Novel resveratrol derivative as well as preparation method and application thereof

Abstract

The invention provides a novel resveratrol derivative as well as a preparation method and application thereof. Specifically, the invention provides a compound or a pharmaceutically acceptable salt thereof, and the compound is shown as a formula A, wherein the variables are as defined herein. The resveratrol derivative provided by the invention has an excellent effect of inhibiting tumor cell proliferation. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology and pharmaceutical chemical synthesis, and specifically relates to a resveratrol derivative and a preparation method and application thereof. Background Art

[0002] Colorectal cancer is the third most common adult cancer and the second most deadly cancer in the world. The occurrence of colorectal cancer is related to many pathophysiological mechanisms, such as abnormal cell proliferation, cell differentiation, anti-apoptosis, invasion of adjacent structures of colorectal tumor cells and distant metastasis. The occurrence of colorectal cancer is related to multiple genes and multiple signaling pathways.

[0003] Resveratrol is a stilbene compound widely found in many plants. Its main pharmacological effects include anti-cancer, anti-inflammatory, antioxidant, antibacterial, anti-aging and chemotherapy protection. Studies have shown that resveratrol can play an anti-colorectal cancer role in vitro and in vivo experiments through a variety of pathways; in human colorectal cancer cells HCT116 and SW480, resveratrol inhibits cancer cell proliferation and invasion in a dose-dependent manner. However, its effectiveness and safety in clinical applications still face many challenges. First, the low bioavailability of resveratrol leads to limited effective concentration in the body, which limits its actual efficacy. Studies have shown that the IC50 value of resveratrol on cancer cells is usually greater than 100 μM. This indicates that it needs to be at high concentrations to exert significant anti-cancer effects. Secondly, in the pharmacological study of resveratrol, it was found that the in vitro and in vivo efficacy of resveratrol was inconsistent, which is because some active sites of resveratrol are not recognized by biological systems. In addition, the long-term safety of resveratrol has not been fully verified, and it may interact with certain drugs, further increasing the complexity of clinical use. Therefore, resveratrol cannot meet the need.

[0004] In summary, there is an urgent need in the art to develop a class of resveratrol derivatives with novel structures and improved activities to meet clinical needs. Summary of the invention

[0005] The purpose of the present invention is to provide a class of resveratrol derivatives with novel structures and preparation methods and applications thereof.

[0006] In the first aspect of the present invention, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is as shown in Formula A;

[0007]

[0008] in,

[0009] R is N (R 1 )R 2 or OH;

[0010] R 1 is H or C1-4 alkyl;

[0011] R 2 For R 8 or -W 1 -R 8 ;

[0012] Or, R 1 and R 2 and together with the nitrogen atom to which they are attached form an optionally substituted 4- to 7-membered nitrogen-containing heteroalkyl group;

[0013] R 3 Selected from the group consisting of H, optionally substituted C1-4 alkyl, hydroxy, optionally substituted C1-4 alkoxy, halogen;

[0014] R 4 , R 5 , R 6 and R 7 Each is independently selected from the group consisting of H, optionally substituted C1-4 alkyl, hydroxy, optionally substituted C1-4 alkoxy, halogen;

[0015] R 8 is selected from the group consisting of an optionally substituted C1-6 alkyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group, an optionally substituted C6-10 aryl group, and an optionally substituted 5- to 10-membered heteroaryl group;

[0016] W 1 Selected from the group consisting of C1-2 alkylene, -SO2-;

[0017] The optionally substituted group means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl and C1-4 alkoxy.

[0018] In another preferred embodiment, R 4 , R 5 , R 6 and R 7 For H.

[0019] In another preferred embodiment, the compound is as shown in formula B;

[0020]

[0021] Among them, R and R 3 As defined above.

[0022] In another preferred embodiment, R 3 is hydroxy, or optionally substituted C1-4 alkoxy.

[0023] In another preferred embodiment, R 3 is an optionally substituted C1-4 alkoxy group.

[0024] In another preferred embodiment, R 3 It is a C1-4 alkoxy group.

[0025] In another preferred embodiment, the compound is as shown in Formula C;

[0026]

[0027] Wherein, R is as defined above.

[0028] In another preferred embodiment, R is N(R 1 )R 2 .

[0029] In another preferred embodiment, R is selected from the following group:

[0030]

[0031] In another preferred embodiment, the compound is as shown in Formula A1;

[0032] (A1)

[0033] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined above.

[0034] In another preferred embodiment, R 1 For H.

[0035] In another preferred embodiment, W 1 It is methylene or -SO2-.

[0036] In another preferred embodiment, the 4- to 7-membered nitrogen-containing heteroalkyl group contains only one nitrogen atom as a heteroatom. In another preferred embodiment, the 4- to 7-membered nitrogen-containing heteroalkyl group is saturated.

[0037] In another preferred embodiment, R is OH.

[0038] In another preferred embodiment, the compound is as shown in Formula A2;

[0039] (A2)

[0040] In another preferred embodiment, R 1 is H;

[0041] R 2 For R 8or -W 1 -R 8 ;

[0042] Or, R 1 and R 2 and the nitrogen atoms to which they are attached together form an optionally substituted 4- to 7-membered nitrogen-containing heteroalkyl group; wherein the 4- to 7-membered nitrogen-containing heteroalkyl group contains only one nitrogen atom as a heteroatom;

[0043] W 1 is methylene or -SO2-;

[0044] R 8 is selected from the group consisting of an optionally substituted C1-6 alkyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group, an optionally substituted C6-10 aryl group, and an optionally substituted 5- to 10-membered heteroaryl group;

[0045] R 3 is a C1-4 alkoxy group;

[0046] R 4 , R 5 , R 6 and R 7 For H.

[0047] The optionally substituted group means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl and C1-4 alkoxy.

[0048] In another preferred embodiment, the compound is selected from the following table:

[0049]

[0050]

[0051] In another preferred embodiment, the compound is selected from the group consisting of RE-02, RE-03, RE-05, RE-06, RE-07, RE-08, RE-09 and RE-10.

[0052] In another preferred embodiment, the compound is selected from the group consisting of RE-02, RE-05, RE-06 and RE-07.

[0053] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising (i) the compound according to the first aspect or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.

[0054] In the third aspect of the present invention, there is provided a use of the compound as described in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0055] In another preferred embodiment, the tumor is colorectal cancer.

[0056] In a fourth aspect of the present invention, there is provided a method for preparing the compound as described in the first aspect, the method comprising step (S1), step (S2) and an optional step (S3);

[0057] (S1) in an inert solvent and in the presence of a base, subjecting the intermediate represented by formula INT1 to a Rap-stoermer reaction with a reaction reagent represented by formula INT2 to obtain an intermediate represented by formula INT3;

[0058]

[0059] (S2) subjecting the intermediate represented by formula INT3 to a demethylation reaction in an inert solvent in the presence of a base to obtain a compound represented by formula A2, i.e., a compound represented by formula I in which R is a hydroxyl group;

[0060]

[0061] (S3) subjecting the compound represented by formula A2 to an intermediate represented by formula INT4 to an amide condensation reaction, thereby obtaining a compound represented by formula A1, wherein R is N(R 1 )R 2 The compound as shown in formula I;

[0062]

[0063] In each formula, X is Cl, Br or F; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in the first aspect.

[0064] In a fifth aspect of the present invention, an intermediate is provided, wherein the intermediate is as shown in formula INT1, INT3 or A2

[0065]

[0066] Among them, R 3 , R 4 , R 5 , R 6 and R 7 As defined in the first aspect.

[0067] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] none DETAILED DESCRIPTION

[0069] After long-term and in-depth research, the inventor unexpectedly discovered a class of resveratrol derivatives with novel structures. Such derivatives have excellent activity in inhibiting tumor cell proliferation. Based on this, the inventor completed the present invention.

[0070] the term

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. As used herein, the term "about" when used in reference to a specific listed value means that the value may vary by no more than 1% from the listed value. For example, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0072] As used herein, unless otherwise defined, the term "alkyl" by itself or as part of another substituent refers to a straight or branched hydrocarbon group having the specified number of carbon atoms (i.e., C1-6 represents 1-6 carbons, C1-4 represents 1-4 carbons). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0073] As used herein, unless otherwise indicated, the term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkane as defined above. An alkylene group typically has 1 to 4 (preferably 1 or 2) carbon atoms.

[0074] Unless otherwise stated, in this article, the term "cycloalkyl" refers to a hydrocarbon ring (preferably a fully saturated hydrocarbon ring) having a specified number of ring atoms (e.g., C3-10 cycloalkyl, C4-6 cycloalkyl) and fully saturated or having no more than one double bond between the ring tops. The term also includes bicyclic and polycyclic hydrocarbon rings, such as bridged rings, fused rings, spiro rings, etc.

[0075] Unless otherwise stated, in this article, the term "heterocycloalkyl" refers to a cycloalkyl group having a specified number of ring atoms (e.g., 4-10 membered heterocycloalkyls) and containing one to five heteroatoms selected from N, O and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Heterocycloalkyl can be a monocyclic, bicyclic or polycyclic system (e.g., a bridged ring, a ring, a spirocyclic ring, etc.). Non-limiting examples of heterocycloalkyls include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Heterocycloalkyl can be connected to the rest of the molecule via a ring carbon or a heteroatom.

[0076] Unless otherwise indicated, the term "aryl" herein refers to a polyunsaturated (usually aromatic) hydrocarbon group which may be a single ring or multiple rings (up to three) fused together or linked covalently. Non-limiting examples of aryl include phenyl, naphthyl, biphenyl and the like.

[0077] Unless otherwise indicated, in this document, the term "heteroaryl" refers to an aryl group (or ring) having the specified number of ring atoms and containing 1 to 5 heteroatoms selected from N, O, and S (e.g., 5 to 10-membered heteroaryl or 5 to 6-membered heteroaryl), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group can be attached to the rest of the molecule through a carbon atom or a heteroatom. Non-limiting examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like.

[0078] Unless otherwise indicated, herein, the term "alkoxy" is used in its conventional sense to refer to an alkyl group as defined above attached to the remainder of the molecule via an oxygen atom. Examples of alkoxy groups include, for example, methoxy, ethoxy, and the like.

[0079] Unless otherwise stated, in this article, "halogen" refers to F, Cl, Br, and I. More preferably, the halogen atom is selected from F, Cl and Br. Similarly, halo refers to a group in which one or more hydrogens are replaced by halogen atoms. Examples of haloalkyl include, for example, trifluoromethyl (-CF3) and the like.

[0080] In some embodiments, unless otherwise defined, the above terms (such as "alkyl", "aryl" and "heteroaryl", etc.) will include substituted and unsubstituted forms of the specified groups. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to substituted or unsubstituted forms as provided below, while the term "alkyl" and related aliphatic groups refer to unsubstituted forms unless indicated to be substituted.

[0081] Unless otherwise defined, substituents on alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) may be various groups selected from the group consisting of: -halogen, -OR a 、-NR a R b 、-SR a 、-SiR a R b R c 、-OC(O)R a 、-C(O)R a 、-CO2R a 、-CONR a R b 、-OC(O)NR a R b 、-NR b C(O)R a 、-NR a -C(O)NR b R c 、-NR b C(O)2R a 、-NH-C(NH2)=NH、-NR a C(NH2)=NH、-NH-C(NH2)=NR a 、-S(O)R a 、-S(O)2R a 、-S(O)2NR a R b 、-NR a S(O)2R b , -CN and -NO2, in numbers ranging from zero to (2M+1), where M is the total number of carbon atoms in the group. a , R b and R c Each independently represents hydrogen, unsubstituted C 1-8Alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted -C 1-4 Alkylene-aryl. When R a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. a R b It is meant to include 1-pyrrolidinyl and 4-morpholinyl.

[0082] Similarly, unless otherwise defined, substituents for aryl and heteroaryl groups are varied and are typically selected from: -halogen, -OR a 、-OC(O)R a 、-NR a R b 、-SR a , -R a 、-CN、-NO2、

[0083] -CO2R a 、-CONR a R b 、-C(O)R a 、-OC(O)NR a R b 、-NR b C(O)R a 、-NR b C(O)2R a 、-NR a -C(O)NR b R c 、-NH-C(NH2)=NH、-NR a C(NH2)=NH、-NH-C(NH2)=NR a 、-S(O)R a 、-S(O)2R a 、-S(O)2NR a R b 、-NR a S(O)2R b , -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, from zero to the total number of open valences on the aromatic ring system; wherein R a , R b and R c are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8Alkynyl, unsubstituted aryl and heteroaryl, unsubstituted -C 1-4 Alkylene-aryl or heteroaryl and unsubstituted -C 1-4 Alkylene-aryloxy.

[0084] As used herein, unless otherwise defined, a bond represented by a dashed line or a bond marked with a wavy line symbol represents a position of attachment to another site in the molecule.

[0085] For the compounds provided herein, a bond from a substituent (typically an R group) to the center of a ring will be understood to mean a bond providing attachment at any available vertex of the aromatic ring.

[0086] Resveratrol derivatives

[0087] As used herein, the term "resveratrol derivative" (also referred to herein as "resveratrol-benzofuran derivative" or "compound of the present invention") refers to the compound as described in the first aspect. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound.

[0088] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0089] Herein, the term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0090] In addition, the compounds of the present invention also include prodrugs of the compounds. The term "prodrug" includes a compound that may be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds as described in the first aspect, or a salt or solution composed of the compounds as described in the first aspect. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0091] The resveratrol of the present invention can be prepared by using resveratrol as a raw material, and undergoing a Vilsmeier formylation reaction to generate resveratrol aldehyde, and then undergoing methylation to obtain resveratrol aldehyde trimethyl ether, and then selectively removing the methyl group ortho to the aldehyde group under the catalysis of boron trichloride, and then undergoing a Rap-stoermer reaction with α-bromoacetic acid methyl ester to generate a furan ring structure, and finally obtaining a series of resveratrol derivatives through hydrolysis and amide condensation. The synthetic route involved in the preparation method is simple to operate, the raw materials are cheap and easy to obtain, and the total yield is high. At the same time, the present invention also lays a foundation for the synthesis and structure-activity relationship of resveratrol derivatives, and provides a new candidate drug of a resveratrol skeleton structure derivative with better activity.

[0092] In some aspects, provided herein is a compound (resveratrol derivative) or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (A), formula (B) or formula (C);

[0093] (A)

[0094] (B)

[0095] (C)

[0096] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in the first aspect.

[0097] In some aspects, the present invention provides a compound (resveratrol derivative) or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (I);

[0098]

[0099] wherein R is as defined in the first aspect.

[0100] In some preferred embodiments, R is a group selected from the group consisting of:

[0101]

[0102] Pharmaceutical compositions and methods of administration

[0103] Since the compounds provided by the present invention have excellent activity in inhibiting the proliferation of tumor cells (especially human colon cancer cell HCT116), the compounds of the present invention can be used to treat a variety of tumors or cancers (such as colorectal cancer, etc.).

[0104] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.

[0105] "Safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is one capsule or tablet.

[0106] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0107] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0108] 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, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl 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 the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0109] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0110] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0111] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0112] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0113] Compositions for parenteral injection may include 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0114] Dosage forms for topical administration of the compounds of the invention 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 that may be required.

[0115] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0116] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0117] Preparation method

[0118] In some aspects, the present invention also provides methods for preparing the resveratrol derivatives of the present invention (or compounds of the present invention) and intermediates.

[0119] In some embodiments, a method for preparing a resveratrol derivative according to Formula I is provided, comprising steps (1) to (5) or (1) to (6) of the following steps:

[0120] (1) subjecting resveratrol to a formylation reaction in an inert solvent in the presence of DMF and phosphorus oxychloride to obtain resveratrol aldehyde;

[0121]

[0122] (2) Under base catalysis conditions, in an inert solvent, the obtained resveratrol aldehyde and methyl iodide are subjected to an etherification reaction to obtain resveratrol aldehyde trimethyl ether;

[0123]

[0124] (3) subjecting resveratrol aldehyde trimethyl ether to a selective demethylation reaction in an inert solvent in the presence of a demethylating agent to obtain (E)-2-hydroxy-4-methoxy-6-(4-methoxyphenyl)benzaldehyde;

[0125]

[0126] (4) in an inert solvent, in the presence of a base, subjecting (E)-2-hydroxy-4-methoxy-6-(4-methoxyphenylvinyl)benzaldehyde and methyl α-bromoacetate to a Rap-stoermer reaction to obtain methyl (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylate;

[0127]

[0128] (5) in an inert solvent, under base catalysis, subjecting (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid methyl ester to a demethylation reaction to obtain a resveratrol derivative as shown in Formula I (wherein R is a hydroxyl group, i.e., (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid); and

[0129]

[0130] (6) (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid and R 2 -NH2 or its salt to carry out amide condensation reaction, thereby obtaining the resveratrol derivative shown in formula I (wherein R is NHR 2 );

[0131]

[0132] In some embodiments, in step (1), the reaction temperature of the formylation is 0-50°C; and / or the reaction time is 18-20 hours; and / or the inert solvent is acetonitrile, water or a combination thereof; and / or the molar ratio of resveratrol, DMF and phosphorus oxychloride is 1:(0.7-1.3):(1-2) (preferably 1:1:1.5).

[0133] In some embodiments, in step (2), the base is anhydrous potassium carbonate; and / or the molar ratio of potassium carbonate to resveratrol aldehyde is (3-5):1; the inert solvent is acetone; and / or the reaction temperature is 50-70°C, such as 60°C; and / or the reaction time is 8-16h; and / or the molar ratio of resveratrol aldehyde to methyl iodide is 1:(2-6), such as 1:4.

[0134] In some embodiments, in step (3), the inert solvent is dichloromethane such as anhydrous dichloromethane; and / or the reaction temperature is from 0°C to room temperature (such as 0 to 30°C); and / or the reaction time is 2 to 4 hours; and / or the demethylation agent is BCl3 (preferably a dichloromethane solution of BCl3, more preferably a 0.5-2 mol / L such as a 1 mol / L dichloromethane solution of BCl3); and / or the molar ratio of the resveratrol aldehyde trimethyl ether and the demethylation agent used is 1:(1-3) (preferably 1:(1.5-3); more preferably 1:2).

[0135] In some embodiments, in step (4), the reaction temperature of the Rap-stoermer reaction is room temperature to 80°C, such as 25°C to 80°C; and / or the reaction time is 12 to 18 hours; and / or the base is a carbonate (preferably sodium carbonate, potassium carbonate or a combination thereof; more preferably, potassium carbonate such as anhydrous potassium carbonate); and / or the inert solvent is DMF; and / or the molar ratio of (E)-2-hydroxy-4-methoxy-6-(4-methoxyphenyl)benzaldehyde to α-methyl bromoacetate is 1:(1-2) (preferably 1:(1-1.5); more preferably 1:1.2).

[0136] In some embodiments, in step (5), the inert solvent is a composite solvent of tetrahydrofuran and water; and / or the reaction temperature is room temperature (such as 20-30° C.); and / or the reaction time is 3 to 6 hours; and / or the base is lithium hydroxide; and / or the molar ratio of the base (such as lithium hydroxide) to (E)-6-methoxy-4-(4-methoxyphenyl)benzofuran-2-carboxylic acid methyl ester is (4 to 8):1.

[0137] In some embodiments, in step (6), the amide condensation reaction is carried out in a polar aprotic solvent in the presence of HATU and DIPEA.

[0138] In some embodiments, in step (6), the polar aprotic solvent is THF or DMF; and / or, R 2 -NH2 or its salts (also referred to as amino-containing molecules) include methylamine hydrochloride, cyclopropylamine, cyclohexylamine hydrochloride, 3-fluoroaniline, benzylamine, pyrrolidine and 3-hydroxypyrrolidine; and / or, the (E)-6-methoxy-4-(4-methoxyphenyl)benzofuran-2-carboxylic acid, HATU, DIPEA and R 2 -NH2 or its salt has a molar ratio of 1:(0.8-1.2):(2-6):(1-1.5) (preferably 1:1:4:1.2); and / or, the reaction temperature of the amide condensation reaction is room temperature (eg, 20-30°C); and / or, the reaction time is 4 to 8 hours.

[0139] In some embodiments, in step (6), the amide condensation reaction is carried out in a polar aprotic solvent in the presence of EDCI and DMAP.

[0140] In some embodiments, R 2 -NH2 or its salt is a molecule containing a sulfonamide amino group (i.e. 1 is -SO2-).

[0141] In some embodiments, the polar aprotic solvent is DMF; and / or, R 2 -NH2 or its salt (i.e., molecule containing sulfonamide amino group) includes benzenesulfonamide and 4-(trifluoromethyl)benzenesulfonamide; and / or, the amount of (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid, EDCI, DMAP and molecule containing sulfonamide amino group satisfies that the molar ratio of (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid, EDCI, DMAP and molecule containing sulfonamide amino group is 1:(0.7-1.3):(1.5-3):(1-1.2) (preferably, 1:1.2:2:1.1); and / or, the reaction temperature of the amide condensation reaction is room temperature (e.g., 20-30°C); and / or, the reaction time is 4 to 8h.

[0142] In some embodiments, the preparation method of the compound is as shown in the following formula:

[0143]

[0144] The main advantages of the present invention include:

[0145] (a) The compounds of the present invention have excellent effects of inhibiting tumor cell proliferation.

[0146] (b) The compounds of the present invention are easy to synthesize, the raw materials are cheap and readily available, and the overall yield of the synthesis is high.

[0147] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0148] Preparation Example

[0149] Example 1: Synthesis of (E)-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxylic acid (RE-01)

[0150]

[0151] Weigh 2.3g (10.08mmol) of resveratrol, dissolve it in 50mL of acetonitrile in a 100mL three-necked flask, add 0.73g (10mmol) of N,N-dimethylformamide (DMF), cool to 0℃ in an ice bath, add 2.3g (15mmol) of phosphorus oxychloride, keep warm for 30min after the addition, then raise to room temperature and react overnight, and a red precipitate is generated. Monitor the reaction on a TLC plate. After the reaction is completed, filter the reaction solution, collect the red precipitate and wash it with cold acetonitrile. Add the red precipitate to 200mL of ice water, adjust the pH to neutral with a dilute NaOH solution, heat to 50℃ for hydrolysis for 3 hours, and the generated yellow precipitate is the target product. The reaction solution was extracted with ethyl acetate for multiple times. The organic phases were combined, washed with water and saturated sodium chloride solution, and finally dried with anhydrous sodium sulfate to remove water. After solid-liquid separation, the product was concentrated under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate C1 (resveratrol aldehyde) as a yellow solid with a yield of 67%.

[0152]

[0153] 1 g (3.9 mmol) of intermediate C1 was weighed and dissolved in a 50 mL three-necked flask with 10 mL of acetone, and 2.22 g (15.6 mmol) of methyl iodide and 1.63 g (11.8 mmol) of potassium carbonate were added, and the mixture was refluxed at 60°C for overnight reaction. TLC tracking was performed, and after the reaction was complete, K2CO3 was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate C2 as a light yellow solid with a yield of 90%.

[0154]

[0155] Weigh 1.5g (5.03mmol) of intermediate C2, dissolve it in 100mL reaction bottle with 40mL anhydrous dichloromethane, cool to 0℃ in ice bath, add 10mL of 1M BCl3 dichloromethane solution, keep warm for 30min and then warm to room temperature for 2 hours. TLC tracking detection, quench with ice water after the reaction is complete, concentrate under reduced pressure, dissolve with saturated NaHCO3 aqueous solution, extract three times with 50mL ethyl acetate, combine the organic phases and wash with water and saturated sodium chloride solution, finally dry with anhydrous sodium sulfate to remove water, concentrate under reduced pressure after solid-liquid separation, and obtain intermediate C3 as a yellow solid with a yield of 85%. 1H NMR(400MHz,Chloroform-d)δ12.47(s,1H),10.21(s,1H),7.48-7.42(m,2H),7.37(d,J=15.9Hz,1H),6 .97-6.88(m,3H),6.60(dd,J=2.4,0.6Hz,1H),6.35(d,J=2.4Hz,1H),3.86(d,J=12.2Hz,6H).ESI-Mass for C 18 H 16 O4:m / z(MH) + 283.1, found 282.4.

[0156]

[0157] 3 g (10.56 mmol) of intermediate C3, 2.42 g (15.82 mmol) of methyl bromoacetate, and 5.83 g (42.18 mmol) of anhydrous potassium carbonate were weighed and dissolved in a 100 mL three-necked flask with 40 mL of DMF. The mixture was reacted at room temperature for 2 hours, followed by TLC detection. After the reaction of the raw materials was completed, the temperature was raised to 80 ° C and the reaction was continued overnight. After the reaction was completed by TLC detection, the reaction solution was filtered, washed with ethyl acetate, washed with water and saturated sodium chloride solution, and finally dried with anhydrous sodium sulfate to remove water. After solid-liquid separation, the mixture was concentrated under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate C4 as a white solid with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J=1.0Hz,1H),7.47-7.40(m,2H),7.17-7.06(m ,2H),7.02(d,J=2.1Hz,1H),6.91-6.84(m,3H),3.91(s,3H),3.80(d,J=16.3Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ159.61,158.92,158.79,156.49,143.38,132.23,130.47,128 .56,127.02,121.70,117.91,113.22,112.21,109.07,93.65,54.72,54.32,51.18.ESI-Mass for C 20 H 18 O5:m / z(M+H) + 339.4, found 339.7.

[0158]

[0159] Weigh 1g (2.96mmol) of intermediate C4, dissolve it in a 100mL reaction bottle with 30mL of THF, dissolve 0.62g (14.76mmol) of LiOH in 10mL of water, add it dropwise to the reaction bottle, react for 6 hours, follow up with TLC, and concentrate under reduced pressure after the reaction of the raw materials. Dilute the concentrate with water, adjust the pH to 4-5 with dilute hydrochloric acid, extract twice with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure to obtain a yellow solid RE-01 with a yield of 80%. Use a high-performance liquid chromatography column for preparation and purification. ESI-Mass for C 19 H 16 O5:m / z(M+H) + 324.1, found 325.3. 1 H NMR(400MHz, DMSO-d6)δ8.16(s,1H),7.76-7.66(m,2H),7.60-7.42(m,3H),7.29(d,J= 2.1Hz, 1H), 7.18 (d, J = 2.0Hz, 1H), 6.98 (dd, J = 8.7, 2.0Hz, 2H), 3.84 (d, J = 30.7Hz, 6H). 13 C NMR(101MHz,DMSO-d6)δ160.67,160.59,159.84,157.28,145.57,133.41,131.47,129 .97,128.93,122.66,119.61,114.60,113.61,108.91,95.47,56.31,55.66.ESI-Mass forC 19 H 16 O5:m / z(M+H) + 325.1, found 325.3.

[0160] Example 2: Synthesis of (E)-6-methoxy-4-(4-methoxyphenylvinyl)-N-methylbenzofuran-2-carboxamide (RE-02)

[0161]

[0162] Weigh 0.12g (0.37mmol) of crude compound RE-1, 0.14g (0.37mmol) of HATU, 0.19g (1.47mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle. After stirring at room temperature for 20 minutes, add 0.03g (0.4mmol) of methylamine hydrochloride and react at room temperature for 6 hours. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate under reduced pressure, and obtain compound RE-02 as a white solid by column chromatography (petroleum ether: ethyl acetate = 1:1). The yield is 83%. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=1.0Hz,1H),7.55-7.44(m,2H),7.24-7.12(m,2H),7.07(d,J=2.1Hz,1H),6 .97-6.90(m,2H),6.87(dd,J=2.2,1.0Hz,1H),6.58(d,J=5.2Hz,1H),3.87(d,J=17.4Hz,6H),3.05(d,J=5.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ159.95,159.77,159.64,156.37,147.98,133.04,131.36,129.64, 128.02,127.85,122.95,119.52,114.26,109.47,109.31,94.70,55.78,55.35,26.06.ESI-Mass for C 20 H 19 NO4:m / z(M+H) + 338.1, found 338.3.

[0163] Example 3: Synthesis of (E)-N-cyclopropyl-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxamide (RE-03)

[0164]

[0165] Weigh 0.12g (0.37mmol) of crude compound RE-1, 0.14g (0.37mmol) of HATU, 0.19g (1.47mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, add 0.03g (0.53mmol) of cyclopropylamine dropwise, and react at room temperature for 6 hours. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 3:1), compound RE-03 is obtained as a white solid with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=1.0Hz,1H),7.54-7.46(m,2H),7.24-7.13(m,2H),7.07(d,J=2.1Hz,1H),6.97-6.89(m,2H),6.89 -6.84(m,1H),6.64(d,J=3.2Hz,1H),3.87(d,J=15.8Hz,6H),2.94(tq,J=7.2,3.7Hz,1H),0.91(td,J=7.1,5.3Hz,2H),0.73-0.64(m,2H). 13 C NMR(101MHz,Chloroform-d)δ160.26,160.00,159.77,156.35,147.82,133.06,131.37,129.63,1 28.03,122.89,119.54,114.26,109.46(d,J=2.6Hz),94.67,55.77,55.35,22.52,6.81.ESI-Mass for C 22 H 21 NO4:m / z(M+H) + 364.2, found 364.3.

[0166] Example 4: Synthesis of (E)-(6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-yl)(pyrrolidin-1-yl)methanone (RE-04)

[0167]

[0168] Weigh 0.12g (0.37mmol) of crude compound RE-1, 0.14g (0.37mmol) of HATU, 0.2g (1.54mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, add 0.03g (0.42mmol) of pyrrolidine, and react at room temperature for 6 hours. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 3:1), compound RE-04 is obtained as a white solid with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=0.9Hz,1H),7.55-7.47(m,2H),7.20(d,J=4.2Hz,2H),7.08(d,J=2.1Hz,1H),6.97-6.8 9(m,3H),3.98(t,J=6.8Hz,2H),3.90(s,3H),3.85(s,3H),3.72(t,J=6.9Hz,2H),2.04(d,J=6.7Hz,2H),1.96(d,J=6.7Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ159.75(d,J=4.5Hz),158.73,156.56,148.90,132.75,131.16,129.74,128 .01,123.07,119.09,114.25,111.13,109.52,94.72,55.77,55.36,48.08,47.36,26.62,23.74.ESI-Mass for C 23 H 23 NO4:m / z(M+H) + 378.2, found 378.3.

[0169] Example 5: Synthesis of (E)-(3-hydroxypyrrolidin-1-yl)(6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-yl)methanone (RE-05)

[0170]

[0171] Weigh 0.12g (0.37mmol) of crude compound RE-1, 0.14g (0.37mmol) of HATU, 0.19g (1.47mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, add 0.04g (0.46mmol) of 3-hydroxypyrrolidine, and react at room temperature for 6 hours. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 3:1), compound RE-05 is obtained as a white solid with a yield of 79%. 1 HNMR(400MHz,Chloroform-d)δ7.64(d,J=8.1Hz,1H),7.49(d,J=8.3Hz,2H),7.16(d,J=9.8Hz,2H),7.04(d,J=12.8Hz,1H),6. 95-6.90(m,2H),6.89-6.82(m,1H),4.62(d,J=26.3Hz,1H),4.20-4.05(m,2H),3.86(d,J=10.2Hz,8H),2.10(d,J=38.0Hz,2H). 13 C NMR (101MHz, Chloroform-d) δ159.73 (d, J = 4.1 Hz), 158.87 (d, J = 4.8 Hz), 156.51 (d, J = 7. 8Hz),148.31(d,J=12.0Hz),132.64(d,J=9.1Hz),131.03(d,J=10.2Hz),129.70,128.04 ,122.85,118.88(d,J=11.5Hz),114.23,111.39,109.44(d,J=9.9Hz),94.48(d,J=11.2H z),71.49,68.73,56.30,56.03-55.43(m),55.36,45.97,45.35,34.81,32.21.ESI-Mass for C 23 H 23 NO5:m / z(M+H) + 394.2, found 394.3.

[0172] Example 6: Synthesis of (E)-N-cyclohexyl-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxamide (RE-06)

[0173]

[0174] Weigh 0.12g (0.37mmol) of crude compound RE-1, 0.14g (0.37mmol) of HATU, 0.19g (1.47mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, add 0.06g (0.44mmol) of cyclohexylamine hydrochloride, and react at room temperature for 6 hours. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 3:1), compound RE-06 is obtained as a white solid with a yield of 81%. 1 HNMR(400MHz,Chloroform-d)δ7.66(s,1H),7.50(d,J=8.7Hz,2H),7.23-7.09(m,2H),7.06(d,J=7.5 Hz,1H),6.91(dd,J=16.6,10.0Hz,3H),4.16-4.09(m,1H),3.86(d,J=9.6Hz,6H),2.11-1.22(m,10H). 13 C NMR(101MHz,DMSO-d6)δ158.74,158.67,156.62,155.12,147.79,131.75,130.13,128.85,127.64,1 21.92,118.65,113.49,107.89,107.52,94.47,55.10,54.52,47.30,31.68,24.51,24.26.ESI-Mass for C 25 H 27 NO4:m / z(M+H) + 406.2, found406.3.

[0175] Example 7: Synthesis of (E)-6-methoxy-4-(4-methoxyphenylvinyl)-N-phenylbenzofuran-2-carboxamide (RE-07)

[0176]

[0177] Weigh 0.18g (0.55mmol) of crude compound RE-1, 0.21g (0.55mmol) of HATU, 0.36g (2.78mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, add 0.074g (0.67mmol) of 3-fluoroaniline, and react at room temperature overnight. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 5:1), compound RE-07 is obtained as a yellow solid with a yield of 72%. 1 H NMR(400MHz,Chloroform-d)δ8.29(s,1H),7.86(d,J=1.0Hz,1H),7.69(d,J=10.8Hz,1H),7.52(d,J=8.8Hz,2H),7.37-7.3 2(m,2H),7.21(d,J=9.0Hz,2H),7.11(d,J=2.1Hz,1H),6.99-6.90(m,3H),6.88(s,1H),3.93(s,3H),3.86(d,J=2.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.72,161.32,160.44,159.88,157.37,156.72,147.91,140.84,140.73,133.29,131.61,130.84,130.74,129.9 3,128.83,122.88,119.68,116.52(d,J=2.6Hz),114.66,111.13,110.90,110.69,109.10,107.65,107.39,95.56,56.30,55.65.ESI-Mass forC 25 H 20 FNO4:m / z(M+H) + 418.1, found 418.3.

[0178] Example 8: Synthesis of (E)-N-benzyl-6-methoxy-4-(4-methoxyphenylvinyl)benzofuran-2-carboxamide (RE-08)

[0179]

[0180] Weigh 0.18g (0.55mmol) of crude compound RE-1, 0.21g (0.55mmol) of HATU, 0.36g (2.78mmol) of DIPEA, and 10mL of THF in a 100mL reaction bottle, stir at room temperature for 20min, drop 0.071g (0.66mmol) of benzylamine, and react overnight at room temperature. TLC tracking detection, after the reaction of the raw materials, concentrate under reduced pressure. Dissolve in dichloromethane, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 3:1), compound RE-08 is obtained as a white solid with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.24-8.20(m,1H),7.83(d,J=7.7Hz,2H),7.70(s,2H),7.46(d,J=4.4Hz,2 H),7.42-7.33(m,2H),7.30(d,J=2.0Hz,1H),7.19-7.10(m,2H),7.00(d,J=8.8Hz,2H),3.90(s,3H),3.81(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.31,159.87,157.21,156.65,148.30,138.99,133.20,131.56,129.96,129 .18,128.83,124.37,122.96,120.86,119.71,114.67,110.63,109.07,95.61,56.32,55.68.ESI-Mass for C 25 H 21 NO4:m / z(M+H) + 400.2, found 400.3.

[0181] Example 9: Synthesis of (E)-6-methoxy-4-(4-methoxyphenylvinyl)-N-(phenylsulfonyl)benzofuran-2-carboxamide (RE-09)

[0182]

[0183] Weigh 0.15g (0.46mmol) of crude compound RE-1, 0.11g (0.57mmol) EDCI, 0.11g (0.9mmol) DMAP, 0.08g (0.51mmol) benzenesulfonamide, 5mL of DMF in a 50mL reaction bottle, and react at room temperature for 6 hours. TLC tracking detection, add 50mL of water after the reaction of the raw materials. Use ethyl acetate to extract three times, combine the organic phases, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (dichloromethane: methanol = 15: 1), compound RE-09 is obtained as a yellow solid with a yield of 75%. 1 H NMR(400MHz,Chloroform-d)δ8.90(s,1H),8.23-8.16(m,2H),7.80(d,J=1.0Hz,1H),7.69-7.64(m,1H),7.62(s,2H),7.58(dd ,J=8.4,6.9Hz,2H),7.50-7.43(m,2H),7.17(d,J=16.4Hz,1H),7.12-7.06(m,2H),6.94-6.87(m,3H),3.87(d,J=25.1Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ159.04,157.84,155.32,154.76,143.13,137.81,132.15,131.66,129.90,127 .71,127.54,126.65,125.97,120.77,116.69,112.59,111.93,108.21,93.21,54.24,53.56.ESI-Mass forC 25 H 21 NO6S:m / z(M+H) + 464.1, found 464.3.

[0184] Embodiment 10:

[0185] Synthesis of (E)-6-methoxy-4-(4-methoxyphenylvinyl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)benzofuran-2-carboxamide (RE-10)

[0186]

[0187] Weigh 0.18g (0.55mmol) of crude compound RE-1, 0.13g (0.68mmol) EDCI, 0.14g (1.14mmol) DMAP, 0.13g (0.58mmol) 4-(trifluoromethyl)benzenesulfonamide, 5mL of DMF in a 50mL reaction bottle, and react at room temperature for 6 hours. TLC tracking detection, add 50mL of water after the reaction of the raw materials. Use ethyl acetate to extract three times, combine the organic phases, wash with water and saturated sodium chloride solution, and finally dry with anhydrous sodium sulfate to remove water, separate the solid and liquid, and concentrate under reduced pressure. After column chromatography (dichloromethane: methanol = 15: 1), compound RE-10 is obtained as a yellow solid with a yield of 72%. 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.37-8.30(m,2H),7.95-7.76(m,3H),7.52-7.43(m,2H),7.17(d, J=16.3Hz,1H),7.09(dd,J=9.2,7.1Hz,2H),6.95-6.88(m,2H),6.89-6.83(m,1H),3.91(s,3H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ161.25,159.96,157.51,157.14,145.17,143.82,134.27-133.13(m),132.04,129.85(d,J=6.8Hz),129.16,128.7 8,128.50,126.93(d,J=3.7Hz),125.19,122.82,122.48,118.84,114.70,110.30,95.30,56.39(d,J=5.8Hz),55.64(d,J=4.4Hz).ESI-Mass for C 26 H 20 NO6S:m / z(M+H) + 532.1, found 532.4.

[0188] Biological test cases

[0189] Test Example 1: Antitumor Activity

[0190] Human colon cancer cells HCT116 were cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin / streptomycin, and the cells were cultured in a 37°C, 5% CO2 incubator. The Cell Counting Kit-8 (CCK-8) kit was used to detect the anti-proliferative ability of resveratrol derivatives on HCT116. HCT116 cells in the logarithmic growth phase in the incubator were digested, centrifuged, counted, and the cells were diluted to an appropriate concentration with culture medium and then plated in a 96-well plate. The cells were counted at 2000 per well and 80 μL of cell suspension was inoculated. The cell state was observed the next day, and the drug was added after the cells were well attached. The compound was diluted with culture medium, and the compound concentration gradient was 100, 20, 4, 0.8, and 0.16 μM; 20 μL of different concentrations of the compound were added to each well and incubated in a 37°C, 5% CO2 incubator in the dark for 72 hours. After the incubation, the 96-well plate was taken out, 10 μL of CCK-8 solution was added to each well, and the absorbance at a wavelength of 450 nm was measured on Envision after incubation for 3 hours. The inhibition rate of tumor cell proliferation by different concentrations of compounds was calculated according to the following formula.

[0191] Inhibition rate (%) = 1-OD S / OD NC ×100%

[0192] In the formula, OD S : absorbance of the sample well (test compound); OD NC : Absorbance value of negative well (cells + culture medium + DMSO). GraphPad Prism 8 software was used to perform nonlinear fitting between compound concentration and HCT116 cell proliferation inhibition rate and calculate IC 50 value.

[0193] The anti-tumor activity results are shown in Table 1:

[0194]

[0195] Table 1 Proliferation inhibitory activity of resveratrol (RE) and its derivatives in HCT116

[0196]

[0197]

[0198] Note: “NA” means activity not determined.

[0199] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula A; in, R is N (R 1 )R 2 or OH; R 1 is H or C1-4 alkyl; R 2 For R 8 or -W 1 -R 8 ; Or, R 1 and R 2 and together with the nitrogen atom to which they are attached form an optionally substituted 4- to 7-membered nitrogen-containing heteroalkyl group; R 3 Selected from the group consisting of H, optionally substituted C1-4 alkyl, hydroxy, optionally substituted C1-4 alkoxy, halogen; R 4 , R 5 , R 6 and R 7 Each is independently selected from the group consisting of H, optionally substituted C1-4 alkyl, hydroxy, optionally substituted C1-4 alkoxy, halogen; R 8 is selected from the group consisting of an optionally substituted C1-6 alkyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group, an optionally substituted C6-10 aryl group, and an optionally substituted 5- to 10-membered heteroaryl group; W 1 Selected from the group consisting of C1-2 alkylene, -SO2-; The optionally substituted group means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl and C1-4 alkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is shown in formula C; wherein R is as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula A1; (A1) Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in claim 1.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 is H; R 2 For R 8 or -W 1 -R 8 ; Or, R 1 and R 2 and the nitrogen atoms to which they are attached together form an optionally substituted 4- to 7-membered nitrogen-containing heteroalkyl group; wherein the 4- to 7-membered nitrogen-containing heteroalkyl group contains only one nitrogen atom as a heteroatom; W 1 is methylene or -SO2-; R 8 is selected from the group consisting of an optionally substituted C1-6 alkyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group, an optionally substituted C6-10 aryl group, and an optionally substituted 5- to 10-membered heteroaryl group; R 3 is a C1-4 alkoxy group; R 4 , R 5 , R 6 and R 7 is H; The optionally substituted group means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl and C1-4 alkoxy.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following table:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises (i) a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.

7. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

8. The use according to claim 8, characterized in that The tumor is colorectal cancer.

9. A method for preparing the compound according to claim 1, characterized in that: The preparation method comprises step (S1), step (S2) and optional step (S3); (S1) in an inert solvent and in the presence of a base, subjecting the intermediate represented by formula INT1 to a Rap-stoermer reaction with a reaction reagent represented by formula INT2 to obtain an intermediate represented by formula INT3; (S2) subjecting the intermediate represented by formula INT3 to a demethylation reaction in an inert solvent in the presence of a base to obtain a compound represented by formula A2, i.e., a compound represented by formula I in which R is a hydroxyl group; (S3) subjecting the compound represented by formula A2 to an intermediate represented by formula INT4 to an amide condensation reaction, thereby obtaining a compound represented by formula A1, wherein R is N(R 1 )R 2 The compound as shown in formula I; In each formula, X is Cl, Br or F; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in claim 1.

10. An intermediate, wherein: The intermediate is shown in formula INT1, INT3 or A2 Among them, R 3 , R 4 , R 5 , R 6 and R 7 As defined in claim 1.

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