurities, relative to the weight of compound 1-1 in a composition.
  • the present invention provides an impurity compound, which is any one of the following:
  • the present invention provides compound 1-3: , or a pharmaceutically acceptable salt thereof.
  • tire present invention provides compound 1-4: pharmaceutically acceptable salt thereof.
  • the present invention provides a composition
  • a composition comprising compound 1-1: or a pharmaceutically acceptable salt thereof, and one or more impurity compounds selected from the group consisting of:
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, and two impurity compounds selected from the group consisting of 1-2, 1-3, and I- 4, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and each of impurity compounds 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compounds 1-2 and 1-3, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compounds 1-3 and 1-4, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, and impurity compounds 1-2 and 1-4, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compound 1-2, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compound 1-3, or a pharmaceutically acceptable salt thereof.
  • the composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, and impurity compound 1-4. or a pharmaceutically acceptable salt thereof.
  • a composition of the present invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, in an amount of at least about 90, 90.5, 91, 91.5, 92, 92.5, 93,
  • a composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, in an amount of at least about 90 wt% of the total weight of the composition. In some embodiments, a composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, in an amount of at least about 92 wt% of the total weight of the composition.
  • a composition of the present invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98,
  • a composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, in an amount of at least about 97 area percent UPLC. In some embodiments, a composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, in an amount of at least about 98 area percent UPLC. In some embodiments, a UPLC method is as described in the examples. [0043] In some embodiments, a composition comprising compound 1-1, or a pharmaceutically acceptable salt thereof, contains an amount of impurities no more than about 5.0, 4.0, 3.0, 2.0, 1.9, 1.8.
  • the amount of total organic impurities is no more than about 3.0 wt% of the total weight of the composition.
  • the amount of total organic impurities is about 0.05-3.0, 0.05-2.9, 0.05-2.8, 0.05-2.7, 0.05-2.6, 0.05-2.5, 0.05-2.4, 0.05-2.3, 0.05-2.2, 0.05-2.1, 0.05-2.0, 0.1-3.0, 0.15-3.0, 0.2-3.0, 0.25-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, or 1.0-3.0 wt% ofthc total w eight of the composition.
  • the amount of total organic impurities is no more than about 2.0 wt% of the total weight of the composition. In some embodiments, the amount of total organic impurities is no more than about 1.0 wt% of the total weight of the composition.
  • a composition comprising compound 1-1, or a pharmaceutically acceptable salt thereof, the amount of total organic impurities is no more than about 5.0, 4.0, 3.0, 2.0, 1.9,
  • the amount of total organic impurities is no more than about 5.0 area percent UPLC. In some embodiments, the amount of total organic impurities is about 2.0- 5.0, 2.0-4.5, 2.0-4.0, 2.0-3.8, 2.0-3.6, 2.0-3.5, 2.0-3.2, 2.0-3.0, 2.0-2.9, 2.0-2.8, 2.0-2.7, 2.0-2.6, 2.0-2.5, 2.0-2.4, 2.0-2.3, 2.0-2.2, or 2.0-2. 1 area percent UPLC.
  • the amount of total organic impurities is no more than about 3.0 area percent UPLC. hr some embodiments, the amount of total organic impurities is about 0.05-3.0, 0.05-2.9. 0.05-2.8, 0.05-2.7, 0.05-2.6, 0.05-2.5, 0.05-2.4, 0.05-2.3, 0.05-2.2, 0.05-2.1, 0.05-2.0, 0. 1-3.0, 0.15-3.0, 0.2-3.0, 0.25-3.0, 0.3-3.0. 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0. 0.8-3.0, 0.9-3.0, or 1.0-3.0 area percent UPLC.
  • a UPLC method is as described in the examples.
  • total organic impurities comprise one or more compounds selected from 1-2, 1-3, and 1-4. In some embodiments, total organic impurities comprises compound 1-2. In some embodiments, total organic impurities comprise 1-3 and 1-4.
  • each organic impurity is, independently, no more than about 3.0. 2.9,
  • each of organic impurities 1-2, 1-3, and 1-4 is, independently, no more than about 3.0 area percent UPLC. In some embodiments, each of organic impurities 1-2, 1-3. and 1-4 is, independently, no more than about 0.4 area percent UPLC. In some embodiments, an organic impurity selected from 1-2.
  • a UPLC method is as described in the examples.
  • the amount of compound 1-2, or a pharmaceutically acceptable salt thereof is about 0.05-2.0, 0. 1-2.0, or 0.5-2.0 area percent UPLC relative to the total area of the UPLC chromatogram. In some embodiments, the amount of compound 1-2, or a pharmaceutically acceptable salt thereof, is about 0.1, 0.5, 1.0, or 1.5 area percent UPLC. In some embodiments, the amount of compound 1-2, or a pharmaceutically acceptable salt thereof, is no more than about 1.0 area percent UPLC. In some embodiments, the amount of compound 1-2, or a pharmaceutically acceptable salt thereof, is about 0.5-1.0 or 1.0- 1.5 area percent UPLC.
  • the amount of compound 1-2, or a pharmaceutically acceptable salt thereof is no more than about 0.5 area percent UPLC.
  • compound I- 2 is absent (as determined by UPLC) from the composition.
  • a UPLC method is as described in the examples.
  • the amount of compound 1-3 and 1-4, or a pharmaceutically acceptable salt thereof is about 0.01-0.5, 0.02-0.2, or 0.03-1.0 area percent UPLC in combination relative to the total area of the UPLC chromatogram. In some embodiments, the amount of compound 1-3 and 1-4, or a pharmaceutically acceptable salt thereof, is 0.01, 0.05, 0.07. or 0.1 area percent UPLC in combination. In some embodiments, the amount of compound 1-3 and 1-4, or a pharmaceutically acceptable salt thereof, is no more than about 1.0 area percent UPLC in combination.
  • the amount of compound 1-3 and 1-4, or a pharmaceutically acceptable salt thereof is about 0.01-0.1 or 0.05-0.1 area percent UPLC in combination. In some embodiments, the amount of compound 1-3 and 1-4, or a pharmaceutically acceptable salt thereof, is no more than about 0. 1 area percent UPLC. In some embodiments, compound I-
  • UPLC UPLC
  • a composition comprises a residual solvent in an amount of no more than about 5000, 4000, 3000, 2000, 1000, 500, or 100 ppm.
  • a residual solvent is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 ppm.
  • a residual solvent is no more than about 100 ppm.
  • residual solvent content is measured by capillary GC.
  • a composition comprises residual solvent tert-butyl methyl ether in an amount of no more than about 5000 ppm. In some embodiments, residual solvent tert-butyl methyl ether is no more than about 4000, 3000, 2000, 1000, 500, or 100 ppm. In some embodiments, residual solvent tert-butyl methyl ether is no more than about 100 ppm. In some embodiments, residual solvent tert-butyl methyl ether is about 10-100, 50-200, 100-300, 150-400. 200-500, 250-600, 300-700, 100-1000, 500-2000, 1000-3000, 1500-4000, or 2000-5000 ppm. In some embodiments, residual solvent tert-butyl methyl ether is absent (as determined by GC) from the composition.
  • a composition comprises residual solvent ethyl acetate in an amount of no more than about 5000 ppm. In some embodiments, residual solvent ethyl acetate is no more than about 4000, 3000, 2000, 1000, 500, or 100 ppm. In some embodiments, residual solvent ethyl acetate is no more than about 100 ppm. In some embodiments, residual solvent ethyl acetate is about 10-100, 50-200, 100- 300. 150-400. 200-500. 250-600. 300-700. 100-1000, 500-2000, 1000-3000, 1500-4000. or 2000-5000 ppm. In some embodiments, residual solvent ethyl acetate is absent (as determined by GC) from the composition.
  • a composition comprises residual solvent isopropyl acetate in an amount of no more than about 5000 ppm.
  • residual solvent isopropyl acetate is no more than about 4000, 3000, 2000, 1000, 500, or 100 ppm.
  • residual solvent isopropyl acetate is no more than about 100 ppm.
  • residual solvent isopropyl acetate is about 10-100, 50-200, 100-300, 150-400, 200-500, 250-600, 300-700, 100-1000, 500-2000, 1000-3000, 1500-4000, or 2000-5000 ppm.
  • residual solvent isopropyl acetate is absent (as determined by GC) from tire composition.
  • a composition comprises residual solvent 2-methyltetrahydrofuran in an amount of no more than about 5000 ppm.
  • residual solvent 2- methyltetrahydrofliran is no more than about 4000, 3000, 2000, 1000, 500, or 100 ppm.
  • residual solvent 2-methyltetrahydrofuran is no more than about 100 ppm.
  • residual solvent 2-methyltetrahydrofuran is about 10-100, 50-200, 100-300, 150-400, 200- 500, 250-600, 300-700, 100-1000. 500-2000, 1000-3000, 1500-4000, or 2000-5000 ppm.
  • residual solvent 2-methyltetrahydrofuran is absent (as detennined by GC) from the composition.
  • a composition comprises residual solvent ethanol in an amount of no more than about 5 wt%. In some embodiments, residual solvent ethanol is no more than about 4, 3, 2, 1, or 0.5 wt%. In some embodiments, residual solvent ethanol is no more than about 2 wt%. In some embodiments, residual solvent ethanol is about 0.1-1, 0.5-2, 1-3, 1.5-4, or 2-5 wt%. In some embodiments, residual solvent ethanol is absent (as determined by GC) from the composition.
  • a composition comprises residual solvent acetonitrile in an amount of no more than about 5000 ppm. In some embodiments, residual solvent acetonitrile is no more than about 4000, 3000, 2000, 1000, 500, or 100 ppm. In some embodiments, residual solvent acetonitrile is no more than about 100 ppm. In some embodiments, residual solvent acetonitrile is about 10-100, 50-200, 100-300, 150-400, 200-500. 250-600, 300-700, 100-1000, 500-2000, 1000-3000, 1500-4000, or 2000-5000 ppm. In some embodiments, residual solvent acetonitrile is absent (as determined by GC) from the composition.
  • a composition comprises residual solvent tetrahydrofuran in an amount of no more than about 5000 ppm. In some embodiments, residual solvent tetrahydrofuran is no more than about 4000, 3000, 2000, 1000, or 500 ppm. In some embodiments, residual solvent tetrahydrofuran is no more than about 100 ppm. In some embodiments, residual solvent tetrahydrofuran is about 10-100, 50- 200. 100-300, 150-400, 200-500, 250-600. 300-700, 100-1000, 500-2000, 1000-3000, 1500-4000, or 2000- 5000 ppm. In some embodiments, residual solvent tetrahydrofuran is absent (as determined by GC) from the composition.
  • the present invention provides any compound described above and disclosed herein in isolated form.
  • isolated means that a compound is provided in a form that is separated from other components that might be present in that compound’s usual environment.
  • an isolated compound is in solid form.
  • an isolated compound is at least about 50% pure as determined by a suitable UPLC method.
  • an isolated compound is at least about 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, 99.99%, or 99.999% pure as determined by a suitable UPLC method. Percent purity may be measured by weight percent of the desired compound (% w/w), by area % relative to the total area of the UPLC chromatogram, or by other methods known in the art.
  • a composition is a liquid formulation.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, in a liquid formulation is in an amount of at least about 97 area percent of the UPLC relative to the total area of the compound 1-1 and impurity compounds peaks in the UPLC chromatogram.
  • the amount of an organic impurity, as described above, in a liquid formulation is no more than about 0.7% area percent of the UPLC relative to the total area of the compound 1-1 and impurity compounds peaks in the UPLC chromatogram.
  • a UPLC method is as described in the examples.
  • the tenn “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or charactcrizablc by standard analytical techniques described herein or well known to the skilled artisan. 5. Analysis, Formulation, and Administration
  • Tire present invention also provides methods for determining an impurity, comprising injecting a reference compound (e.g., compound 1-2, 1-3, or 1-4) or a phannaceutically acceptable salt thereof, into an UPLC column under a set of conditions to obtain a first UPLC chromatogram, wherein the amount and/or chemical identity of the compound present in the reference solution is known; injecting a sample solution comprising compound 1-1. or a pharmaceutically acceptable salt thereof, into the UPLC column under said set of conditions to obtain a second UPLC chromatogram; and determining the presence and/or the amount of the compound in the sample solution.
  • the reference solution is injected multiple times.
  • Tire present invention also provides methods for determining an impurity in a material consisting essentially of compound 1-1, or a pharmaceutically acceptable salt thereof, comprising injecting, in a single or series of injections, a solution in which the material is dissolved into an UPLC column and obtaining an UPLC chromatogram; determining the amount in the material of a compound having a known structure (e.g., compound 1-2, 1-3, or 1-4) or a pharmaceutically acceptable salt thereof; and documenting in a written form the chemical identity of the compound and the amount of the compound as an impurity in the material.
  • a compound having a known structure e.g., compound 1-2, 1-3, or 1-4
  • the present invention provides methods for determining the presence and/or amount of compound II-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof.
  • compound II-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof may be formed as an impurity during the synthesis of compound 1-1.
  • impurity may refer to degradants which arise during storage of compound 1-1 and/or by-products fonned during the chemical manufacturing of compound 1-1.
  • Tire reference solution may be formed by dissolving a sample (e.g., solid sample) of a compound of Formula 1-1, or a pharmaceutically acceptable salt thereof, in a first solvent, and the sample solution may be fomred by dissolving a solid sample in a second solvent.
  • the reference solution may contain an additional compound(s). wherein the amount and/or identity of the additional compound(s) is also known.
  • the sample e.g., sample solution
  • the invention may encompass other samples suspected of containing compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof.
  • the amount of a compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in the sample solution may be determined by comparing the area of peaks in the first UPLC chromatogram with the area of peaks in the second UPLC chromatogram, and calculating from these the content of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in the sample solution.
  • the present invention provides methods for determining an impurity in a material consisting essentially of compound 1-1, wherein a sample solution containing the material and spiked with a reference compound having a known chemical structure of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, as described herein, is injected into an UPLC column and an UPLC chromatogram is obtained to determine the presence and/or the amount of the compound in the material.
  • Methods of the invention may further comprise documenting in a written form the chemical identity of tire compound and the amount of the compound as an impurity in the material.
  • the present invention provides methods for determining an impurity in a material consisting essentially of compound 1-1. wherein a solution in which the material is dissolved is injected into an UPLC column and an UPLC chromatogram is obtained to determine the amount in the material of a compound known to have the structure of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, as described herein. The chemical identity of the compound and the amount of the compound as an impurity in the material may then be documented.
  • Tire amount in the material of the compound may be determined by (i) identifying a peak on the chromatogram that corresponds to a peak on a control chromatogram, (ii) identifying a peak on the chromatogram that corresponds to a relative retention time of a compound known to have the structure of compound 1-2, 1-3, or 1-4, or pharmaceutically acceptable salt thereof, and/or (iii) identifying a peak on the chromatogram that corresponds to a known amount of a spike of the compound known to have the structure of compound 1-2, 1-3, or 1-4, or a phannaceutically acceptable salt thereof.
  • Some embodiments of the invention may be useful in determining the amount and/or presence of compound 1-2. 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in a sample comprising compound 1-1.
  • the sample may be a sample of freshly manufactured material or the sample may be one stored for a given period of time.
  • a sample of compound 1-1 may be stored and periodically analyzed using methods described herein to determine the presence and/or amount of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in the sample which may have been fonned by, for example, degradation of compound 1-1.
  • the sample may be placed under stressed conditions, i.e., conditions to intentionally promote degradation of compound 1-1 such as elevated temperatures and/or elevated humidity, wherein the sample is periodically analyzed using methods described herein to determine the presence and/or amount of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in the sample.
  • stressed conditions i.e., conditions to intentionally promote degradation of compound 1-1 such as elevated temperatures and/or elevated humidity
  • the sample is periodically analyzed using methods described herein to determine the presence and/or amount of compound 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, in the sample.
  • the invention provides a phannaceutical composition
  • a phannaceutical composition comprising a provided composition as described in detail herein, infra, and a phannaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and two impurity compounds selected from the group consisting of 1-2, 1-3, or 1-4, or a pharmaceutically acceptable salt thereof, and a phannaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and each of impurity compounds 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compounds 1-2 and 1-3, or a phannaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compounds 1-3 and 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, and impurity compounds 1-2 and 1-4, or a phannaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compound 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a phannaceutically acceptable salt thereof, and impurity compound 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and impurity compound 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the invention provides a liquid formulation or unit dosage form comprising compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2. 1-3. or 1-4, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient (e g., a buffer) and/or carrier (e.g., water).
  • a pharmaceutically acceptable excipient e g., a buffer
  • carrier e.g., water
  • the amount of compound 1-1 in liquid formulations or unit dosage forms of this invention is such that it is effective to measurably degrade and/or inhibit MDM2 protein, or a mutant thereof, in a patient.
  • a liquid formulation or unit dosage form of this invention is formulated for administration to a patient in need of such composition.
  • liquid formulation or unit dosage form of this invention is formulated for parenteral (e.g., intravenous) administration to a patient.
  • Tire liquid formulation or unit dosage form of the present invention may be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) as the liquid fonnulation or in unit dosage forms or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • the the liquid formulation or unit dosage form of the present invention is administered by intravenous transfusion.
  • the liquid formulations or unit dosage form comprising compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to buffers, surfactants, solubilizing agents, dispersants, emulsifiers, viscosity modifying agents, and combination thereof.
  • a liquid fonnulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 0.05-5% w/w of the total weight of the formulation or unit dosage form.
  • a liquid fonnulation or unit dosage fonn of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2. 1-3, or 1-4. or phannaceutically acceptable salts thereof at a concentration of about 0.05-0.5%. about 0.
  • a liquid formulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.05%, about 1.10%, about 1.15%, about 1.20%, about 1.25%, about 1.30%, about 1.35%, about 1.40%, about 1.45%, or about 1.50% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 1-20 mg/mL.
  • a liquid formulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 1-5 mg/mL, about 1-10 mg/mL, about 6-14 mg/mL, about 6.5-13.5 mg/mL, about 7-13 mg/mL, about 7.5-12.5 mg/mL, about 8-12 mg/mL, about 8.5-11.5 mg/mL, about 9-11 mg/mL, or about 9.5-10.5 mg/mL.
  • a liquid formulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 8 mg/mL, about 8.5 mg/mL, about 9 mg/mL, about 9.5 mg/mL, about 10 mg/mL, about 10.5 mg/mL, about 11 mg/mL, about 11.5 mg/mL, or about 12 mg/mL.
  • the liquid fonnulations or unit dose forms are packaged in solutions with one or more aqueous buffer.
  • the liquid formulations or unit dosage forms are packaged in solutions with sterile isotonic aqueous buffers.
  • the liquid formulations or unit dosage forms are buffered at about pH 5-8 for parenteral administration upon dilution. Suitable buffers or buffering agents include, but are not limited to, phosphate buffers, citrate buffers, acetate buffers, histidine buffers, or succinate buffers.
  • the buffer is one or more phosphate buffer.
  • the liquid fonnulation or unit dosage form may also include a solubilizing agent.
  • the components of the formulation can be either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder (which can be reconstituted before use with a carrier such as saline) or concentrated solution in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent. If the composition is to be administered by infusion, it can be dispensed with an infusion bottle or bag containing sterile pharmaceutical grade water or saline. Where tire formulation is administered by injection, an ampoule of sterile water or saline can be provided so that the ingredients may be mixed prior to injection.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, com oil, sesame oil, etc.), and combinations thereof.
  • polyols e.g., glycerol, propylene glycol, and liquid polyethylene glycol
  • oils such as vegetable oils (e.g., peanut oil, com oil, sesame oil, etc.)
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
  • isotonic agents for example, sugars or sodium chloride.
  • the carrier is ethanol, a polyol, or a mixture of ethanol and a polyol.
  • the ethanol is 200 proof (i.e., food grade) ethanol.
  • the polyol is a liquid polyethylene glycol, such as polyethylene glycol 400.
  • a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 60-90% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 60-80%, about 70-85%, or about 75-90% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises at first carrier (e.g., a polyol) at a concentration of about 60-80% of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises a second carrier (e.g., ethanol) at a concentration of about 5-20% of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises a first carrier and a second carrier in a ratio of about 1: 10 to about 10: 1.
  • the first carrier is apolyol (e.g., polyethylene glycol 400) and the second carrier is ethanol in a ratio of about 5: 1 to about 9: 1, for example about 6: 1, about 7: 1, or about 8: 1.
  • a liquid formulation or unit dosage form of the invention comprises a carrier (e.g.. ethanol and a polyol) at a concentration of about 400-1500 mg/mL
  • a liquid formulation or unit dosage form of the invention comprises compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more impurity compound selected from the group consisting of 1-2, 1-3, or 1-4, or pharmaceutically acceptable salts thereof at a concentration of about 400-600 mg/mL, about 500- 700 mg/mL, about 600-800 mg/mL, about 700-900 mg/mL, about 800-1000 mg/mL, about 900-1100 mg/mL, about 1000-1200 mg/mL. about 1100-1300 mg/mL.
  • a liquid formulation or unit dosage form of the invention comprises a first carrier (e.g., a polyol) at a concentration of about 650-850 mg/mL.
  • a liquid formulation or unit dosage form of the invention comprises a second carrier (e.g., ethanol) at a concentration of about 50-150 mg/mL.
  • Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl and sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates (e.g.
  • polysorbate 80 polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer ⁇ 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl -beta-alanine, sodium N-lauryipiminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.
  • a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 10-30% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage fonn of the invention comprises a surfactant (e g., polysorbate 80) at a concentration of about 10-20%, about 15-25%, or about 20-30% w/w of the total weight of the formulation or unit dosage form.
  • a liquid fonnulation or unit dosage fonn of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 15%, about 16%, about 17%, about 18%. about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%. about 26%, about 27%, about 28%, about 29%, or about 30% w/w of the total weight of the formulation or unit dosage form.
  • a surfactant e.g., polysorbate 80
  • a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 100-500 mg/mL of the total weight of the formulation or unit dosage fomr.
  • a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 100-300, about 200-400, or about 300-500 mg/mL.
  • a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g.. polysorbate 80) at a concentration of about 110. about 120, about 130.
  • about 140 about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mg/mL.
  • the formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • the formulation may also contain an antioxidant to prevent degradation of the active agent(s).
  • a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.001-0.1% w/w of the total weight of the formulation or unit dosage fonn.
  • a liquid formulation or unit dosage fonn of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.001- 0.01%, about 0.005-0.05%, or about 0.01-0.1% w/w of the total weight of the formulation or unit dosage form.
  • a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.01-1 mg/mL.
  • a liquid formulation or unit dosage fonn of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.01-0.1 mg/mL, about 0.05-0.5 mg/mL, or about 0.1-1 mg/mL.
  • the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of from about 1 mL to about 10 mL.
  • the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL. about 8 mL, about 9 mL, or about 10 mL.
  • Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
  • the liquid formulation may include a solubilizing agent.
  • the solubilizing agent is a cyclodcxtnn.
  • Cyclodextrins include members of a family of cyclic oligosaccharides, composed of 5 or more a-D-glucopyranoside units linked between positions 1 and 4, as known for amylose, a fragment of starch.
  • the cyclodextrin is an a-cyclodextrin. [3- cyclodextrin, and/or y-cyclodextrin.
  • Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously stcrilc-filtcrcd solution thereof.
  • the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art.
  • a specific dosage and treatment regimen for any 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 being treated.
  • a pharmaceutical composition herein is administered in a single composition as a single dosage form.
  • a pharmaceutical composition herein may comprise compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof.
  • the amounts of one or more impurity compounds 1-2, 1-3. and 1-4, or pharmaceutically acceptable salts thereof is as described herein.
  • a pharmaceutical composition comprising compound 1-1, or a pharmaceutically acceptable salt thereof further comprises one or more of compounds selected from 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition herein further comprises water, and/or one or more residual solvent.
  • the present invention provides a pharmaceutical composition comprising compound 1-1 as the active ingredient, or a pharmaceutically acceptable salt thereof.
  • the liquid formulations or unit dosage form comprising compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof of present invention are administered intravenously.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3. and 1-4. or pharmaceutically acceptable salts thereof is administered by an IV injection.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered by an IV infusion.
  • tire methods and uses described herein such as the method of or use in treating a solid cancer or hematological malignancy in a patient in need thereof, is achieved by administering (e.g., intravenously) a therapeutically effective amount of compound 1-1 or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof), such as up to 100 mg in a single or multiple dosage units.
  • a therapeutically effective amount of compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • the method can include administering (e.g., intravenously), in a single or multiple dosage units ranging from about 1 to about 100 mg/dosage form, such as about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or about 100 mg.
  • a liquid formulation can include 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg. 40 mg, 45 mg, or 50 mg/
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2. 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 15 mg to the patient.
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • compound 1-1 or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof
  • a liquid pharmaceutical composition comprising 5 mg to about 50 mg of compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient or carrier.
  • a liquid pharmaceutical composition is provided, wherein the pharmaceutically composition comprises 25 mg to about 45 mg of compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient or carrier.
  • a liquid pharmaceutical composition comprising compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from I- 2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of up to about 30 mg/m 2 .
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of up to about 25 mg/m 2 , or up to about 20 mg/m 2 , or up to about 15 mg/m 2 .
  • compound 1-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered intravenously to a patient at a dose of about 1 mg/m 2 to about 5 mg/m 2 , or about 3 mg/m 2 to about 8 mg/m 2 , or about 5 mg/m 2 to about 10 mg/m 2 .
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of about 30 mg/m 2 , about 27 mg/m 2 , about 20 mg/m 2 , about 17 mg/m 2 , about 15 mg/m 2 , about 12 mg/m 2 , about 10 mg/m 2 , about 7 mg/m 2 , about 5 mg/m 2 , about 3 mg/m 2 , or about 1 mg/m 2 .
  • a liquid pharmaceutical composition comprising compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from I- 2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of up to about 0.8 mg/kg.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of up to about 0.6 mg/kg, or up to about 0.3 mg/kg, or up to about 0.1 mg/kg.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or phannaceutically acceptable salts thereof is administered intravenously to a patient at a dose of about 0.01 mg/kg to about 0.05 mg/kg. or about 0.03 mg/kg to about 0.08 mg/kg. or about 0.05 mg/kg to about 0.1 mg/kg, or about 0.07 mg/kg to about 0.12 mg/kg, or about 0.1 mg/kg to about 0.15 mg/kg, or about 0.12 mg/kg to about 0.17 mg/kg.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered intravenously to a patient at a dose of about 1 mg/kg, about 0.8 mg/kg, about 0.5 mg/kg, about 0.3 mg/kg. about 0. 1 mg/kg, about 0.08 mg/kg, or about 0.06 mg/kg.
  • compound 1-1, or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof is administered to a patient at a dosing schedule appropriate to give the desired tumor regression effect with minimum side effects.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered to a patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or phannaceutically acceptable salts thereof is administered to a patient daily (QD).
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2. 1-3, and 1-4. or pharmaceutically acceptable salts thereof is administered to a patient biweekly (BW).
  • BW biweekly
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered to a patient weekly (QW).
  • compound 1-1, or a phannaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2. 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered to a patient every two weeks (Q2W).
  • compound 1-1, or a pharmaceutically acceptable salt thereof, and one or more of impurity compounds selected from 1-2, 1-3, and 1-4, or pharmaceutically acceptable salts thereof is administered to a patient every three weeks (Q3W).
  • an IV infusion of a pharmaceutical composition of the invention lasts about 5-30 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 30-90 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 2, 2.5, 3, 3.5, or 4 hours.
  • a pharmaceutical composition of the invention is administered intravenously weekly at a dose of from about 0.1 mg/m 2 to about 30 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered intravenously weekly at a dose of from about 1 mg/m 2 to about 10 mg/m 2 .
  • the present disclosure provides a method of administering compound I- 1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof), to a patient in need thereof, wherein the patient suffers from a solid cancer or hematological malignancy.
  • the present disclosure provides a method of treating a solid cancer and/or hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method for treating a MDM2- mediated disorder comprising the step of administering to a patient in need thereof Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof).
  • MDM2 -mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which MDM2 protein or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which MDM2 protein or a mutant thereof, arc known to play a role.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.
  • the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-
  • the cancer is selected from adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell
  • B-cell lymphoma basal cell carcinoma, bile duct cancer, biliary tract cancer, bladder cancer, blastoma, bone cancer, myelofibrosis.
  • Brenner tumor Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniophary ngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma.
  • embryonal carcinoma embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepat
  • non-Hodgkin's lymphoma invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocy toma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer, meso
  • T- lymphoblastic lymphoma precursor T- lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Ewing sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, Merkel cell carcinoma, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, syn
  • MDM2 hyperactivity due to amplification/overexpression or mutational inactivation of the ARF locus, inhibits the function of wild type p53 and can lead to the development of a wide variety of cancers.
  • the MDM2 hyperactivity which can be treated according to the methods of this invention is a human cancer.
  • the human cancer which can be treated according to the methods of this invention is selected from a solid cancer or hematological malignancy.
  • the wild type p53 cancer is mesothelioma, melanoma, DLBCL, prostate cancer, cholangiocarcinoma, cervical cancer, AML, renal cell cancer, uveal melanoma, thyroid cancer, liposarcoma, HCC, or breast cancer.
  • the solid cancer includes solid tumors that have an abnormal mass of tissue that may not contain cysts or liquid areas.
  • Solid tumors may be benign or malignant.
  • examples of solid tumors include sarcomas, carcinomas, and lymphomas.
  • the solid cancer is carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, gastrointestinal cancer, such as colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, such as Hodgkin’s and Non-Hodgkin’s, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma,
  • the hematological malignancy is a cancer that affects the blood, bone marrow, and lymph nodes.
  • the hematological malignancy includes leukemias, lymphomas, and myelomas, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B- cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt lymphoma/leukemia, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL).
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • LGL-L large granular lymphocytic leukemia
  • AML acute myeloid leukemia
  • Burkitt lymphoma/leukemia Burkitt lymphom
  • ABSDLBCL advanced B-cell diffuse large B-cell lymphoma
  • intravascular large B-cell lymphoma lymphoplasmacytic lymphoma
  • Waldenstrom’s macroglobulinemia (WM) splenic marginal zone lymphoma
  • multiple myeloma plasmacytoma, uveal melanoma, myelodysplastic syndrome (MDS), or myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
  • MDS myelodysplastic/myeloproliferative neoplasms
  • the solid cancer or hematological malignancy is relapsed and/or refractory (R/R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R/R lymphoma, or R/R solid tumors.
  • R/R refractory
  • ALL acute lymphocytic leukemia
  • R/R lymphoma R/R solid tumors.
  • the AML is caused by protein (e g., of KMT2A or MLL) mutation or fusion.
  • the AML is a mutant or fusion protein AML, such as IDH1, DNMT3A, NPM1, ASXL1, FLT3-ITD, KMT2A-MLLT3, MLL-MLLT3, or MLL-AF9.
  • the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary' tumors, prolactinoma, pseudotumor cerebri, seborrheic keratosis, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • a benign proliferative disorder such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors,
  • the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
  • the cancer is NUT-midline carcinoma.
  • the cancer is multiple myeloma.
  • the cancer is a lung cancer such as small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • tire cancer is a neuroblastoma.
  • the cancer is Burkitt's lymphoma.
  • the cancer is cervical cancer.
  • the cancer is esophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the present invention provides a method of treating triple negative breast cancer in a patient in need thereof, comprising administering the composition comprising Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) to the patient.
  • the present invention provides a method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a pharmaceutically acceptable salt thereof) to the patient.
  • ALL acute lymphoblastic leukemia
  • the present invention provides a method of treating chronic lymphocytic leukemia (CLL), comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2. 1- 3, and 1-4. or a pharmaceutically acceptable salt thereof) to the patient.
  • CLL chronic lymphocytic leukemia
  • the present invention provides a method of treating large granular lymphocytic leukemia (LGL-L) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) to the patient.
  • LGL-L large granular lymphocytic leukemia
  • the present invention provides a method of treating B-cell prolymphocytic leukemia, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) to the patient.
  • the present invention provides a method of treating acute myeloid leukemia (AML) in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3. and 1-4. or a pharmaceutically acceptable salt thereof) to the patient.
  • AML acute myeloid leukemia
  • the present invention provides a method of treating leukemia (e.g., AML) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) of the present invention or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax).
  • leukemia e.g., AML
  • BCL-2 inhibitor e.g., venetoclax
  • leukemia e.g., AML
  • a combination of Compound 1-1, or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • a BCL-2 inhibitor e.g., venetoclax
  • leukemia e.g., AML
  • a combination of Compound I- 1 , or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • a BCL-2 inhibitor e.g., venetoclax
  • the present invention provides a method of treating leukemia (e.g., AML) in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) of the present invention or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax), wherein the lymphoma is resistant to treatment (e.g., refractor ⁇ ) with the BCL-2 inhibitor (e.g., venetoclax) alone.
  • a BCL-2 inhibitor e.g., venetoclax
  • Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2. 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient at the doses and schedules provided herein and the BCL- 2 inhibitor (e.g., venetoclax) is administered to the patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.
  • the BCL- 2 inhibitor e.g., venetoclax
  • the BCL-2 inhibitor e g., venetoclax
  • the BCL-2 inhibitor is administered to tire patient daily (QD).
  • the BCL-2 inhibitor e.g., venetoclax
  • the BCL-2 inhibitor is administered to the patient orally.
  • the BCL-2 inhibitor is administered to the patient at a dose of about 5 mg/kg to about 20 mg/kg (e.g., about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg).
  • the present invention provides a method of treating melanoma (e.g., uveal melanoma) comprising administering to a patient in need thereof Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof) and a BCL-2 inhibitor (e.g., venetoclax).
  • a method of treating melanoma e.g., uveal melanoma
  • a method of treating melanoma comprising administering to a patient in need thereof Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof) and a BCL-2 inhibitor (e.g., venetoclax).
  • a BCL-2 inhibitor
  • a combination of Compound 1-1, or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof
  • a BCL-2 inhibitor e.g., venetoclax
  • a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • a BCL-2 inhibitor e.g., venetoclax
  • the present invention provides a method of treating melanoma (e.g., uveal melanoma) comprising administering to a patient in need thereof Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and a BCL-2 inhibitor (e.g., venetoclax), wherein the melanoma is resistant to treatment with the BCL-2 inhibitor (e.g., venetoclax) alone.
  • melanoma e.g., uveal melanoma
  • a BCL-2 inhibitor e.g., venetoclax
  • the present invention provides a method of treating leukemia (e.g., AML) comprising administering to a patient in need thereof Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and a FLT3 inhibitor (e.g., midostaurin).
  • leukemia e.g., AML
  • Compound 1-1 e.g., AML
  • a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • a FLT3 inhibitor e.g., midostaurin
  • leukemia e.g., AML
  • a combination of Compound 1-1, or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • FLT3 inhibitor e.g.. midostaurin
  • leukemia e.g., AML
  • a combination of Compound 1-1, or a pharmaceutically acceptable salt thereof in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof
  • a FLT3 inhibitor e.g., midostaurin
  • the present invention provides a method of treating leukemia (e.g., AML) comprising administering to a patient in need thereof Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and a FLT3 inhibitor (e.g., midostaurin), wherein the lymphoma is resistant to treatment with the FLT3 inhibitor (e.g., midostaurin) alone.
  • leukemia e.g., AML
  • Compound 1-1 or a pharmaceutically acceptable salt thereof
  • a FLT3 inhibitor e.g., midostaurin
  • the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and azacitidine.
  • the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and cytarabine.
  • the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof a provided Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2. 1-3, and 1-4, or a pharmaceutically acceptable salt thereof) and a MEK inhibitor (e.g., selumetinib).
  • a MEK inhibitor e.g., selumetinib
  • Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof) of the present invention is administered to a patient at the doses and schedules provided herein and the MEK inhibitor (e.g., selumetinib) is administered to the patient once every 1, 2, 3, 4. 5, 6, 7, 14, or 21 days.
  • the MEK inhibitor e.g., selumetinib
  • the MEK inhibitor e.g., selumetinib
  • the MEK inhibitor is administered to the patient daily (QD).
  • the MEK inhibitor e.g., selumetinib
  • the MEK inhibitor is administered to the patient orally.
  • the MEK inhibitor is administered to the patient at a dose of about 0.01 mg/kg to about 5 mg/kg (e.g., about 0.1 mg/kg, about 0.5 mg/kg, or about 1 mg/kg).
  • the present invention provides a method of treating Burkitt lymphoma/leukemia in a patient in need thereof, comprising administering Compound 1-1. or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating primary effusion lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3. and 1-4. or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating peripheral T-cell lymphoma (PTCL) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof).
  • PTCL peripheral T-cell lymphoma
  • the present invention provides a method of treating cutaneous T-cell lymphoma (CTCL) in a patient in need thereof, comprising administering Compound 1-1. or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • CTCL cutaneous T-cell lymphoma
  • the present invention provides a method of treating advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • ABSDLBCL advanced B-cell diffuse large B-cell lymphoma
  • the present invention provides a method of treating intravascular large B-cell lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof).
  • the present invention provides a method of treating lymphoplasmacytic lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • WM macroglobulinemia
  • the present invention provides a method of treating splenic marginal zone lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4. or a phannaceutically acceptable salt thereof).
  • the present invention provides a method of treating multiple myeloma in a patient in need thereof, comprising administering Compound 1-1 , or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating plasmacytoma in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating myelodysplastic syndrome (MDS) in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • MDS myelodysplastic syndrome
  • the present invention provides a method of treating myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from tire group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • MDS/MPN myelodysplastic/myeloproliferative neoplasms
  • the present invention provides a method of treating malignant peripheral nerve sheath tumors (MPNST) in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • MPNST malignant peripheral nerve sheath tumors
  • the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating primary CNS lymphomas in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof).
  • the present invention provides a method of treating Hodgkin’s lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating primary cutaneous T-cell lymphoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating solid and liquid tumors in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a phannaceutically acceptable salt thereof).
  • the present invention provides a method of treating MYD88 mutant Waldenstrom macroglobulinemia in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating NSCLC in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating uveal melanoma in a patient in need thereof, comprising administering Compound 1-1. or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method of treating Ewing sarcoma in a patient in need thereof, comprising administering Compound 1-1, or a pharmaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2. 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received no prior therapy (i .e ., treatment with Compound 1-1 is a first line treatment).
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received one prior therapy.
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received two prior therapies.
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received three prior therapies.
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least one prior therapy.
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least two prior therapies.
  • the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least three prior therapies.
  • the one or more prior therapies is a standard of care (SoC) treatment.
  • SoC treatment is chemotherapy, targeted therapy, hormone therapy, radiopharmaceuticals, ablation and embolization, surgery, radiation therapy, immunotherapy (e.g., immune checkpoint inhibitors), photocoagulation, thermotherapy, or mixtures thereof.
  • the present invention provides a method of increasing one or more protein markers (e.g., GFD15, p53, p21, and PUMA) in a patient in need thereof, comprising administering Compound 1-1, or a phannaceutically acceptable salt thereof (in a composition comprising one or more impurity compound selected from the group consisting of 1-2, 1-3, and 1-4, or a pharmaceutically acceptable salt thereof).
  • the method of increasing one or more protein markers comprises treating a solid cancer or hematological malignancy in a patient.
  • compound 1-1 is prepared and characterized according to the following procedures. Synthesis of starting materials can be found, for example, in WO 2021/188948, the contents of which are incorporated herein by reference in their entireties.
  • Compound 1-1 is manufactured from two starting materials according to the following scheme.
  • Step 1 A solution of compound 1 in 2 -methyltetrahydrofuran (2-MeTHF) is cooled to about 0 °C. Lithium hydroxide monohydrate in water is charged and the batch is stirred at about 0 °C for about 18 hours until reaction completion, monitored by LC. The resulting layers are separated, and the batchcontaining aqueous layer is treated with hydrochloric acid to a pH of ⁇ 5 during which the product precipitates. The product is collected by filtration and washed with tert-butyl methyl ether (MTBE). The solids are slurried with ethanol (EtOH) at about 20 °C for about 16 hours to reduce impurities. The solids are collected by filtration, washed with EtOH, and dried at about 45 °C under reduced pressure to produce compound 2.
  • 2-MeTHF 2 -methyltetrahydrofuran
  • Step 2 Compound 3 is dissolved in isopropyl acetate (iPrOAc). Hydrogen chloride (HC1) in iPrOAc is charged to the batch at about 25 °C. The batch is agitated for about 17 hours until reaction completion, monitored by LC. The resulting precipitated product is collected by filtration and washed with isopropyl acetate. The collected solids are slurried at about 25 °C with acetonitrile (MeCN) for about 20 hours to reduce impurities. The solids are collected by filtration, washed with MeCN, and dried at about 40 °C under reduced pressure to produce compound 4.
  • iPrOAc isopropyl acetate
  • Hydrogen chloride (HC1) in iPrOAc is charged to the batch at about 25 °C. The batch is agitated for about 17 hours until reaction completion, monitored by LC. The resulting precipitated product is collected by filtration and washed with isopropyl acetate. The collected solid
  • Step 3 Compound 2, Compound 4, and N-methylimidazole (NMI) are dissolved in MeCN. Tire resulting solution is cooled to about 0 °C and to this solution tetramethylchloroformamidinium hexafluorophosphate (TCFH) in MeCN is charged. The resulting mixture is stirred at about 0 °C for about 2 hours until reaction completion, monitored by LC. Once complete, a solution of aqueous citric acid is charged to quench the reaction to precipitate the product. The batch is stirred at about 0 °C for about 13 hours. The precipitated product is collected by filtration. The solids are slurried in MeCN for about 20 hours at about 25 °C to reduce impurities. The solids are collected by filtration, washed with MeCN, and dried at about 40 °C for at least 20 hours under reduced pressure to produce compound 1-1 (crude).
  • TCFH tetramethylchloroformamidinium hexafluorophosphate
  • Step 4 Compound 1-1 (crude) is dissolved in tetrahydrofuran (THF) at about 0 °C. After dissolution the batch in THF is charged via a 0.2 pm filter to 0.2 pm filtered ethyl acetate (EtOAc) while maintaining a batch temperature of about -10 °C, during which the batch precipitates. The batch is further agitated at about -10 °C for about 8 hours. The precipitated solids are collected by filtration, washed with 0.2 pm filtered EtOAc, and dried at up to about 45 °C for at least 24 hours under reduced pressure. Tire dried solids are slurried in 0.2 pm filtered EtOH at about 10 °C for about 12 hours to reduce impurities. The solids are collected by filtration, washed with 0.2 pm filtered EtOH, and dried at up to about 45 °C for at least 24 hours under reduced pressure, affording compound 1-1 drug substance.
  • THF tetrahydrofuran
  • Infrared (IR) spectroscopy was used to verify the identity of the drug substance. Identification was based on comparison of the sample IR spectrum to the spectrum of compound 1-1 reference standard.
  • Ultra-Performance Liquid Chromatography was used to verify the identity of the drug substance, assay, and impurities. Identification was based on comparison of the sample retention time to the retention time of the compound 1-1 reference standard using the following method.
  • the limit for Assay (on anhydrous solvent-free basis) is established as 90.0 - 110.0 wt%. The limit is based on the batch history from development lots and is considered appropriate for early-phase development.
  • Impurity 1-2 is a diastereomeric impurity of compound 1-1. Tire limit of not more than (NMT) 3.0% area for Impurity 1-2 is supported by batch history from development lots and non-clinical safety studies. The level of Impurity A was up to 2.5 % area in the test article used in GLP rat and monkey toxicology studies.
  • Impurity 1-3 and 1-4 is fonned due to hydrolysis (addition of water to compound 1-1).
  • the limit of NMT 1.0% area for Impurity 1-3 and 1-4 is based on batch history from development lots. In addition, this limit is more conservative than the limit of 8.3% supported by the modified Haber’s law.
  • Tire limit of NMT 0.50% area for individual unspecified impurities compound 1-1 drug substance is based on batch history from development lots.
  • the proposed limit of NMT 0.50% is further supported by the modified Haber’s law (Harvey et al., Regulatory Toxicology and Pharmacology, 84 (2017), 116-123).
  • Tire intended clinical dosing regimen of compound 1-1 comprises of one dose every 21 days, up to 12-month duration (equivalent to approximately 17 total doses).
  • the maximum proposed clinical dose is 2 mg/kg, which translates to 140 mg as the maximum dose assuming a patient weight of 70 kg.
  • Compound 1-1 has four chiral centers at carbons 12, 35, 38, and 39:
  • the diastereomeric impurities related to the chiral centers at carbons 35, 38, and 39 are detected by the achiral impurity UPLC method.
  • the ratio of the diastereomers, compound (R)-I-l and (S)-I-l, resulting from the racemic chiral center at carbon 12, is determined by the chiral HPLC method: YMC CHIRAL ART Cellulose-SC, 4.6x150 mm, 3 pm at 25 °C; Mobile phase A: 0.1% formic acid in water: Mobile phase B: 0.1% formic acid in 1: 1 ACN:MeOH; Detection: 220 nm; Gradient: 10% A to 20 min; Flow rate: 1.0 mL/min.
  • TAMC Total Aerobic Microbial Count
  • TYMC Total Yeast and Mold Count

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions utiles pour la modulation de la protéine murine double minute 2 (MDM2) par ubiquitination et/ou dégradation et leurs utilisations dans le traitement de diverses maladies.
PCT/US2024/021049 2023-03-22 2024-03-22 Agents de dégradation de mdm2 et leurs utilisations Pending WO2024197219A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021188948A1 (fr) * 2020-03-19 2021-09-23 Kymera Therapeutics, Inc. Agents de dégradation de mdm2 et leurs utilisations
US20210309666A1 (en) * 2018-10-08 2021-10-07 The Regents Of The University Of Michigan Small molecule mdm2 protein degraders
US20220411432A1 (en) * 2016-04-06 2022-12-29 The Regents Of The University Of Michigan Mdm2 protein degraders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220411432A1 (en) * 2016-04-06 2022-12-29 The Regents Of The University Of Michigan Mdm2 protein degraders
US20210309666A1 (en) * 2018-10-08 2021-10-07 The Regents Of The University Of Michigan Small molecule mdm2 protein degraders
WO2021188948A1 (fr) * 2020-03-19 2021-09-23 Kymera Therapeutics, Inc. Agents de dégradation de mdm2 et leurs utilisations

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