WO2015193768A1 - Lactames à fusion aryle à utiliser en tant que modulateurs ezh2 - Google Patents

Lactames à fusion aryle à utiliser en tant que modulateurs ezh2 Download PDF

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Publication number
WO2015193768A1
WO2015193768A1 PCT/IB2015/054353 IB2015054353W WO2015193768A1 WO 2015193768 A1 WO2015193768 A1 WO 2015193768A1 IB 2015054353 W IB2015054353 W IB 2015054353W WO 2015193768 A1 WO2015193768 A1 WO 2015193768A1
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Prior art keywords
methyl
oxo
dimethyl
dihydroisoquinolin
dichloro
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PCT/IB2015/054353
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English (en)
Inventor
Robert Arnold Kumpf
Pei-Pei Kung
Scott Channing Sutton
Martin James Wythes
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Pfizer Inc.
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Publication of WO2015193768A1 publication Critical patent/WO2015193768A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • High EZH2 expression has been correlated with poor prognosis, high grade, and high stage in several cancer types, including breast, colorectal, endometrial, gastric, liver, kidney, lung, melanoma, ovarian, pancreatic, prostate, and bladder cancers.
  • breast, colorectal, endometrial, gastric, liver, kidney, lung, melanoma, ovarian, pancreatic, prostate, and bladder cancers See Crea et al., Crit. Rev. Oncol. Hematol. 2012, 83: 184-193, and references cited therein; see also Kleer et al., Proc. Natl. Acad. Sci. USA 2003, 100: 1 1606-1 1 ; Mimori et al., Eur. J. Surg. Oncol. 2005, 31 :376-80; Bachmann et al., J. Clin. Oncol.
  • R 1 is CI or Br
  • the invention provides a compound of one of the formulae described herein, or pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.
  • the uses described herein comprise the use of a compound of one of the formulae described herein or pharmaceutically acceptable salt thereof, in combination with one or more substances selected from anti-tumor agents, anti-angiogenesis agents, signal transduction inhibitors and antiproliferative agents.
  • Such groups may also be referred to herein as methoxy, ethoxy, isopropoxy, fe/f-butyloxy, etc.
  • Alkoxy groups may be unsubstituted or substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl.
  • alkoxy groups may be substituted by one or more halo groups, up to the total number of hydrogen atoms present on the alkyl portion.
  • Ci-C 4 alkoxy includes halogenated alkoxy groups, e.g., trifluoromethoxy and 2,2- difluoroethoxy (i.e., -OCF 3 and -OCH 2 CHF 2 ).
  • cycloalkyi rings include, but are not limited to, the following:
  • ring N atoms may be optionally substituted by groups suitable for an amine, e.g., alkyl, acyl, carbamoyl, sulfonyl substituents, etc.
  • ring S atoms may be optionally substituted by one or two oxo groups (i.e., S(0) q , where q is 0, 1 or 2).
  • Preferred heterocycles include 3-12 membered heterocyclyl groups in accordance with the definition herein.
  • 5- or 6-membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, pyrazinyl or pyridazinyl rings.
  • the heteroaryl group may be unsubstituted or substituted as further described herein.
  • monocyclic heteroaryl groups include, but are not limited to: T IB2015/054353
  • Heteroarylalkyl refers to a heteroaryl group as described above that is attached to the base molecule through an alkylene linker, and differs from “arylalkyl” in that at least one ring atom of the aromatic moiety is a heteroatom selected from N, 0 and S. Heteroarylalkyl groups are sometimes described herein according to the total number of non-hydrogen atoms (i.e., C, N, S and 0 atoms) in the ring and linker combined, excluding substituent groups. Thus, for example, pyridinylmethyl may be referred to as a "C 7 "-heteroarylalkyl.
  • the substituents may be on either the divalent linker portion or on the aryl or heteroaryl portion of the group.
  • the substituents optionally present on the alkylene or heteroalkylene portion are the same as those described above for alkyl or alkoxy groups generally, while the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl or heteroaryl groups generally.
  • Unsubstituted amino refers to a group -NH 2 . Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NR x R y , where each or R x and R y is independently H, alkyi, alkenyl, alkynyl, cycloalkyl, heterocyclyl, acyl, thioacyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl, in each case having the specified number of atoms and optionally substituted as described herein.
  • halo refers to fluoro or chloro (F or CI).
  • each R 11 is independently Ci-C 6 alkyl, C 3 -C 8 cycloalkyi or 3-12 membered heterocyclyl, where said Ci-C 6 alkyl is optionally substituted by one or more R c , and said C3-C8 cycloalkyi or 3-12 membered heterocyclyl is optionally substituted by one or more R D ;
  • R 5 is 5-12 membered heteroaryl, where each said 5-12 membered heteroaryl is optionally substituted one or more by R B .
  • R 5 is a 5- or 6-membered heteroaryl.
  • said 5- or 6-membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, and triazolyl groups, each optionally substituted by one or more R B .
  • R 4 is CI or Br; R 4 is CI; or
  • R 2 is -OR 5 and R 5 is 5-12 membered heteroaryl optionally substituted by one or more R B ;
  • the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an anti-tumor agent, which amounts are together effective in treating said abnormal cell growth.
  • the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • the invention provides a method for the treatment of a disorder mediated by EZH2 in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder.
  • references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
  • salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1 ,6-dioate, hexylresorcinate
  • the compounds of the invention that include a basic moiety, such as an amino group may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when the solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.
  • prodrugs in accordance with the invention include:
  • metabolites of compounds of the formulae described herein i.e. , compounds formed in vivo upon administration of the drug.
  • the compounds of the formulae provided herein may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line ( ), a solid wedge ( ⁇ ), or a dotted wedge ( " ).
  • nervous system for example, neoplasms of the central nervous system (CNS), primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
  • CNS central nervous system
  • skull cancer osteoma, hemangioma, granuloma, xanthoma, osteitis deformans
  • skin for example, malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids;
  • the invention provides methods for inducing cell apoptosis, comprising contacting cells with a compound described herein in an amount effective to induce apoptosis of the cells.
  • Contacting refers to bringing a compound or pharmaceutically acceptable salt of the invention and a cell expressing EZH2 together in such a manner that the compound can affect the activity of EZH2, either directly or indirectly. Contacting can be accomplished in vitro (i.e., in an artificial environment such as, e.g., without limitation, in a test tube or culture medium) or in vivo (i.e., within a living organism such as, without limitation, a mouse, rat or rabbit.)
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.1 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient.
  • the choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Non-limiting examples of materials therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 1 1. (6), 981 -986 by Liang and Chen (2001 ), the disclosure of which is incorporated herein by reference in its entirety.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • compositions include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Suitable modified release formulations are described in U.S. Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • electroporation iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • iontophoresis iontophoresis
  • phonophoresis phonophoresis
  • sonophoresis e.g. PowderjectTM, BiojectTM, etc.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.
  • the compounds of the invention may be used in combination with one or more additional anti-cancer agents which are described below.
  • the one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of the invention.
  • the additional anti-cancer agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention.
  • the additional anti-cancer agent is administered to the mammal after administration of the compound of the invention.
  • the additional anti-cancer agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention.
  • the invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of anti-angiogenesis agents and signal transduction inhibitors and a pharmaceutically acceptable carrier, wherein the amounts of the active agent and the combination anti-cancer agents when taken as a whole is therapeutically effective for treating said abnormal cell growth.
  • a pharmaceutical composition for the treatment of abnormal cell growth in a mammal including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of anti-angiogenesis agents and signal transduction inhibitors and a pharmaceutically acceptable carrier, wherein
  • the anti-cancer agent used in conjunction with a compound of the invention and pharmaceutical compositions described herein is an anti-angiogenesis agent (e.g., an agent that stops tumors from developing new blood vessels).
  • anti-angiogenesis agents include for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, ⁇ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix- metalloprotienase 9) inhibitors.
  • anti-angiogenesis agents which can be used in conjunction with a compound of the invention and pharmaceutical compositions described herein include celecoxib (CelebrexTM), parecoxib (DynastatTM), deracoxib (SC 59046), lumiracoxib (PreigeTM), valdecoxib (BextraTM), rofecoxib (VioxxTM), iguratimod ⁇ CareramTM), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (ArcoxiaTM).
  • anti-angiogenesis agents include acitretin (NeotigasonTM), plitidepsin (aplidineTM), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (TempostatinTM), PanzemTM (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (RemovabTM), lenalidomide (RevlimidTM), squalamine (EVIZONTM), thalidomide (ThalomidTM), UkrainTM (NSC 631570), VitaxinTM (MEDI 522), and zoledronic acid (ZometaTM).
  • acitretin NeotigasonTM
  • plitidepsin aplidineTM
  • cilengtide EMD 121974
  • CA4P
  • the anti-cancer agent is a so called signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell).
  • Signal transduction inhibitors include small molecules, antibodies, and antisense molecules.
  • Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors.
  • Preferred signal transduction inhibitors include gefitinib (IressaTM), cetuximab (ErbituxTM), erlotinib (TarcevaTM), trastuzumab (HerceptinTM), sunitinib (SutentTM), imatinib (GleevecTM), and PD325901 (Pfizer).
  • signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 1 12 (One Bio), BMS 387032 (Bristol-Myers Squibb), PD 0332991 (Pfizer), and AG 024322 (Pfizer).
  • antineoplastic agents used in combination with compounds of the invention include but are not limited to suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101 ; Onconase (ranpirnase),PS-341 (MLN-341 ), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCI (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10- hydroxycamp
  • antineoplastic agents used in combination therapy with a compound of the invention optionally with one or more other agents include, but are not limited to, as Advexin (ING 201 ), TNFerade (GeneVec, a compound which express TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol- Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor,
  • Another embodiment of the present invention of particular interest relates to a method for the treatment of breast cancer in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole and anastrozole.
  • one or more (preferably one to three) anti-cancer agents selected from the group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole and anastrozole.
  • the invention provides a method of treating colorectal cancer in a mammal, such as a human, in need of such treatment, by administering an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents.
  • anti-cancer agents include those typically used in adjuvant chemotherapy, such as FOLFOX, a combination of 5- fluorouracil (5-FU) or capecitabine (Xeloda), leucovorin and oxaliplatin (Eloxatin).
  • Further examples include 17-DMAG, ABX- EFR, AMG-706, AMT-2003, ANX-510 (CoFactor), aplidine (plitidepsin, Aplidin), Aroplatin, axitinib (AG-13736), AZD-0530, AZD-2171 , bacillus Calmette-Guerin (BCG), bevacizumab (Avastin), BIO-1 17, BIO-145, BMS-184476, BMS-275183, BMS-528664, bortezomib (Velcade), C-131 1 (Symadex), cantuzumab mertansine, capecitabine (Xeloda), cetuximab (Erbitux), clofarabine (Clofarex), CMD-193, combretastatin, Cotara, CT-2106, CV-247, decitabine (Dacogen), E-7070, E-7820, edotecarin
  • Another embodiment of the present invention of particular interest relates to a method for the treatment of renal cell carcinoma in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of axitinib (AG 13736), capecitabine (Xeloda), interferon alpha, interleukin-2, bevacizumab (Avastin), gemcitabine (Gemzar), thalidomide, cetuximab (Erbitux), vatalanib (PTK-787), sunitinib (SutentTM), AG-13736, SU-1 1248, Tarceva, Iressa, Lapatinib and Gleevec, wherein the amounts of the active agent together with the amounts of the combination anticancer agents is effective in treating renal cell carcinoma.
  • anti-cancer agents selected from the group consisting of axitinib (AG 13736), capecita
  • Another embodiment of the present invention of particular interest relates to a method for the treatment of melanoma in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of interferon alpha, interleukin-2, temozolomide (Temodar), docetaxel (Taxotere), paclitaxel, dacarbazine (DTIC), carmustine (also known as BCNU), Cisplatin, vinblastine, tamoxifen, PD-325,901 , axitinib (AG 13736), bevacizumab (Avastin), thalidomide, sorafanib, vatalanib (PTK-787), sunitinib (SutentTM), CpG-7909, AG-13736, Iressa, Lapatinib and Gleevec, wherein the amounts of the active
  • N-iodosuccinimide (5.27 g, 23.43 mmol) was added in portions to a solution of 5- amino-7-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1 (2H)-one (2d, 5.5 g, 21 .3 mmol) in glacial acetic acid (400 mL) and the resulting mixture stirred at room temperature for three days. A second portion of N-iodosuccinimide (2.6 g, 12.7 mmol) was then added and stirring continued at room temperature overnight. The mixture was concentrated under vacuum to remove acetic acid.
  • Example 3 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1 ,2-dihvdropyridin-3-yl)methyl1-7- methylamino)-3,4-dihvdroisoquinolin-1 (2H)-one.
  • Example 5 (5£)-1 ,4-anhvdro-3,6-dideoxy-2-0- ⁇ 5,8-dichloro-2-r(4,6-dimethyl-2-oxo-1 ,2- dihvdro-pyridin-3-yl)methyl1-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-L-threo-hexitol.
  • Copper (I) cyanide (3.60 g, 40.2 mmol) was placed in a three-necked flask under nitrogen and dried by gentle heating with a heat gun under vacuum. It was then allowed to cool to room temperature under nitrogen. This process was repeated three times, and then anhydrous tetrahydrofuran (80 mL) was added. The resulting mixture was cooled to -78 °C, and then vinyl magnesium bromide (1 M solution in tetrahydrofuran, 88.5 mL, 88.5 mmol) was added dropwise while maintaining the internal temperature below -68 °C. The heterogeneous mixture was warmed to -20 °C and stirred at this temperature for 30 minutes.
  • reaction mixture was diluted with ethyl acetate (50mL), washed with water (2 x 50mL) and brine (50mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give 2,5-anhydro-3-deoxy-4-0-(5,8-dichloro-1 -oxo-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 -0-(4-nitrobenzoyl)-L-i/?reo-pentitol (5g, 128 mg, 31 % yield) as a solid.
  • reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane), affording 1 ,4-anhydro-2-0- (2- ⁇ [2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl ⁇ -5,8-dichloro-1 -oxo-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-3-deoxy-L-i/?reo-pentitol (5h, 36 mg, 26% yield) as a solid.
  • Methylmagnesium bromide (3.0 M in diethyl ether, 0.036 mL, 0.13 mmol) was added to a cooled (0 °C) solution of 2,5-anhydro-4-0-(2- ⁇ [2-(benzyloxy)-4,6- dimethylpyridin-3-yl]methyl ⁇ -5,8-dichloro-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3- deoxy-L-ffrreo-pentose (5i, 60 mg, 0.1 1 mmol) in dry tetrahydrofuran (10 mL). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with sat.
  • Trifluoroacetic acid (5 mL) was added to a cooled (0 °) solution of (5 ⁇ )-1 ,4- anhydro-2-0-(2- ⁇ [2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl ⁇ -5,8-dichloro-1 -oxo- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,6-dideoxy-L-i/?reo-hexitol (5j, 40 mg, 0.07 mmol) in dichloromethane (5 mL). The ice bath was removed and the stirring continued at 25 °C for 6 hours. The mixture was concentrated and the residue dissolved in dichloromethane (20 mL) and sat.
  • Example 6 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1 ,2-dihvdropyridin-3-yl)methvH-7-( ⁇ 1 - [(2R)-2-hvdroxybutanoyllpiperidin-4-yl)oxy)-3,4-dihydroisoquinolin-1 (2H)-one.
  • Example 8 7-tert-butoxy-8-chloro-2-[(4,6-dimethyl-2-oxo-1 ,2-dihvdropyridin-3- yl)methyl -3,4-dihvdroisoquinolin-1 (2H)-one
  • WT and mutant EZH2 were purified using the same procedure.
  • the genes for EZH2, EED, SUZ12, and RBBP4 proteins were cloned into pBacPAK9 vectors
  • RBBP4 was FLAG tagged on the N-terminal end.
  • Final reaction conditions are PRC2 4-protein complex at 4 nM when using WT EZH2 or 6 nM when using Y641 N mutant EZH2, 1 .5 ⁇ SAM, 25 ⁇ g/mL oligonucleosomes, 50 nM rH1 in a 50 ⁇ reaction volume.
  • IC 50 values were determined by fitting the data to a 4-parameter IC 50 equation using proprietary curve fitting software.
  • Kj app values were obtained by fitting the dose response curve to a model for competitive inhibition using proprietary curve fitting software.

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Abstract

La présente invention concerne des composés de formule générale (I), dans laquelle R1, R2, R3, R4, X et Z ont la signification indiquée dans la description, et les sels pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques contenant de tels composés et sels, et des procédés d'utilisation de tels composés, sels et compositions pour le traitement de la croissance cellulaire anormale, notamment du cancer.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
WO2017132518A1 (fr) * 2016-01-29 2017-08-03 Epizyme, Inc. Polythérapie pour le traitement du cancer
WO2018135556A1 (fr) 2017-01-19 2018-07-26 第一三共株式会社 Composition pharmaceutique destinée à être mise en œuvre pour traiter la myélopathie associée au htlv-1
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
WO2020011607A1 (fr) 2018-07-09 2020-01-16 Fondation Asile Des Aveugles Inhibition de sous-unités de prc2 permettant de traiter des troubles oculaires
CN111909157A (zh) * 2019-05-07 2020-11-10 南京药石科技股份有限公司 Ezh2抑制剂及其用途
US10898490B2 (en) 2015-08-24 2021-01-26 Epizyme, Inc. Method for treating cancer
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
JP2022522648A (ja) * 2019-02-19 2022-04-20 ハンミ ファーマシューティカル カンパニー リミテッド 新規なヘテロトリシクリック誘導体化合物およびその用途
CN116194108A (zh) * 2020-08-13 2023-05-30 韩美药品株式会社 新型二氧代异喹啉酮衍生物及其用途
WO2023209591A1 (fr) 2022-04-27 2023-11-02 Daiichi Sankyo Company, Limited Combinaison d'un conjugué anticorps-médicament avec un inhibiteur de l'ezh1 et/ou de l'ezh2

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2013049770A2 (fr) * 2011-09-30 2013-04-04 Glaxosmithkline Llc Méthodes de traitement du cancer
WO2014049488A1 (fr) * 2012-09-28 2014-04-03 Pfizer Inc. Composés de benzamide et hétérobenzamide
WO2014097041A1 (fr) * 2012-12-21 2014-06-26 Pfizer Inc. Lactames fusionnés à un aryle et hétéroaryle

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO2013049770A2 (fr) * 2011-09-30 2013-04-04 Glaxosmithkline Llc Méthodes de traitement du cancer
WO2014049488A1 (fr) * 2012-09-28 2014-04-03 Pfizer Inc. Composés de benzamide et hétérobenzamide
WO2014097041A1 (fr) * 2012-12-21 2014-06-26 Pfizer Inc. Lactames fusionnés à un aryle et hétéroaryle

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
BACHMANN ET AL., J. CLIN. ONCOL., vol. 24, 2006, pages 268 - 273
BREUER ET AL., NEOPLASIA, vol. 6, 2004, pages 736 - 43
CREA ET AL., CRIT. REV. ONCOL. HEMATOL., vol. 83, 2012, pages 184 - 193
E L ELIEL: "Stereochemistry of Organic Compounds", 1994, WILEY
FINNIN; MORGAN, J PHARM SCI, vol. 88, no. 10, October 1999 (1999-10-01), pages 955 - 958
H BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
H. LIEBERMAN; L. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
HALEBLIAN, J PHARM SCI, vol. 64, no. 8, August 1975 (1975-08-01), pages 1269 - 1288
KLEER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 100, 2003, pages 11606 - 11
LIANG; CHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
LU ET AL., CANCER RES., vol. 67, 2007, pages 1757 - 1768
MAJER ET AL., FEBS LETTERS, vol. 586, 2012, pages 3448 - 3451
MATSUKAWA ET AL., CANCER SCI., vol. 97, 2006, pages 484 - 491
MCCABE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 109, 2012, pages 2989 - 2994
MIMORI ET AL., EUR. J. SURG. ONCOL., vol. 31, 2005, pages 376 - 80
MORIN ET AL., NAT. GENETICS, vol. 42, no. 2, February 2010 (2010-02-01), pages 181 - 185
OUGOLKOV ET AL., CLIN. CANCER RES., vol. 14, 2008, pages 6790 - 6796
SASAKI ET AL., LAB. INVEST., vol. 88, 2008, pages 873 - 882
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
SUDO ET AL., BR. J. CANCER, vol. 92, no. 9, 2005, pages 1754 - 1758
T HIGUCHI; W STELLA: "ACS Symposium Series", vol. 14, article "Pro-drugs as Novel Delivery Systems"
VARAMBALLY ET AL., NATURE, vol. 419, 2002, pages 624 - 629
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
WAGENER ET AL., INT. J. CANCER, vol. 123, 2008, pages 1545 - 1550
WEIKERT ET AL., INT. J. MOL. MED., vol. 16, 2005, pages 349 - 353

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US10898490B2 (en) 2015-08-24 2021-01-26 Epizyme, Inc. Method for treating cancer
US11642349B2 (en) 2015-08-24 2023-05-09 Epizyme, Inc. Method for treating cancer
US9718838B2 (en) 2015-08-27 2017-08-01 Eli Lilly And Company Inhibitors of EZH2
WO2017132518A1 (fr) * 2016-01-29 2017-08-03 Epizyme, Inc. Polythérapie pour le traitement du cancer
US11951108B2 (en) 2016-01-29 2024-04-09 Epizyme, Inc. Combination therapy for treating cancer
WO2018135556A1 (fr) 2017-01-19 2018-07-26 第一三共株式会社 Composition pharmaceutique destinée à être mise en œuvre pour traiter la myélopathie associée au htlv-1
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
US11485738B2 (en) 2018-01-31 2022-11-01 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11220509B2 (en) 2018-01-31 2022-01-11 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
WO2020011607A1 (fr) 2018-07-09 2020-01-16 Fondation Asile Des Aveugles Inhibition de sous-unités de prc2 permettant de traiter des troubles oculaires
JP2022522648A (ja) * 2019-02-19 2022-04-20 ハンミ ファーマシューティカル カンパニー リミテッド 新規なヘテロトリシクリック誘導体化合物およびその用途
JP7358491B2 (ja) 2019-02-19 2023-10-10 ハンミ ファーマシューティカル カンパニー リミテッド 新規なヘテロトリシクリック誘導体化合物およびその用途
CN113365989A (zh) * 2019-05-07 2021-09-07 南京药石科技股份有限公司 Ezh2抑制剂及其用途
WO2020224607A1 (fr) * 2019-05-07 2020-11-12 南京药石科技股份有限公司 Inhibiteur d'ezh2 et son utilisation
CN111909157B (zh) * 2019-05-07 2023-02-03 南京药石科技股份有限公司 Ezh2抑制剂及其用途
CN111909157A (zh) * 2019-05-07 2020-11-10 南京药石科技股份有限公司 Ezh2抑制剂及其用途
CN116194108A (zh) * 2020-08-13 2023-05-30 韩美药品株式会社 新型二氧代异喹啉酮衍生物及其用途
WO2023209591A1 (fr) 2022-04-27 2023-11-02 Daiichi Sankyo Company, Limited Combinaison d'un conjugué anticorps-médicament avec un inhibiteur de l'ezh1 et/ou de l'ezh2

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