WO2021249305A1 - Composé biphényle - Google Patents

Composé biphényle Download PDF

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Publication number
WO2021249305A1
WO2021249305A1 PCT/CN2021/098381 CN2021098381W WO2021249305A1 WO 2021249305 A1 WO2021249305 A1 WO 2021249305A1 CN 2021098381 W CN2021098381 W CN 2021098381W WO 2021249305 A1 WO2021249305 A1 WO 2021249305A1
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compound
och
acid
pharmaceutically acceptable
present
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PCT/CN2021/098381
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English (en)
Chinese (zh)
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廖勇刚
钱文远
林军
韦昌青
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202180032515.8A priority Critical patent/CN115551842B/zh
Publication of WO2021249305A1 publication Critical patent/WO2021249305A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new biphenyl compounds, in particular to compounds represented by formula (II) and pharmaceutically acceptable salts thereof.
  • the human homolog 2 (enhancer of zeste homolog 2, EZH2) of the enhancer of the Drosophila zest gene is one of the important members of the epigenetic suppressor PcG family (polycomb group), and is the epigenetic regulatory factor polycomb inhibitory complex 2 (polycomb repressive complex 2, PRC2) catalytic subunit, EZH2 is located on chromosome 7q35, covers nearly 40Kb in length, contains 20 exons, and forms a complex with the other two non-catalytic subunits (EED and SUZ12) of PRC2 It has stable histone methyltransferase activity and trimethylates the lysine at position 27 of histone H3 (H3K27me3), thereby inhibiting target gene transcription and participating in the regulation of cell cycle, cell senescence, and cell decision Physiological or pathological processes such as
  • Histone lysine methyltransferase EZH2 catalyzes the transfer of cofactor S adenosylmethionine (SAM) active methyl group to the ⁇ -NH2 of histone H3 lysine 27 (H3K27), leading to the trimethylation of H3K27 (H3K27me3) and subsequent transcriptional silencing of target genes, thereby regulating cancer progression and stem cell stemness maintenance and other life activities.
  • SAM cofactor S adenosylmethionine
  • EZH2 can also function by methylating non-histone proteins in a way that does not depend on PRC2; or it can form a transcription complex with other factors to activate the transcription of downstream target genes and increase the expression of target genes. ; It can also regulate stem cell maintenance and generational differentiation. Therefore, the signal pathway mediated by EZH2 is considered to be the internal cause of various pathological processes such as cancer. Inhibition of abnormal EZH2 activity may be an attractive treatment for cancer.
  • EZH2 overexpression or mutation of EZH2 has been detected in a variety of tumor tissues.
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • Y641 tyrosine mutation at position 641 (Y641) of EZH2 protein in %FL tissue
  • H3K27me3 level is related to tumorigenesis and is associated with poor prognosis.
  • the EZH2 inhibitor Tazverik (tazemetostat) developed by Epizyme has been approved for marketing in pediatric and adult patients with metastatic or locally advanced epithelioid sarcoma (ES) who are 16 years of age and older and do not meet the conditions for complete resection.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • T 1 and T 2 are each independently selected from CH 2 , NH and O;
  • R 1 is selected from H, OH, C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 Ra replace;
  • R a is independently selected from F, Cl, Br and I;
  • n is selected from 0 and 1;
  • n is selected from 0 and 1.
  • the above-mentioned R 1 is selected from H, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 and OCH (CH 3) 2 optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • R 1 is selected from OH, CH 3 and OCH 3 , and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 is as defined in the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, OH, C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 Ra replace;
  • R a is independently selected from F, Cl, Br and I.
  • the above-mentioned R 1 is selected from H, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 and OCH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 and OCH (CH 3) 2 optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • the present invention also provides the following compounds or their pharmaceutically acceptable salts,
  • the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating various diseases related to EZH2 receptors.
  • the compound of the present invention has a good inhibitory effect on the EZH2 enzyme and the proliferation of Karpas422 cells, and the compound of the present invention has good pharmacokinetic properties.
  • the compound of the present invention has no significant effect on animal body weight, and the compound of the present invention has good safety.
  • the compound of the present invention can effectively inhibit tumor growth, and the inhibitory effect increases with increasing dose, and can produce tumor shrinkage effect.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
  • the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Express.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring, and 9
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultivated single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • the compound is used according to the conventional naming principle in the field or The software is named, and the commercially available compounds use the supplier catalog name.
  • FIG. 1 Body weight changes of each group of tumor-bearing mice.
  • step 1
  • step 1
  • step 1
  • the cell plating and compound treatment are shown in Table 1.
  • Table 1 Schematic diagram of cell plating and compound treatment in vitro cell viability experiment ( ⁇ M).
  • Vehicle control only cells are added without medicine; blank control: only cell culture medium is added, without cells.
  • the tumor cell lines were cultured in an incubator at 37°C and 5% CO 2 according to the culture conditions shown in Table 3. Passage regularly, and take cells in the logarithmic growth phase for plating.
  • Table 4 Schematic diagram of 400X compound storage plate ( ⁇ M).
  • the culture plate is placed at room temperature for 10 minutes to stabilize the luminescence signal.
  • IR(%) (1-(RLU compound-RLU blank control)/(RLU vehicle control-RLU blank control)*100%.
  • the test results are shown in Table 5:
  • the compound of the present invention has a good inhibitory effect on the proliferation of Karpas422 cells.
  • mice Male, 7-10 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.
  • the intravenous group was administered at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, and the intragastric group was administered at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, respectively.
  • Blood was collected from the saphenous vein and centrifuged to obtain plasma.
  • the LC-MS/MS method was used to determine the blood drug concentration, and the WinNonlin TM Version 6.3 pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by the non-compartmental model linear log trapezoidal method.
  • Table 6 The test results are shown in Table 6:
  • AUC 0-inf the area under the plasma concentration-time curve from time 0 to extrapolated to infinity
  • the compound of the present invention has good oral bioavailability in mice, and higher exposure is beneficial to produce good in vivo efficacy.
  • EZH2 reaction buffer 50mM Tris-HCl (pH 8.0), 0.01% Brij35, 1mM EDTA, 1mM DTT, 1mM PMSF, 1% DMSO;
  • Methyl donor S-adenosine-1-[methyl- 3 H]methionine (SAM);
  • Substrate 5M histone, or nucleosomes of 0.05mg/mL HeLa cells or core histones from chicken, 1 ⁇ M S-adenosyl-L-[methyl- 3 H-]methionine (3H- SAM).
  • the compound of the present invention has significant EZH2 enzyme inhibitory activity.
  • This experiment uses the human lymphoma Karpas422 cell subcutaneous xenograft BALBc nude mouse model to evaluate the anti-tumor effects of the compounds of the examples.
  • mice BALBc nude mice, female, 6-8 weeks old, Shanghai Jihui Experimental Animal Breeding Co., Ltd.
  • Vehicle blank control group; p.o. oral administration; BID: twice a day
  • Human lymphoma Karpas422 is cultured in monolayer in vitro, and the culture conditions are RPMI 1640 medium with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37°C and 5% CO 2 incubator. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • the solvent used in the experiment is 0.5% sodium carboxymethyl cellulose (viscosity 600-800cps)/0.1% Tween-80 aqueous solution, tazemetostat and test compound are formulated into a uniform suspension of corresponding concentration, stored at 4 degrees Celsius, one week Prepare once.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • TGI (%) [1- (Average tumor volume at the end of a certain treatment group-the average tumor volume at the start of the treatment group) / (Average tumor volume at the end of the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the statistical analysis is based on the average data of the tumor volume at the end of the experiment, using GraphPad Prism 5 software to analyze with two-way ANOVA. p ⁇ 0.05 considered a significant difference.
  • Figure 1 shows the body weight change of the test substance in the nude mouse model of human lymphoma Karpas422 cells transplanted subcutaneously with tumor female BALBc.
  • Vehicle represents the blank control group; *P ⁇ 0.05, **P ⁇ 0.005, ***P ⁇ 0.001 compared with the blank control group.
  • TGI Tumor growth inhibition
  • the p value is based on the tumor volume, compared with the blank control group *P ⁇ 0.05, **P ⁇ 0.005, ***P ⁇ 0.001.

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Abstract

L'invention concerne un nouveau composé biphényle. En particulier, l'invention concerne un composé tel que représenté par la formule (II) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2021/098381 2020-06-08 2021-06-04 Composé biphényle WO2021249305A1 (fr)

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CN104080769A (zh) * 2011-04-13 2014-10-01 Epizyme股份有限公司 芳基或杂芳基取代苯化合物
WO2015010049A1 (fr) * 2013-07-19 2015-01-22 Epizyme, Inc. Composés de benzène substitués
CN105037360A (zh) * 2014-04-28 2015-11-11 四川大学 吡啶酮衍生物及其制备方法和用途
WO2016140501A1 (fr) * 2015-03-04 2016-09-09 Kainos Medicine, Inc. N-oxyde de pyridine pour activateur d'inhibiteurs d'homologue 2 de zeste
CN110191879A (zh) * 2017-01-25 2019-08-30 恩瑞生物医药科技（上海）有限公司 一种组蛋白甲基转移酶ezh2抑制剂、其制备方法及其医药用途
WO2020020374A1 (fr) * 2018-07-27 2020-01-30 苏州信诺维医药科技有限公司 Composé de benzène polysubstitué et son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
WO2017174023A1 (fr) * 2016-04-08 2017-10-12 南京明德新药研发股份有限公司 Composé biphényle servant comme inhibiteur de l'ezh2

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080769A (zh) * 2011-04-13 2014-10-01 Epizyme股份有限公司 芳基或杂芳基取代苯化合物
WO2014100646A1 (fr) * 2012-12-21 2014-06-26 Epizyme, Inc. Composés 1,4-pyridones
WO2015010049A1 (fr) * 2013-07-19 2015-01-22 Epizyme, Inc. Composés de benzène substitués
CN105037360A (zh) * 2014-04-28 2015-11-11 四川大学 吡啶酮衍生物及其制备方法和用途
WO2016140501A1 (fr) * 2015-03-04 2016-09-09 Kainos Medicine, Inc. N-oxyde de pyridine pour activateur d'inhibiteurs d'homologue 2 de zeste
CN110191879A (zh) * 2017-01-25 2019-08-30 恩瑞生物医药科技（上海）有限公司 一种组蛋白甲基转移酶ezh2抑制剂、其制备方法及其医药用途
WO2020020374A1 (fr) * 2018-07-27 2020-01-30 苏州信诺维医药科技有限公司 Composé de benzène polysubstitué et son procédé de préparation et son utilisation

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