CN115974855A - EZH2 and HDAC (Histone-like kinase) double-target inhibitor, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
EZH2 and HDAC (Histone-like kinase) double-target inhibitor, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- CN115974855A CN115974855A CN202211450153.7A CN202211450153A CN115974855A CN 115974855 A CN115974855 A CN 115974855A CN 202211450153 A CN202211450153 A CN 202211450153A CN 115974855 A CN115974855 A CN 115974855A
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Abstract
The invention discloses an EZH2 and HDAC double-target inhibitor or a medicinal salt thereof, a medicinal composition containing the same, and a preparation method and application of the medicinal composition. The cyclic lactam structure in the structure of the compound of the general formula is a key pharmacophore for inhibiting the activity of EZH2, and the hydroxamic acid part can effectively inhibit the activity of HDAC, thereby realizing double inhibition of EZH2 and HDAC, having stronger activity, which can be used for preventing and/or treating diseases related to double targets of EZH2 and HDAC, especially tumors, cancers and inflammatory intestinal diseases, such as lymphoma, sarcoma, melanoma, lung cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, thyroid cancer, laryngeal cancer, tongue cancer, head and neck cancer, multiple myeloma, B-cell lymphoma, leukemia and inflammatory intestinal diseases, and can play a synergistic role in preventing and treating tumors, cancers and inflammatory intestinal diseases.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to an EZH2 and HDAC double-target inhibitor or a medicinal salt thereof, and a preparation method and application thereof.
Background
Currently, in the field of EZH2 and HDAC dual-target inhibitors, only two articles are reported, the first article is the first EZH2 and HDAC dual-target inhibitor reported by ACS Med Chem Lett, although the compound reported in the article has strong inhibitory activity to two targets, the inhibitory activity to tumor cell proliferation is at a medium level, and combined administration is required. Another is a double-target EZH2 and HDAC inhibitor published in the Journal of Medicinal Chemistry, which reports that the lead compound shows strong activity both at the enzyme level and the cellular level, but the research does not disclose that the double-target EZH2 and HDAC inhibitor can treat inflammatory intestinal diseases, so the development of new double-target EZH2 and HDAC inhibitors is still of great significance.
Disclosure of Invention
Based on the above needs in the art, the present invention provides a dual target inhibitor of EZH2 and HDAC.
In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is an oxygenated heterocycloalkyl, cycloalkyl or L-C (O) -, wherein L is alkyl, cycloalkyl or aryl;
R 2 is alkyl or alkoxy;
x may be aryl (alkoxy), (aryl) (amido) alkyl, (alkynyl) alkyl, (aryl) (alkoxy) aryl, (aryl) (alkoxy) (aryl) alkenyl, aryl, or aryl (alkenyl).
Preferably, said R is 1 When the group is an oxygen-containing heterocyclic group, 4-tetrahydropyranyl group and 3-tetrahydrofuranyl group are preferable.
Preferably, said R is 1 When L-C (O) -, L in the L-C (O) -is C 1-6 Alkyl or C 3-8 A cycloalkyl group.
Preferably, said R is 2 Is C 1-6 Alkyl or C 1-6 An alkoxy group.
Preferably, said R is 2 Is methyl or methoxy.
Preferably, X is selected from C 6-10 Aryl radical (C) 1-8 Alkoxy group), (C) 6-10 Aryl) (amido) C 1-8 Alkyl, (alkynyl) C 1-6 Alkyl, (C) 6-10 Aryl) (C 1-3 Alkoxy) C 6-10 Aryl group, (C) 6-10 Aryl) (C 1-3 Alkoxy) (C 6-10 Aryl) alkenyl, C 6-10 Aryl or C 6-10 Aryl (alkenyl).
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from table 1.
A second aspect of the present invention provides a pharmaceutical composition comprising an effective amount of the above-described compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides the use of the above compound or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the preparation of an EZH2 and HDAC dual-target inhibitor.
In a fourth aspect, the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use in the prevention and/or treatment of tumors and/or cancer and/or inflammatory bowel diseases.
In a fourth aspect, the present invention provides said dual target inhibitors of EZH2 and HDAC for the prevention and/or treatment of tumors and/or cancer and/or inflammatory bowel disease, in particular cancer. Preferably, the cancer comprises lymphoma, sarcoma, melanoma, lung cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, thyroid cancer, laryngeal cancer, tongue cancer, head and neck cancer, multiple myeloma, B-cell lymphoma, leukemia, inflammatory bowel disease.
The beneficial effects of the invention at least comprise:
the use of both EZH2 inhibitors and HDAC inhibitors with synergistic antitumor activity has been reported in the literature, and this provides a theoretical basis for the development of dual-target EZH2 and HDAC drugs. The cyclic lactam structure in the structure of the EZH2 and HDAC dual-target inhibitor of the present invention is a key pharmacophore for inhibiting EZH2 activity, and the hydroxamic acid moiety can effectively inhibit HDAC activity, thereby achieving dual inhibition of EZH2 and HDAC, having stronger activity, which can be used for preventing and/or treating diseases associated with EZH2 and HDAC dual-target, especially tumors and/or cancers and/or inflammatory bowel diseases, such as lymphoma, sarcoma, melanoma, lung cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, thyroid cancer, laryngeal cancer, tongue cancer, head and neck cancer, multiple myeloma, B-cell lymphoma, leukemia, inflammatory bowel diseases, and can play a synergistic role in the prevention and treatment of tumors, cancers and inflammatory bowel diseases.
The features and advantages of the present invention will be described in detail in the detailed description that follows.
Drawings
FIGS. 1 (a) and 1 (b) show the results of the inhibition rate of EZH2 at 100nM by 132 representative compounds of the present invention.
FIGS. 2 (a) and 2 (b) show the inhibition of HDAC cocktail enzyme (Hela nuclear extract) by 132 representative compounds of the present invention at 200 nM.
FIG. 3 is a graph showing the results of an immunoblot assay of EH-19.
FIG. 4 shows that EH-19 is effective in inhibiting ulcerative colitis in mice, significantly extending the colon length of the mice.
FIG. 5 is a bar graph showing that EH-19 is effective in inhibiting ulcerative colitis in mice, significantly extending the length of the colon in mice.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings and specific embodiments. Examples of which are illustrated in the accompanying drawings. It should be understood that the specific examples described in the following detailed description of the invention are intended merely as illustrations of specific embodiments of the invention, and are not intended to limit the invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to encompass values close to these ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein. In the description of the present application, the terms "a", "an", "the" and the like mean two or more unless otherwise specified.
[ glossary of terms ]
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value.
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed.
As used herein, definitions of standardized chemical terms (e.g., radicals) can be found in the literature references in the field.
Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a definition is specifically given, the terminology used herein in connection with the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C 1-6 Alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably and refer to a stereoisomer, enantiomer, or pharmaceutically acceptable salt of a compound of general formula (la). The term also includes racemates, optical isomers, isotopic compounds (e.g., deuterated compounds), or prodrugs.
"stereoisomers" refers to compounds consisting of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When the compounds of the present invention contain an olefinic double bond, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
Conventional techniques for preparing/separating the individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.
The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes of compounds that can be listed as the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms comprising such compounds are within the scope of the present invention. Certain isotopically-labeled compounds, for example, radioisotopes, are also useful in the present invention for use in tissue distribution assays for drugs and substrates. For example tritium, i.e. 3 H and carbon 14, i.e. 14 C, their preparation and detection are relatively easy. Is the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e. 2 H, due toTheir good metabolic stability may be advantageous in certain therapies, for example to increase the half-life in vivo or to reduce the dosage, and may therefore be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples. In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, perchlorate, and the like; organic acid salts include, but are not limited to, formates, acetates, p-toluenesulfonates, methanesulfonates, benzensulfonates, 2,2-dichloroacetate, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, pyroglutamate, citrates, isethionates, citrates, and the like. These salts can be prepared by methods known in the art.
As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to limit in any way the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.
Pharmaceutical compositions and methods of administration
The pharmaceutical composition provided by the invention is used for preventing and/or treating cancers, immune diseases, metabolic diseases and the like. In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to a living body, facilitate absorption of the active ingredient, and exert biological activity. The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
The compound can be widely used for preventing and/or treating diseases related to EZH2 and HDAC double targets, in particular for preventing and/or treating tumors and/or cancers and/or inflammatory intestinal diseases. The term "preventing" as used herein includes reducing the likelihood of occurrence or worsening of a disease or disorder in a subject.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., arresting its development;
(iii) Alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv) Alleviating the symptoms caused by the disease or disorder.
The "cancer" or "tumor" of the present invention includes, but is not limited to, lymphoma, sarcoma, melanoma, lung cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, thyroid cancer, laryngeal cancer, tongue cancer, head and neck cancer, multiple myeloma, B-cell lymphoma, leukemia, etc.
The "inflammatory bowel disease" described herein includes Ulcerative colitis (Ulcerative colitis) and Crohn's disease.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant disorder-relieving effect. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art. In a preferred embodiment, the compounds and compositions of the present invention are administered orally, and formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units, such as tablets, capsules or cachets each containing a predetermined amount of the active ingredient. In other preferred embodiments, the compounds and compositions of the present invention are injections and powders.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor, and sesame oils or mixtures of these materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants.
The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary. The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities.
When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (including a human) in need of treatment at a dosage that is pharmaceutically acceptable for effective administration. For a person with a body weight of 60kg, the daily dose administered is usually 100 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.
The present invention also provides a method of treatment comprising the steps of: administering to a subject in need of treatment a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for inhibiting EZH2 and HDAC.
A process for the preparation of a compound of the formula
It is to be noted that various materials and reagents used in the following examples are materials and reagents commonly used in the art, and are commercially available; the amounts mentioned in the following examples are molar times.
Example 1
The method and the reagent: A. tetrahydropyranone, acetic acid, sodium triacetoxyborohydride, dichloroethane; B. acetaldehyde, acetic acid, sodium triacetoxyborohydride, dichloroethane; 1m lithium hydroxide, tetrahydrofuran; HOBt, EDCI, methylmorpholine, anhydrous DMSO; pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃ and overnight; F. anhydrous potassium carbonate, DMF; G. hydroxylamine potassium, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
dissolving 1 time of methyl 2-methyl-3-amino-5-bromobenzoate in anhydrous dichloroethane, adding 1.1 times of tetrahydropyranone at room temperature, adding 2 times of acetic acid, stirring at room temperature for 3 hours, adding 3 times of sodium triacetoxyborohydride, and reacting at room temperature overnight. The dichloroethane was distilled off under reduced pressure, then saturated sodium bicarbonate was added, extraction was carried out with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution 2 times, the ethyl acetate layer was dried over anhydrous sodium sulfate, and purification was carried out by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain pure product 1.
The compound 1 (1-fold amount) was dissolved in anhydrous dichloroethane, and 1.1-fold amount of acetaldehyde tetrahydrofuran solution (1M) was added thereto at room temperature, 2-fold amount of acetic acid was further added thereto, and after stirring at room temperature for 3 hours, 3-fold amount of sodium triacetoxyborohydride was added thereto, and the reaction was allowed to proceed overnight at room temperature. After removing dichloroethane by evaporation under reduced pressure, saturated sodium bicarbonate was added, extraction was performed with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution 2 times, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain pure product 2.
10 g of Compound 2 are dissolved in 30 ml of tetrahydrofuran, 30 ml of 1M aqueous lithium hydroxide solution are added and the mixture is stirred at room temperature overnight. The tetrahydrofuran was distilled off under reduced pressure, and the residual liquid was adjusted to pH 6-7 with 0.5M HCl. The resulting solid was filtered and washed 4 times with double distilled water to obtain pure product 3.
Dissolving a compound 3 (1 time of the amount of the compound 3), a compound 4 (1.2 times of the amount of the compound 4) and HOBt (1.5 times of the amount of the compound) in anhydrous DMSO, adding EDCI (2 times of the amount of the compound) and N-methylmorpholine (6 times of the compound) at room temperature, stirring the mixed solution at room temperature for 24 hours, and adding a sufficient amount of saturated sodium bicarbonate aqueous solution to enable the pH of the solution to reach 8-9. Stirring is continued for 1 hour, the mobile phone is filtered to obtain a light pink solid, and the light pink solid is washed by double distilled water for 3 times and petroleum ether for 3 times to finally obtain a pure product 5.
Compound 5 (1-fold amount), p-hydroxybenzoic acid (1.5-fold amount), sodium carbonate (3-fold amount) and tetrakistriphenylphosphine palladium (0.01-fold amount) were placed in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product 6 as a brown solid.
Compound 6 (1-fold amount) was dissolved in anhydrous DMF, and methyl bromoalkane (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Example 2
The method and the reagent: A. acetaldehyde, acetic acid, sodium triacetoxyborohydride, dichloroethane; B. triethylamine, anhydrous dichloromethane; 1m lithium hydroxide, tetrahydrofuran; HOBt, EDCI, methylmorpholine, anhydrous DMSO; pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃ and overnight; F. anhydrous potassium carbonate, DMF; G. hydroxylamine potassium, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
the compound 1 (1-fold amount) was dissolved in anhydrous dichloroethane, and 1.1-fold amount of acetaldehyde tetrahydrofuran solution (1M) was added thereto at room temperature, 2-fold amount of acetic acid was further added thereto, and after stirring at room temperature for 3 hours, 3-fold amount of sodium triacetoxyborohydride was added thereto, and the reaction was allowed to proceed overnight at room temperature. The dichloroethane was distilled off under reduced pressure, then saturated sodium bicarbonate was added, extraction was carried out with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution 2 times, the ethyl acetate layer was dried over anhydrous sodium sulfate, and purification was carried out by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain pure product 1.
Dissolving the compound 1 in anhydrous dichloromethane, adding 1.2 times of triethylamine, dropwise adding anhydrous dichloromethane solutions of different acyl chlorides under an ice bath condition, and stirring and reacting for 3 hours at room temperature. The product was purified by direct separation on silica gel column (petroleum ether: ethyl acetate = 6:1) to give pure 2.
Compound 2 (8 g) was dissolved in 30 ml of tetrahydrofuran, and 30 ml of 1M aqueous lithium hydroxide solution was added thereto and stirred at room temperature overnight. The tetrahydrofuran was distilled off under reduced pressure and the residual liquid was adjusted to pH 6-7 with 0.5M HCl. The resulting solid was filtered and washed 4 times with double distilled water to obtain pure product 3.
Dissolving a compound 3 (1 time of the amount of the compound 3), a compound 4 (1.2 times of the amount of the compound 4) and HOBt (1.5 times of the amount of the compound) in anhydrous DMSO, adding EDCI (2 times of the amount of the compound) and N-methylmorpholine (6 times of the compound) at room temperature, stirring the mixed solution at room temperature for 24 hours, and adding a sufficient amount of saturated sodium bicarbonate aqueous solution to enable the pH of the solution to reach 8-9. Stirring is continued for 1 hour, the mobile phone light pink solid is filtered, and the solution is washed by double distilled water for 3 times and petroleum ether for 3 times, so that a pure product 5 is finally obtained.
Compound 5 (1-fold amount), p-hydroxybenzoic acid (1.5-fold amount), sodium carbonate (3-fold amount) and palladium tetrakistriphenylphosphine (0.01-fold amount) were put in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed with a saturated aqueous sodium chloride solution 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50).
Compound 6 (1-fold amount) was dissolved in anhydrous DMF, and methyl bromoalkane (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Example 3
The method and the reagent are as follows: pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃ and overnight; hatu, DIPEA, anhydrous DMF; C. hydroxylamine potassium, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
the compound 1 (1 time), the pinacol ester of p-aminobenzeneboronic acid 2 (1.5 times), the sodium carbonate (3 times) and the palladium tetratriphenylphosphine (0.01 time) are placed in a double-mouth bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product 3 as a brown solid.
The compound 3 (1-fold amount) was dissolved in anhydrous DMF, and monomethyl diacid 4 (1.2-fold amount), HATU (1.5-fold amount) and DIPEA (3-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Example 4
The method and the reagent: pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃, and overnight; hatu, DIPEA, anhydrous DMF; C. potassium hydroxylamine, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
the compound 1 (1 time), the pinacol ester of p-aminobenzeneboronic acid 2 (1.5 times), the sodium carbonate (3 times) and the palladium tetratriphenylphosphine (0.01 time) are placed in a double-mouth bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed with a saturated aqueous sodium chloride solution 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50).
The compound 3 (1-fold amount) was dissolved in anhydrous DMF, and monomethyl diacid 4 (1.2-fold amount), HATU (1.5-fold amount) and DIPEA (3-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Example 5
The method and the reagent are as follows: pd (PPh) 3 ) 4 CuI, triethylamine, DMF,90 ℃ and over night; B. hydroxylamine potassium, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
compound 1 (1-fold amount), terminal alkynyl formate (1.1-fold amount), triethylamine (2-fold amount), cuprous iodide (0.1-fold amount), and palladium tetratriphenylphosphine (0.01-fold amount) were placed in a two-necked flask. The flask was replaced with argon. Argon purged DMF was added. The mixture was reacted at 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed with a saturated aqueous sodium chloride solution 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50).
Example 6
The method and the reagent: pd (PPh) 3 ) 4 CuI, triethylamine, DMF,90 ℃ and overnight; B. potassium hydroxylamine, anhydrous methanol, 1M hydrochloric acid.
The method comprises the following specific steps:
compound 1 (1-fold amount), terminal alkynyl formate (1.1-fold amount), triethylamine (2-fold amount), cuprous iodide (0.1-fold amount), and palladium tetratriphenylphosphine (0.01-fold amount) were placed in a two-necked flask. The flask was replaced with argon. Argon was added to drive off DMF. The mixture was reacted at 90 ℃ overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product 2 as a white solid.
Example 7
The method and the reagent are as follows: pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃ and overnight; B. potassium hydroxylamine, anhydrous methanol, 1M hydrochloric acid. Hatu, DIPEA, anhydrous DMF; C. anhydrous potassium carbonate, DMF.
The method comprises the following specific steps:
compound 1 (1-fold amount), compound 2 (1.5-fold amount), sodium carbonate (3-fold amount) and tetrakistriphenylphosphine palladium (0.01-fold amount) were placed in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product as a 3-position brown solid.
Compound 1 (1 time), p-hydroxy phenylboronic acid (1.5 times), sodium carbonate (3 times) and palladium tetratriphenylphosphine (0.01 times) were placed in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed with a saturated aqueous sodium chloride solution 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50).
Compound 4 (1-fold amount) was dissolved in anhydrous DMF, and methyl 4-bromomethylbenzoate (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Compound 4 (1-fold amount) was dissolved in anhydrous DMF, and Compound 6 (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
Example 8
The method and the reagent are as follows: pd (PPh) 3 ) 4 ,Na 2 CO 3 Dioxane, water, 90 ℃ and overnight; B. potassium hydroxylamine, anhydrous methanol, 1M hydrochloric acid. Hatu, DIPEA, anhydrous DMF; C. anhydrous potassium carbonate, DMF.
The method comprises the following specific steps:
compound 1 (1-fold amount), compound 2 (1.5-fold amount), sodium carbonate (3-fold amount) and tetrakistriphenylphosphine palladium (0.01-fold amount) were placed in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction was filtered through celite, and the filter cake was rinsed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product 3 as a brown solid.
Compound 1 (1 time), p-hydroxy phenylboronic acid (1.5 times), sodium carbonate (3 times) and palladium tetratriphenylphosphine (0.01 times) were placed in a two-necked bottle. The flask was replaced with argon. A mixture of argon-vented dioxane and water was added (v/v = 5:1). The mixture was reacted with 90 ℃ overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate until no fluorescence was eluted. The collected filtrate was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50) to obtain a pure product 4 as a brown solid.
Compound 4 (1-fold amount) was dissolved in anhydrous DMF, and methyl 4-bromomethylbenzoate (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
The compound 4 (1-fold amount) was dissolved in anhydrous DMF, and the compound 6 (1.2-fold amount) and anhydrous potassium carbonate (1.5-fold amount) were added. After stirring at room temperature overnight, the reaction mixture was added with saturated aqueous sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate layer was washed 3 times with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane: methanol = 50.
The number, nomenclature and structure of the representative compounds are shown in table 1 below:
the results of high resolution mass spectrometry for representative compounds are shown in table 2 below:
(first) enzyme activity inhibition results:
first, 132 compounds were tested for their inhibition of EZH2 at 100nM, comprising the following steps: mixing each 100nM of compound with 5nM of recombinant PRC2 complex in 50mM Tris (pH 8.6), 0.02% 2 And 1mM TCEP (total volume 40. Mu.l) for 30 minutes. Then, 3.3 μ M of H3K27me peptide and 100 μ M SAM were added and the mixture was incubated for another 3 hours. The luminescence of the samples was then measured in a BioTek Synergy 2 and the inhibition rate was calculated. The results are shown in FIGS. 1 (a) and 1 (b). As can be seen from the results, all 132 compounds exhibited strong inhibitory activity against EZH2 at a concentration of 100 nM.
Then 132 representative compounds were tested for their inhibition of HDAC cocktail enzyme (Hela nuclear extract) at 200nM, comprising the steps of: each compound solution at 200nM was mixed with HDAC mix enzyme, fluorogenic substrate (Boc-Lys (Ac) -pNA), BSA, and buffer solution, and reacted at 37 ℃ for 30 minutes. After completion of the reaction, HDAC Developer was added, incubated at 37 ℃ for another 15 minutes, and the fluorescence intensity (excitation wavelength 390nm, emission wavelength 460 nm) was measured to calculate the inhibition rate. The results are shown in FIGS. 2 (a) and 2 (b).
As can be seen from the results, all 132 compounds exhibited some inhibitory activity against HDAC at a concentration of 200 nM. And as the length of the connecting chain increases, the inhibitory activity increases. Compounds with a benzene ring or benzyl group as the linking chain have a low inhibition rate, since these compounds may inhibit mainly the HDAC6 subtype.
(II) the proliferation inhibition activity of individual compounds on human osteosarcoma cells HOS and follicular lymphoma cells was also tested, and the specific steps included: preparing single cell suspension by using culture solution containing 10% fetal calf serum, and inoculating 10000 cells per hole to a 96-hole plate, wherein the volume of each hole is 200 microliter; incubation for 72 hours after compound addition; then 20. Mu.l MTT solution (5 mg/ml in PBS) was added to each wellRaising and continuing to incubate for 4 hours; the culture was terminated, and the culture supernatant in the well was carefully aspirated, and after centrifugation was required for suspension cells, the culture supernatant in the well was aspirated. Adding 150 microliters of DMSO into each hole, and oscillating for 10 minutes to fully melt the crystal; selecting 490nm wavelength, measuring light absorption value of each well on enzyme-linked immunosorbent assay, recording result, drawing cell growth curve with time as abscissa and light absorption value as ordinate, and calculating GI 50 The value is obtained. The results are shown in table 3 below:
as can be seen from the results, representative compounds exhibited strong proliferation inhibitory activity against both cancer cells, and individual compounds GI 50 Values were most active at the submicromolar level, especially compound EH-19, and superior to the two positive controls, tazemetostat and SAHA.
(III) in a western blot experiment, HOS cells were first incubated with different concentrations of EH-19 or DMSO for 48 hours; cells were washed three times with 1mL cold PBS and lysed in 50 μ Ι _ cold RIPA buffer for 10 min; cell lysates were centrifuged at 12000rpm for 15 min at 4 ℃; protein concentration was determined by BCA method; the same amount of cell extract was separated by SDS-PAGE and transferred to nitrocellulose membrane; treated with an Ac-HH3 antibody and an H3K27me3 antibody. As a result, it was found that: the compound EH-19 can significantly reduce the expression of H3K27me3 in HOS cells and increase the expression of Ac-histone H3 in a dose-dependent manner, as shown in FIG. 3, and the result further proves that the compound is an EZH2 and HDAC dual-target inhibitor.
(IV) it was also tested whether compound EH-19 could ameliorate colitis in mice. The method comprises the following specific steps: mice were randomly assigned into three groups (n =10 mice per group): group 1, physiological saline and dimethyl sulfoxide (5%, v/v); group 2 was given DSS (2%, w/v), saline and DMSO; group 3 was a dosing group containing EH-19, DSS (2%, w/v), physiological saline and DMSO (5%, v/v). EH-19 was administered at a dose of 5mg per kg orally once a day for 8 consecutive days, and after 8 days, the mice were sacrificed, the colon removed, and the length measured.
As a result, it was found that: EH-19 was also effective in inhibiting DSS-induced mouse ulcerative colitis at a dosing dose of 5mg per kg, significantly extending the colon length of the mice (as shown in fig. 4), where the colon length of the normal control group (i.e., normal mice) mice averaged 12.3 cm, the DSS group was 7.6 cm, and the DSS + EH-19 group was 10.5 cm, as shown in fig. 5, demonstrating that compound EH-19 can significantly ameliorate DSS-induced mouse colitis.
Finally, the above embodiments are only used to illustrate the technical solutions of the present invention, and do not limit the present invention. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an oxygen-containing heterocycloalkyl, cycloalkyl or L-C (O) -, wherein L is alkyl, cycloalkyl or aryl;
R 2 is alkyl or alkoxy;
x may be aryl (alkoxy), (aryl) (amido) alkyl, (alkynyl) alkyl, (aryl) (alkoxy) aryl, (aryl) (alkoxy) (aryl) alkenyl, aryl, or aryl (alkenyl).
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 When it is an oxygen-containing heterocyclic group, it is selected from 4-tetrahydropyridineFuryl and 3-tetrahydrofuryl.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 When L-C (O) -, L in the L-C (O) -is C 1-6 Alkyl or C 3-8 A cycloalkyl group.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 2 Is C 1-6 Alkyl or C 1-6 An alkoxy group.
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein R is 2 Is methyl or methoxy.
6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from C 6-10 Aryl radical (C) 1-8 Alkoxy group), (C) 6-10 Aryl) (amido) C 1-8 Alkyl, (alkynyl) C 1-6 Alkyl, (C) 6-10 Aryl) (C 1-3 Alkoxy) C 6-10 Aryl group, (C) 6-10 Aryl) (C 1-3 Alkoxy) (C 6-10 Aryl) alkenyl, C 6-10 Aryl or C 6-10 Aryl (alkenyl).
7. A compound or pharmaceutically acceptable salt thereof, wherein said compound is selected from table 1.
8. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or carrier.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of an EZH2 and HDAC dual-target inhibitor.
10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use in the prevention and/or treatment of tumours and/or cancer and/or inflammatory bowel disease.
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