A novel resveratrol derivative, its preparation method and application

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the technical fields of medicine and pharmaceutical chemical synthesis, and particularly relates to a resveratrol derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Colorectal cancer is the third most common cancer in adults and the second most lethal 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 by 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 present in many plants, and its main pharmacological effects include anti-cancer, anti-inflammatory, antioxidant, antibacterial, anti-aging, and chemoprotection. Research shows that resveratrol can play an anti-colorectal cancer role in in vitro and in vivo experiments through multiple pathways; in human colorectal cancer cells HCT116 and SW480, resveratrol inhibits the proliferation and invasion of cancer cells in a dose-dependent manner. However, its efficacy and safety in clinical applications still face many challenges. First, the bioavailability of resveratrol is relatively low, resulting in limited effective concentration in vivo, which limits its actual efficacy. Research shows that the IC50 value of resveratrol on cancer cells is usually greater than 100 μM. This indicates that it needs to be at a high concentration to play a significant anti-cancer role. Second, in the pharmacological research of resveratrol, it is found that the in vitro and in vivo pharmacodynamic effects of resveratrol are inconsistent, which is because some active sites of resveratrol are not recognized by the biological system. In addition, the long-term use 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 needs.

[0004] In summary, there is an urgent need in this field to develop a class of resveratrol derivatives with novel structures and improved activities and other effects 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, a preparation method thereof, and an application thereof.

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

[0007]

[0008] Wherein,

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

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

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

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

[0013] R 3 is 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 are each 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: optionally substituted C1-6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heteroalkyl, optionally substituted C6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

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

[0017] Said optionally substituted 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, hydroxy and C1-4 alkoxy.

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

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

[0020]

[0021] wherein, R and R 3 are as defined above.

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

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

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

[0025] In another preferred example, the compound is as shown in formula I;

[0026]

[0027] wherein, R is as defined above.

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

[0029] In another preferred example, R is selected from the group consisting of:

[0030]

[0031] In another preferred example, the compound is as shown in formula A1;

[0032]

[0033] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.

[0034] In another preferred example, R 1 is H.

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

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

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

[0038] In another preferred example, the compound is as shown in formula A2;

[0039]

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

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

[0042] Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached 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: optionally substituted C1-6 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 4- to 10-membered heteroalkyl, optionally substituted C6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl;

[0045] R 3 is C1-4 alkoxy;

[0046] R 4 、R 5 、R 6 and R 7 is H.

[0047] The optional substitution 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, hydroxy, 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, there is provided a pharmaceutical composition comprising (i) a compound as described in 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 the use of a 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 example, the tumor is colorectal cancer.

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

[0057] (S1) In an inert solvent and in the presence of a base, subject the intermediate as shown in formula INT1 to a Rap-stoermer reaction with a reaction reagent as shown in formula INT2, thereby obtaining an intermediate as shown in formula INT3;

[0058]

[0059] (S2) In an inert solvent and in the presence of a base, subject the intermediate as shown in formula INT3 to a demethylation reaction, thereby obtaining a compound as shown in formula A2, i.e., a compound as shown in formula I where R is a hydroxyl group;

[0060]

[0061] (S3) Subject the compound as shown in formula A2 to an amide condensation reaction with an intermediate as shown in formula INT4, thereby obtaining a compound as shown in formula A1, i.e., a compound as shown in formula I where R is N(R 1 )R 2 ;

[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 are as defined in the first aspect.

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

[0065]

[0066] wherein, R 3 , R 4 , R 5 , R 6 and R 7 are 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 hereinafter (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] None DETAILED DESCRIPTION OF THE INVENTION

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

[0070] TERMINOLOGY

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, when referring to a specifically recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, the expression "about 100" includes all values between 99 and 101 (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-chain or branched-chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-6 means 1-6 carbons, and C1-4 means 1-4 carbons). Examples of alkyl 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] Unless otherwise stated, in this document, the term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkane as defined above. Alkylene generally has 1-4 (preferably 1 or 2) carbon atoms.

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

[0075] Unless otherwise stated, as used herein, the term "heterocycloalkyl" refers to a cycloalkyl having a specified number of ring atoms (e.g., 4- to 10-membered heterocycloalkyl) and containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. The heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic system (such as a bridged, fused, spiro, etc.). Non-limiting examples of heterocycloalkyl 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. The heterocycloalkyl can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0076] Unless otherwise stated, as used herein, the term "aryl" denotes a polyunsaturated (usually aromatic) hydrocarbon group, which can be monocyclic or polycyclic (up to three rings) fused together or covalently linked. Non-limiting examples of aryl include phenyl, naphthyl, biphenyl, etc.

[0077] Unless otherwise stated, as used herein, the term "heteroaryl" refers to an aryl (or ring) having a 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 atoms are optionally quaternized. The heteroaryl can be attached to the remainder of the molecule through a carbon atom or a heteroatom. Non-limiting examples of heteroaryl include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc.

[0078] Unless otherwise stated, as used herein, the term "alkoxy" is used in its conventional sense and refers to an alkyl as defined above attached to the remainder of the molecule through an oxygen atom. Examples of alkoxy include, for example, methoxy, ethoxy, etc.

[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 with 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 are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 3 -, 4 -, 5 -, 6 - or 7 - membered ring. For example, - NR a R b refers to including 1 - pyrrolidinyl and 4 - morpholinyl.

[0082] Similarly, unless otherwise defined, the substituents of aryl and heteroaryl are diverse and are generally 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, in numbers ranging from zero to the total number of open valences on the aromatic ring system; where 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 represents a position connected to other parts in the molecule.

[0085] For the compounds provided herein, the bond from the substituent (usually the R group) to the center of the ring will be understood to refer to the bond providing connection at any available vertex of the aromatic ring.

[0086] Resveratrol derivatives

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

[0088] As used herein, the term "pharmaceutically acceptable salt" refers to salts formed by the compounds of the present invention with acids or bases that are suitable for use as drugs. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc.; 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, naphthalenesulfonic acid, etc.; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid. Another preferred class of salts is the salts formed by the compounds of the present invention with bases, such as alkali metal salts (such as sodium salt or potassium salt), alkaline earth metal salts (such as magnesium salt or calcium salt), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as 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 by morpholine, piperazine, lysine respectively.

[0089] As used herein, the term "solvate" refers to a complex formed by the coordination of the compounds of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compounds 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 those which may be biologically active or inactive per se, and which, when administered by an appropriate method, are metabolized or chemically reacted in the human body to be converted into, for example, a class of compounds as described in the first aspect, or salts or solutions composed of the compounds as described in the first aspect. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the compounds.

[0091] The resveratrol of the present invention can use resveratrol as a raw material, generate resveratrol aldehyde through the Vilsmeier formylation reaction, obtain trimethyl ether of resveratrol aldehyde after methylation, then selectively remove the methyl group adjacent to the aldehyde group under the catalysis of boron trichloride, generate a furan ring structure with methyl α-bromoacetate through the Rap-stoermer reaction, and finally obtain a series of resveratrol derivatives through hydrolysis and amide condensation. The synthetic route involved in this preparation method is simple in operation, the raw materials are cheap and easily available, and the total yield is relatively high. At the same time, the present invention also lays a foundation for the synthesis and structure-activity relationship of resveratrol derivatives, as well as for providing new candidate drugs with better active resveratrol skeleton structure derivatives.

[0092] In some aspects, the present invention provides a compound (resveratrol derivative) or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (A), formula (B) or formula (C);

[0093]

[0094] (C)

[0095] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the first aspect.

[0096] In some aspects, the present invention provides a compound (resveratrol derivative) or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I);

[0097]

[0098] wherein R is as defined in the first aspect.

[0099] In some preferred embodiments, R is a group selected from the following group:

[0100]

[0101] Drug Compositions and Administration Methods

[0102] Since the compounds provided by the present invention have excellent activity in inhibiting the proliferation of tumor cells (especially human colon cancer cell line HCT116), the compounds of the present invention can be used for the treatment of various tumors or cancers (such as colorectal cancer, etc.).

[0103] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier.

[0104] "Safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, 10 - 500 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0105] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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 dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0106] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0107] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate dibasic, or with the following components: (a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropyl methylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retardants, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0108] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions can be delayed and released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0109] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. Besides the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art such as water or other solvents, solubilizing agents, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil or mixtures of these substances.

[0110] Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfumes.

[0111] Besides the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar or mixtures of these substances.

[0112] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous 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.

[0113] 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 that may be required, if necessary.

[0114] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0115] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is an effective dosage considered pharmaceutically. 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 consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0116] Preparation Method

[0117] In some aspects, the present invention also provides a method for preparing resveratrol derivatives (or compounds of the present invention) of the present invention and intermediates.

[0118] In some embodiments, a method for preparing a resveratrol derivative as described in Formula I is provided, including (1) to (5) or (1) to (6) of the following steps:

[0119] (1) In an inert solvent, in the presence of DMF and phosphorus oxychloride, resveratrol is subjected to a formylation reaction to obtain resveratrol aldehyde;

[0120]

[0121] (2) Under base-catalyzed conditions, in an inert solvent, the obtained resveratrol aldehyde and methyl iodide are subjected to an etherification reaction to obtain resveratrol aldehyde trimethyl ether;

[0122]

[0123] (3) In an inert solvent, in the presence of a demethylating agent, resveratrol aldehyde trimethyl ether is subjected to a selective demethylation reaction to obtain (E)-2-hydroxy-4-methoxy-6-(4-methoxystyryl)benzaldehyde;

[0124]

[0125] (4) In an inert solvent and in the presence of a base, (E)-2-hydroxy-4-methoxy-6-(4-methoxystyryl)benzaldehyde and methyl α-bromoacetate are subjected to a Rap-stoermer reaction to obtain methyl (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylate;

[0126]

[0127] (5) In an inert solvent and under base-catalyzed conditions, methyl (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylate is subjected to a demethylation reaction to obtain the resveratrol derivative shown in formula I (wherein R is a hydroxyl group, i.e., (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid); and

[0128]

[0129] (6) (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid is subjected to an amide condensation reaction with R 2 -NH2 or its salt to obtain the resveratrol derivative shown in formula I (where R is NHR 2 );

[0130]

[0131] In some embodiments, in step (1), the formylation reaction temperature is 0 to 50 °C; and / or, the reaction time is 18 to 20 h; 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).

[0132] 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 to 70 °C such as 60 °C; and / or, the reaction time is 8 to 16 h; and / or, the molar ratio of resveratrol aldehyde to methyl iodide is 1:(2 - 6) such as 1:4.

[0133] 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 h; and / or, the demethylating reagent is BCl3 (preferably a dichloromethane solution of BCl3, more preferably a 0.5 - 2 mol / L such as 1 mol / L dichloromethane solution of BCl3); and / or, the molar ratio of the resveratraldehyde trimethyl ether used to the demethylating reagent is 1:(1 - 3) (preferably 1:(1.5 - 3); more preferably 1:2).

[0134] In some embodiments, in step (4), the reaction temperature of the Rap-stoermer reaction is from room temperature to 80 °C such as 25 °C to 80 °C; and / or, the reaction time is 12 to 18 h; 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-methoxystyryl)benzaldehyde to methyl α-bromoacetate is 1:(1 - 2) (preferably 1:(1 - 1.5); more preferably 1:1.2).

[0135] 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 h; and / or, the base is lithium hydroxide; and / or, the molar ratio of the base (such as lithium hydroxide) to methyl (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylate is (4 - 8):1.

[0136] 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.

[0137] In some embodiments, in step (6), the polar aprotic solvent is THF or DMF; and / or, R 2 -NH2 or its salt (also referred to as an amino group-containing molecule) includes methylamine hydrochloride, cyclopropylamine, cyclohexylamine hydrochloride, 3-fluoroaniline, benzylamine, pyrrolidine and 3-hydroxypyrrolidine; and / or, the molar ratio of (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid, HATU, DIPEA and R 2 -NH2 or its salt is 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 (such as 20 - 30 °C); and / or, the reaction time is 4 to 8 h.

[0138] 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.

[0139] In some embodiments, R 2 -NH2 or its salt is a molecule containing a sulfonamide amino group (i.e., W 1 is -SO2-).

[0140] In some embodiments, the polar aprotic solvent is DMF; and / or, R 2 -NH2 or its salt (i.e., the molecule containing a sulfonamide amino group) includes benzenesulfonamide and 4-(trifluoromethyl)benzenesulfonamide; and / or, the dosages of (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid, EDCI, DMAP, and the molecule containing a sulfonamide amino group satisfy that the molar ratio of (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid, EDCI, DMAP, and the molecule containing a 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 (such as 20 - 30 °C); and / or, the reaction time is 4 - 8 h.

[0141] In some embodiments, the preparation method of the compound is shown as follows:

[0142]

[0143] The main advantages of the present invention include:

[0144] (a) The compounds of the present invention have excellent effects in inhibiting the proliferation of tumor cells.

[0145] (b) The compounds of the present invention are easy to synthesize, the raw materials are cheap and easily available, and the total yield of the synthesis is relatively high.

[0146] The present invention will be further illustrated below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally according to conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise stated, the percentages and parts are weight percentages and weight parts.

[0147] Preparation Examples

[0148] Example 1: Synthesis of (E)-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxylic acid (RE-01)

[0149]

[0150] Weigh 2.3 g (10.08 mmol) of resveratrol, dissolve it in 50 mL of acetonitrile in a 100 mL three-necked flask, add 0.73 g (10 mmol) of N,N-dimethylformamide (DMF), cool it to 0 °C in an ice bath, and dropwise add 2.3 g (15 mmol) of phosphorus oxychloride. After the addition is complete, keep it warm for 30 min, then raise the temperature to room temperature and react overnight. A red precipitate is formed. Monitor the reaction by 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 200 mL of ice water, adjust the pH to neutral with dilute NaOH solution, heat it to 50 °C and hydrolyze for 3 hours. The resulting yellow precipitate is the target product. Extract the reaction solution with ethyl acetate multiple times, combine the organic phases, wash them with water and saturated sodium chloride solution, and finally dry them over anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate under reduced pressure, and through column chromatography (petroleum ether:ethyl acetate = 3:1), obtain intermediate C1 (resveratraldehyde), which is a yellow solid with a yield of 67%.

[0151]

[0152] Weigh 1 g (3.9 mmol) of intermediate C1, dissolve it in 10 mL of acetone in a 50 mL three-necked flask, add 2.22 g (15.6 mmol) of methyl iodide and 1.63 g (11.8 mmol) of potassium carbonate, and reflux at 60 °C overnight. Monitor by TLC tracking. After the reaction is complete, filter off K2CO3, concentrate the filtrate under reduced pressure, and through column chromatography (petroleum ether:ethyl acetate = 5:1), obtain intermediate C2, which is a pale yellow solid with a yield of 90%.

[0153]

[0154] Weigh 1.5 g (5.03 mmol) of intermediate C2, dissolve it in 40 mL of anhydrous dichloromethane in a 100 mL reaction flask, cool it to 0 °C in an ice bath, dropwise add 10 mL of a 1 M solution of BCl3 in dichloromethane, keep it warm for 30 min, then raise the temperature to room temperature and react for 2 hours. Monitor by TLC tracking. After the reaction is complete, quench it with ice water, concentrate under reduced pressure, dissolve it in saturated aqueous NaHCO3 solution, extract it three times with 50 mL of ethyl acetate, combine the organic phases, wash them with water and saturated sodium chloride solution, and finally dry them over anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate under reduced pressure, and through column chromatography (petroleum ether:ethyl acetate = 5:1), obtain intermediate C3, which is a yellow solid with a yield of 85%. 11H NMR (400 MHz, Chloroform-d) δ 12.47 (s, 1H), 10.21 (s, 1H), 7.48 - 7.42 (m, 2H), 7.37 (d, J=15.9 Hz, 1H), 6.97 - 6.88 (m, 3H), 6.60 (dd, J=2.4, 0.6 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 3.86 (d, J=12.2 Hz, 6H). ESI-Mass for C 18 H 16 O4: m / z (M - H) + 283.1, found 282.4。

[0155]

[0156] Weigh 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. Dissolve them in 40 mL of DMF in a 100-mL three-necked flask. React at room temperature for 2 hours first, and monitor by TLC. After the raw materials are reacted completely, raise the temperature to 80 °C and continue to react overnight. After the reaction is completed as detected by TLC, filter the reaction solution by suction, wash it with ethyl acetate, wash it with water and saturated sodium chloride solution successively, and finally dry it with anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate it under reduced pressure. Through column chromatography (petroleum ether:ethyl acetate = 5:1), intermediate C4 is obtained as a white solid with a yield of 79%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=1.0 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.17 - 7.06 (m, 2H), 7.02 (d, J=2.1 Hz, 1H), 6.91 - 6.84 (m, 3H), 3.91 (s, 3H), 3.80 (d, J=16.3 Hz, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.61, 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。

[0157]

[0158] Weigh 1 g (2.96 mmol) of intermediate C4, dissolve it in 30 mL of THF in a 100 mL reaction flask. Dissolve 0.62 g (14.76 mmol) of LiOH in 10 mL of water, add it dropwise to the reaction flask, and react for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dilute the concentrated solution with water, adjust the pH to 4 - 5 with dilute hydrochloric acid, extract twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate to remove water, separate the solid and liquid by filtration, and then concentrate under reduced pressure to obtain a yellow solid RE - 01 with a yield of 80%. Purify it by preparative high - performance liquid chromatography. ESI - Mass for C 19 H 16 O5: m / z(M + H) + 324.1, found 325.3。 1 1H NMR(400 MHz, DMSO - d6)δ8.16(s, 1H), 7.76 - 7.66(m, 2H), 7.60 - 7.42(m, 3H), 7.29(d, J = 2.1 Hz, 1H), 7.18(d, J = 2.0 Hz, 1H), 6.98(dd, J = 8.7, 2.0 Hz, 2H), 3.84(d, J = 30.7 Hz, 6H). 13 13C NMR(101 MHz, 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。

[0159] Example 2: Synthesis of (E) - 6 - methoxy - 4 - (4 - methoxystyryl) - N - methylbenzofuran - 2 - carboxamide (RE - 02)

[0160]

[0161] Weigh 0.12 g (0.37 mmol) of the crude product of compound RE-1, 0.14 g (0.37 mmol) of HATU, 0.19 g (1.47 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 minutes, then add 0.03 g (0.4 mmol) of methylamine hydrochloride and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dissolve with 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. Through column chromatography (petroleum ether: ethyl acetate = 1:1), compound RE-02 is obtained as a white solid with a yield of 83%. 1 H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 1.0 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.24 - 7.12 (m, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.87 (dd, J = 2.2, 1.0 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 3.87 (d, J = 17.4 Hz, 6H), 3.05 (d, J = 5.0 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 159.95, 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。

[0162] Example 3: Synthesis of (E)-N-cyclopropyl-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxamide (RE-03)

[0163]

[0164] Weigh 0.12 g (0.37 mmol) of the crude product of compound RE-1, 0.14 g (0.37 mmol) of HATU, 0.19 g (1.47 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, then add dropwise 0.03 g (0.53 mmol) of cyclopropylamine, and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dissolve with 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. Through 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 (400 MHz, Chloroform-d) δ 7.71 (d, J = 1.0 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.24 - 7.13 (m, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 6.64 (d, J = 3.2 Hz, 1H), 3.87 (d, J = 15.8 Hz, 6H), 2.94 (tq, J = 7.2, 3.7 Hz, 1H), 0.91 (td, J = 7.1, 5.3 Hz, 2H), 0.73 - 0.64 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 160.26, 160.00, 159.77, 156.35, 147.82, 133.06, 131.37, 129.63, 128.03, 122.89, 119.54, 114.26, 109.46 (d, J = 2.6 Hz), 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。

[0165] Example 4: Synthesis of (E)-(6-methoxy-4-(4-methoxystyryl)benzofuran-2-yl)(pyrrolidin-1-yl)methanone (RE-04)

[0166]

[0167] Weigh 0.12 g (0.37 mmol) of the crude product of compound RE-1, 0.14 g (0.37 mmol) of HATU, 0.2 g (1.54 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, add 0.03 g (0.42 mmol) of pyrrolidine, and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dissolve with 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. Purify by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound RE-04 as a white solid with a yield of 79%. 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 0.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.20 (d, J = 4.2 Hz, 2H), 7.08 (d, J = 2.1 Hz, 1H), 6.97 - 6.89 (m, 3H), 3.98 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.72 (t, J = 6.9 Hz, 2H), 2.04 (d, J = 6.7 Hz, 2H), 1.96 (d, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 159.75 (d, J = 4.5 Hz), 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。

[0168] Example 5: Synthesis of (E)-(3-Hydroxypyrrolidin-1-yl)(6-methoxy-4-(4-methoxystyryl)benzofuran-2-yl)methanone (RE-05)

[0169]

[0170] Weigh 0.12 g (0.37 mmol) of the crude product of compound RE-1, 0.14 g (0.37 mmol) of HATU, 0.19 g (1.47 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, add 0.04 g (0.46 mmol) of 3-hydroxypyrrolidine, and react at room temperature for 6 hours. Monitor by TLC. After the raw materials are reacted, concentrate under reduced pressure. Dissolve with 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. Through 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=4.1Hz),158.87(d,J=4.8Hz),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=11.2Hz),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。

[0171] Example 6: Synthesis of (E)-N-cyclohexyl-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxamide (RE-06)

[0172]

[0173] Weigh 0.12 g (0.37 mmol) of the crude compound RE-1, 0.14 g (0.37 mmol) of HATU, 0.19 g (1.47 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, add 0.06 g (0.44 mmol) of cyclohexylamine hydrochloride, and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dissolve with 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. Through 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=7.5Hz,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)δ158.74,158.67,156.62,155.12,147.79,131.75,130.13,128.85,127.64,121.92,118.65,113.49,107.89,107.52,94.47,55.10,54.52,47.30,31.68,24.51,24.26.ESI-Mass for C 25 H 27 NO4:m / z(M+H) + 406.2,found406.3。

[0174] Example 7: Synthesis of (E)-6-methoxy-4-(4-methoxystyryl)-N-phenylbenzofuran-2-carboxamide (RE-07)

[0175]

[0176] Weigh 0.18 g (0.55 mmol) of the crude product of compound RE-1, 0.21 g (0.55 mmol) of HATU, 0.36 g (2.78 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, add 0.074 g (0.67 mmol) of 3-fluoroaniline, and react overnight at room temperature. Monitor by TLC. After the raw materials are reacted completely, concentrate under reduced pressure. Dissolve with 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 perform column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound RE-07 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),7.37-7.32(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)δ163.72,161.32,160.44,159.88,157.37,156.72,147.91,140.84,140.73,133.29,131.61,130.84,130.74,129.93,128.83,122.88,119.68,116.52(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。

[0177] Example 8: Synthesis of (E)-N-benzyl-6-methoxy-4-(4-methoxystyryl)benzofuran-2-carboxamide (RE-08)

[0178]

[0179] Weigh 0.18 g (0.55 mmol) of the crude product of compound RE-1, 0.21 g (0.55 mmol) of HATU, 0.36 g (2.78 mmol) of DIPEA, and 10 mL of THF into a 100 mL reaction flask. Stir at room temperature for 20 min, then add dropwise 0.071 g (0.66 mmol) of benzylamine, and react overnight at room temperature. Monitor the reaction by TLC. After the raw materials are completely reacted, concentrate under reduced pressure. Dissolve with 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. Through 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 (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.24 - 8.20 (m, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.70 (s, 2H), 7.46 (d, J = 4.4 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.31, 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。

[0180] Example 9: Synthesis of (E)-6-methoxy-4-(4-methoxystyryl)-N-(phenylsulfonyl)benzofuran-2-carboxamide (RE-09)

[0181]

[0182] Weigh 0.15 g (0.46 mmol) of the crude product of compound RE-1, 0.11 g (0.57 mmol) of EDCI, 0.11 g (0.9 mmol) of DMAP, 0.08 g (0.51 mmol) of benzenesulfonamide, and 5 mL of DMF into a 50 mL reaction flask, and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are reacted completely, add 50 mL of water. Extract with ethyl acetate three times. Combine the organic phases, wash them with water and saturated sodium chloride solution, and finally dry over anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate under reduced pressure. Through column chromatography (methylene chloride:methanol = 15:1), compound RE-09 is obtained as a yellow solid with a yield of 75%. 1 H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.23 - 8.16 (m, 2H), 7.80 (d, J = 1.0 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.62 (s, 2H), 7.58 (dd, J = 8.4, 6.9 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.17 (d, J = 16.4 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.94 - 6.87 (m, 3H), 3.87 (d, J = 25.1 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 159.04, 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 for C 25 H 21 NO6S: m / z (M + H) + 464.1, found 464.3。

[0183] Example 10:

[0184] (E)-6-Methoxy-4-(4-methoxystyryl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)benzofuran-2-carboxamide (RE-10) Synthesis

[0185]

[0186] Weigh 0.18 g (0.55 mmol) of the crude product of compound RE-1, 0.13 g (0.68 mmol) of EDCI, 0.14 g (1.14 mmol) of DMAP, 0.13 g (0.58 mmol) of 4-(trifluoromethyl)benzenesulfonamide, and 5 mL of DMF into a 50 mL reaction flask, and react at room temperature for 6 hours. Monitor the reaction by TLC. After the raw materials are completely reacted, add 50 mL of water. Extract with ethyl acetate three times, combine the organic phases, wash with water and saturated sodium chloride solution, and finally dry over anhydrous sodium sulfate to remove water. After solid-liquid separation, concentrate under reduced pressure, and perform column chromatography (methylene chloride:methanol = 15:1) to obtain compound RE-10 as a yellow solid with a yield of 72%. 1 H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.37 - 8.30 (m, 2H), 7.95 - 7.76 (m, 3H), 7.52 - 7.43 (m, 2H), 7.17 (d, J = 16.3 Hz, 1H), 7.09 (dd, J = 9.2, 7.1 Hz, 2H), 6.95 - 6.88 (m, 2H), 6.89 - 6.83 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.25, 159.96, 157.51, 157.14, 145.17, 143.82, 134.27 - 133.13 (m), 132.04, 129.85 (d, J = 6.8 Hz), 129.16, 128.78, 128.50, 126.93 (d, J = 3.7 Hz), 125.19, 122.82, 122.48, 118.84, 114.70, 110.30, 95.30, 56.39 (d, J = 5.8 Hz), 55.64 (d, J = 4.4 Hz). ESI-Mass for C 26 H 20 NO6S: m / z (M + H) + 532.1, found 532.4。

[0187] Biological Test Examples

[0188] Test Example 1: Antitumor Activity

[0189] The human colon cancer cell line HCT116 was cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin / streptomycin, and the cells were incubated in an incubator at 37°C with 5% CO2. The anti-proliferative ability of resveratrol derivatives against HCT116 was detected using the Cell Counting Kit-8 (CCK-8) assay. HCT116 cells in the logarithmic growth phase in the incubator were digested, centrifuged, counted, and diluted to an appropriate concentration with the medium, and then plated in 96-well plates at a cell count of 2000 cells per well, with 80 μL of cell suspension inoculated per well. The cell status was observed the next day, and drug addition was started after the cells had adhered well. The compound was diluted with the medium, and the compound concentration gradient was 100, 20, 4, 0.8, 0.16 μM; 20 μL of the compound at different concentrations was added to each well, and the plate was incubated in the dark at 37°C with 5% CO2 for 72 hours. After incubation, the 96-well plate was taken out, 10 μL of CCK-8 solution was added to each well, and the plate was incubated in the incubator for 3 hours, and then the absorbance at 450 nm was measured on an Envision. The proliferation inhibition rate of the tumor cells by the compound at different concentrations was calculated according to the following formula.

[0190] Inhibition rate (%) = 1 - OD S / OD NC × 100%

[0191] In the formula, OD S : absorbance value of the sample well (test compound); OD NC : absorbance value of the negative well (cells + medium + DMSO). The compound concentration and the HCT116 cell proliferation inhibition rate were non-linearly fitted using GraphPad Prism 8 software, and the IC 50 value was calculated.

[0192] The anti-tumor activity results are shown in Table 1:

[0193]

[0194] Table 1 Proliferation inhibition activities of resveratrol (RE) and its derivatives in HCT116

[0195]

[0196]

[0197] Note: "NA" represents that the activity was not detected.

[0198] All documents mentioned in this invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound described is shown by formula A; wherein, R is N(R 1 )R 2 ; R 1 is H; R 2 is R 8 or -W 1 -R 8 ; Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached jointly 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; R 3 selected from the group consisting of: hydroxy, C1-4 alkoxy; R 4 、R 5 、R 6 and R 7 are each independently selected from the group consisting of: H, C1-4 alkyl; R 8 selected from the group consisting of: optionally substituted C1-6 alkyl, optionally substituted C4-6 cycloalkyl, and optionally substituted phenyl; W 1 selected from the group consisting of methylene, -SO2-; the optional substitution means that the group is unsubstituted or substituted by one or more substituents selected from the following group: D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy and C1-4 alkoxy.

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

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound described is shown by formula A1; wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 are 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 is R 8 or -W 1 -R 8 ; Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached 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 selected from the group consisting of: optionally substituted C1-6 alkyl, optionally substituted C4-6 cycloalkyl, and optionally substituted phenyl; R 3 is a C1-4 alkoxy group; R 4 、R 5 、R 6 and R 7 are H; the optional substitution means that the group is unsubstituted or substituted by one or more substituents selected from the following group: D, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy and C1-4 alkoxy.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound described 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 1-5 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

8. The use according to claim 7, characterized in that, The tumor is colorectal cancer.

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

10. An intermediate, wherein, The intermediate is shown by INT3 or A2 wherein, R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1.

Images