CN111072610B - Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor - Google Patents
Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor Download PDFInfo
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Abstract
The invention discloses a substituted benzofuran 2-formyl hydrazone LSD1 inhibitor, a preparation method thereof and application thereof in tumor resistance. In particular to a compound of formula (I) or pharmaceutically acceptable salt thereof, which has better inhibition effect on LSD1 enzyme. The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases associated with the expression of LSD1 enzyme, including but not limited to the treatment of various cancers. The compound or the pharmaceutically acceptable salt thereof can be combined with other medicines (including but not limited to targeted medicines, various immunomodulators, antitumor antibodies and the like) to obtain better effect of treating cancers.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a substituted benzofuran 2-formyl hydrazone derivative and a preparation method and application thereof.
Background
LSD1 is a highly conserved FAD-dependent amino oxidase, has a wide range of biological functions, such as participating in p53 demethylation, acting as DNA methyltransferase and E2F transcription factor, and is involved in the development of various diseases, and plays an important role in maintaining normal physiological functions. LSD1 is highly expressed in various tumors (such as prostate cancer, breast cancer, gastric cancer and the like), and the inhibition of LSD1 activity or the reduction of LSD1 expression by a small molecule compound or an RNA interference technology can effectively inhibit the proliferation, invasion and metastasis of tumor cells, so that the LSD1 is proved to be an epigenetic regulatory protein which can be used for tumor treatment.
At present, a plurality of LSD1 inhibitors (such as ORY-1001, GSK2879552, IMG-7289 and the like) enter clinical experiments and are used for treating small cell lung cancer and leukemia. LSD1 inhibitors in the clinical study stage were all irreversible inhibitors of the phenylcyclopropylamine type. Although some reversible LSD1 inhibitors with high activity and high selectivity have been reported, none of them has entered clinical development stage, and designing new non-covalently bound LSD1 inhibitors for tumor therapy is still a relatively challenging task with high practical application value.
Acylhydrazone compounds are Schiff base compounds formed by condensation (dehydration) of hydrazide and aldehyde or ketone, and show good biological activity, strong coordination capacity and various coordination modes in an organophilic environment, so that the acylhydrazone compounds are widely concerned in the fields of medicines, pesticides, materials, analytical reagents and the like. A great deal of literature reports and wide application are available in the aspects of luminescent materials, fluorescence analysis, metalloenzyme simulation, clinical treatment of certain diseases and the like.
The acylhydrazone compounds contain nitrogen atoms and oxygen atoms, so that the acylhydrazone compounds can participate in the formation of hydrogen bonds in organisms, increase the affinity between receptors, and further possibly inhibit various physiochemical processes in organisms, such as hyperglycemia resistance and tumor resistance, and especially have attracted attention in recent years on the aspects of antifungal, immunosuppressant preparation (such as diseases like rheumatoid diseases, psoriasis and the like) and the like.
The literature synthetic and biological evaluation of N ' - (4-substuttedphenyl) -3' -methoxybenzofuran-2' -carbohydrazine derivatives as potential anticancerogen agents; indian Journal of Heterocyclic Chemistry,2015,24:353-358 reported that Compound a was significantly cytotoxic to Ehrlich Ascites Carcinoma (EAC) cells and the HEP2 cell line.
The document benzofurans as potential scaffold in the displacement of multiple drugs, Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity; european Journal of Medicinal Chemistry, 2018,156,118-125 reported that compound b showed growth inhibitory effects on erythroleukemia K562 and Colo-38 melanoma human cells.
Disclosure of Invention
The inventor finds that the 4-hydroxy 3-methyl phenylpropane furan formyl hydrazone compound has the function of inhibiting the activity of the LSD1 enzyme in long-term research. The invention provides a novel LSD1 inhibitor taking a 3-methyl-4-hydroxybenzofurancarbonylhydrazone structure as a mother nucleus, which has inhibitory activity on proliferation of tumor cell strains (U-87, HT-29, MCF-7, PANC-1 and the like).
The technical scheme provided by the invention for solving the technical problems is as follows:
the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring A is phenyl, furyl, thienyl, pyridyl or naphthyl;
each R is 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-8 Alkyl or C 1-8 Alkoxy radical, said C 1-8 Alkyl radical, C 1-8 Alkoxy is optionally substituted by 1, 2 or 3R a Substitution;
each R is 2 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-8 Alkyl radical, C 18 Alkoxy radical, said C 1-8 Alkyl radical, C 1-8 Alkoxy is optionally substituted by 1, 2 or 3R b Substitution;
m is 0,1, 2 or 3;
n is 0,1, 2,3 or 4;
each R is a 、R b Each independently F, Cl, Br, I, OH, NO 2 Or CN;
when the structural unit
Is composed of
Time, structural unit
Is not that
The 4-hydroxy 3-methyl phenylpropyl furan formyl hydrazone compound has strong inhibition effect on LSD1 enzyme. If the hydroxyl group at the 4-position is removed, the inhibitory activity of the compound against LSD1 is significantly reduced.
Further, said R 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-3 Alkyl or C 1-3 Alkoxy radical, said C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted by 1, 2 or 3R a And (4) substitution.
Further, said R 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH(CH 3 ) 2 、-CF 3 、-CH 2 CF 3 or-CH 2 CH 2 CF 3 。
Further, the structural unit
Is composed of
Further, said R 2 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-3 Alkyl or C 1-3 Alkoxy radical, said C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted by 1, 2 or 3R b And (4) substitution.
Further, m is 0 or 1.
Further, the structural unit
Is composed of
Further, the compound of formula (I) or the pharmaceutically acceptable salt thereof is,
wherein, A, R 1 N is as defined herein.
Further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is
The pharmaceutically acceptable salt is sodium salt, potassium salt, ammonium salt, calcium salt, zinc salt or magnesium salt.
The invention provides a pharmaceutical composition, which comprises (I) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable auxiliary material.
The invention provides a preparation method of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps: mixing the compound of formula (II), the compound of formula (III) and alcohols, reacting for 3-24h at 20-100 ℃, adding water, filtering, and obtaining a filter cake as the compound of formula (I); the molar ratio of the compound of formula (II) to the compound of formula (III) is 1: 1-2;
wherein, A ring, R 1 、R 2 M and n are defined as the invention.
Further, the present invention provides a process for the preparation of said compound of formula (IA) or a pharmaceutically acceptable salt thereof, comprising the steps of: dispersing 1, 3-cyclohexanedione and alkali in a solvent 1, reacting for 5-10min at 25-60 ℃, and adding a solvent 2 containing ethyl chloroacetoacetate; reacting for 5-96h at 25-60 ℃, acidifying, filtering and obtaining a filter cake as a compound of a formula (1-b); the mol ratio of the 1, 3-cyclohexanedione to the alkali to the ethyl chloroacetoacetate is 1: 1-2: 1-2;
dissolving the compound of the formula (1-b) by using a solvent 3, heating the system to 60-100 ℃, adding N-bromosuccinimide and azobisisobutyronitrile, reacting for 3-10h at 60-100 ℃, quenching, extracting, concentrating, and recrystallizing by using a solvent 4 to obtain the compound of the formula (1-c), wherein the molar ratio of the compound of the formula (1-b), the N-bromosuccinimide and the azobisisobutyronitrile is 1: 1-1.5: 0.01-0.1;
dispersing the compound of the formula (1-c) and hydrazine hydrate in a solvent 5, sealing the solvent under the protection of nitrogen, heating to 50-100 ℃, and keeping the temperature for 3-12 hours; evaporating the solvent 5, adding water, and filtering to obtain a filter cake which is a compound shown as the formula (I-d), wherein the molar ratio of the compound shown as the formula (1-c) to the hydrazine hydrate is 1: 1-10;
mixing the compound of formula (I-d), the compound of formula (III) and alcohols, reacting at room temperature-100 ℃ for 3-24h, adding water, filtering to obtain a filter cake, namely the compound of formula (IA); the molar ratio of the compound of formula (I-d) to the compound of formula (III) is 1: 1-2;
wherein, A ring, R 1 N is as defined herein.
The solvent 1 is water or methanol.
The solvent 2 is methanol or ethanol.
The solvent 3 is carbon tetrachloride or chloroform.
The solvent 4 is dichloromethane, ethanol, methanol or tetrahydrofuran.
The solvent 5 is methanol, ethanol or tetrahydrofuran.
The alcohol is methanol or ethanol, and preferably, the alcohol is ethanol.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a LSD1 inhibitor.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to abnormal expression of LSD 1.
The diseases related to the abnormal expression of the LSD1 are breast cancer, lymph cancer, leukemia, lung cancer, ovarian cancer, liver cancer, melanoma, colon cancer, rectal cancer, renal cell carcinoma, small intestine cancer, esophagus cancer, bladder cancer, prostate cancer or pharyngeal cancer.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention has the following beneficial effects:
(1) the furoyl hydrazone derivative provided by the invention can be used for preparing antitumor lead compounds based on targeting LSD 1.
(2) Through the detection of the enzyme activity of LSD1, the series of compounds are found to have better inhibition effect on LSD1 enzyme, can be used as lead compounds, and lay a foundation for further designing novel LSD inhibitors. The synthesis method is simple and feasible and has higher yield.
Definitions and description:
as used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
The term "pharmaceutically acceptable" as used herein, is intended to refer to those compounds, materials, compositions, and/or dosage forms. They are within the scope of sound medical judgment and are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention found to have particular substituents with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including such acids as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsuccinic, citric, tartaric, and methanesulfonic acids; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.
Unless otherwise indicated, the term "non-corresponding isomer" refers to a stereoisomer in which the molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
Unless otherwise indicated, the term "(+)" means dextrorotatory, "(-) -" means levorotatory and "(±)" means racemic.
Using solid wedge keys, unless otherwise indicated
And wedge dotted bond
Showing the absolute configuration of a solid centre, using straight solid keys
And straight dotted line bond
Showing the relative configuration of a solid centre by wavy lines
Representing solid-line keys of wedge shape
Or wedge dotted bond
By wave lines
Indicating straight solid-line keys
Or straight dotted bond
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with a radioisotope, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the described event or circumstance occurs and instances where it does not.
Unless otherwise indicated, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., ═ O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When the number of one linking group is 0, e.g. - (CRR) 0 -, represents that the linking group is a single bond.
When a variable is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example where L represents a single bond in A-L-Z, it means that the structure is actually A-Z.
When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A. When the substituent is not specified as being attached to the substituted group through which atom, such substituent may be bonded through any atom thereof, for example, a pyridyl group as the substituent may be attached to the substituted group through any carbon atom on the pyridyl ring.
When the linking group is listed without specifying its direction of attachment, the direction of attachment is arbitrary, for example,
wherein the linking group L is-M-W-, in which case-M-W-can be formed by connecting the ring A and the ring B in the same direction as the reading sequence from left to right
The ring A and the ring B may be connected in the reverse direction of the reading sequence from left to right
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "C 1-8 Alkyl "is used to denote a straight or branched chain saturated carbon group containing 1 to 8 carbon atoms. Said C is 1-8 The alkyl group comprising C 1-8 、C 1-7 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-8 、C 2-7 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-8 、C 5-7 、C 5-6 、C 6-8 、C 7-6 、C 8-7 、C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 C8 alkyl, and the like. It may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C 1-8 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl)) Pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, heptyl, octyl, and the like. The term "C 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).
Unless otherwise specified, the term "alkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge, and unless otherwise specified, the term "C 1-8 Alkoxy includes the radical "C 1-8 、C 1-7 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-8 、C 2-7 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-8 、C 5-7 、C 5-6 、C 6-8 、C 7-6 、C 8-7 、C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 C8 alkoxy, and the like. C 1-8 Examples of alkoxy groups include, but are not limited to, methoxy (Me), ethoxy (Et), propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, heptyloxy, octyloxy, and the like. The term "C 1-3 Examples of alkoxy "include, but are not limited to, methoxy (Me), ethoxy (Et), propoxy (including n-propoxy and isopropoxy).
The term "treating" as used herein means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" of the present invention means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term of the invention certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The term "pharmaceutical composition" of the present invention refers to a mixture of one or more compounds of the present application or salts thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" according to the invention means those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The terms "co-administration," "co-administration with … …," and grammatical equivalents thereof, herein encompass the administration of two or more agents to an animal, including a human, such that the agents and/or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration as separate compositions, administration at different times as separate compositions, or administration as a composition in which both agents are present. The drugs used include, but are not limited to, targeted drugs, immunomodulators, and antibodies.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combinations thereof with other embodiments formed by chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
The solvents used in the present invention are commercially available.
The compounds are prepared by hand or
And naming the software. Commercially available compounds are under the supplier catalogue name.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1: preparation of Compound 1
1, 3-cyclohexanedione (1-a,20g,0.178mol) and KOH (10g,178mmol) were dissolved in water (240 mL). After stirring for 5 minutes, a solution of ethyl chloroacetoacetate (29.35g,178mmol) in methanol (60mL) was added to the mixture. The reaction was stirred at room temperature for 5 days. The reaction mixture was acidified with aqueous HCl (4N, 300mL) and extracted with ethyl acetate (3X 250 mL). The combined extracts were washed with brine (300mL) and then anhydrous Na 2 SO 4 And (5) drying. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give ethyl 3-methyl-4-oxo-4, 5,6, 7-tetrahydrofuran-2-carboxylate (1-b,25.7g, yield: 65%).
Ethyl 3-methyl-4-oxo-4, 5,6, 7-tetrahydrofuran-2-carboxylate (1-b,10g,45mmol) was dissolved in carbon tetrachloride (100mL), heated to 80 deg.C, then N-bromosuccinimide (12g,67.5mmol) and azobisisobutyronitrile (0.44g,2.7mmol) were added and the reaction was held at 80 deg.C for 5 h. The reaction solution was cooled to room temperature, quenched with water, and extracted 3 times with dichloromethane. The combined extracts were washed once with water and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from methylene chloride to obtain ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (1-c,5.45g, yield: 55%).
Ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (1-c,1g,4.5mmol) and hydrazine hydrate (2mL) were uniformly dispersed in a methanol (10mL) solution in a sealed tube, which was capped under nitrogen protection, and the sealed tube was heated to 75 ℃ for 6 h. Most of the methanol was distilled off under reduced pressure, and water of the same volume as the reaction solution was added thereto, followed by filtration to obtain pure 4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,0.79g, yield: 85%) as a white solid.
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and salicylaldehyde (59.2mg,0.49mmol) were uniformly dispersed in methanol (3mL) at room temperature and reacted for 3 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (2-hydroxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (1,129.2mg, yield: 85%). 1 H NMR(400MHz,DMSO-d 6 )δ12.25(s,1H),11.36(s,1H),10.33(s,1H),8.73(s,1H),7.56–7.45(m,1H),7.35–7.23(m,2H),7.04(d,J＝8.3Hz,1H),6.93(dd,J＝10.6,7.8Hz,2H),6.69(d,J＝8.0Hz,1H),2.74(s,3H)。
Example 2: preparation of Compound 2
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2,3, 4-trihydroxybenzaldehyde (75.5mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. Filtering the precipitated solid to collectThe mixture was washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (2,3, 4-trihydroxybenzylidene) benzofuran-2-carbohydrazide (2,150.8mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.12(s,1H),11.59(s,1H),10.34(s,1H),9.52(s,1H),8.55(s,2H),7.27(t,J＝8.1Hz,1H),7.03(d,J＝8.3Hz,1H),6.71(dd,J＝25.4,8.2Hz,2H),6.40(d,J＝8.4Hz,1H),2.73(s,3H)。
Example 3: preparation of Compound 3
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2, 5-dihydroxybenzaldehyde (67.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 60 ℃ for 14 hours. An equal volume of water was added to the mixture and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2, 5-dihydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (3,143.8mg, 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.13(s,1H),10.49(s,1H),10.32(s,1H),9.01(s,1H),8.65(s,1H),7.27(t,J＝8.1Hz,1H),7.03(d,J＝8.3Hz,1H),6.93(d,J＝2.5Hz,1H),6.81–6.72(m,2H),6.68(d,J＝8.0Hz,1H),2.73(s,3H)。
Example 4: preparation of Compound 4
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 6-fluorosalicylaldehyde (68.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 70 ℃ for 12 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2-fluoro-6-hydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (4,132.8mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.51(s,1H),12.12(s,1H),10.36(s,1H),8.93(s,1H),7.41–7.25(m,2H),7.05(d,J＝8.2Hz,1H),6.85–6.74(m,2H),6.70(d,J＝8.0Hz,1H),2.74(s,3H)。
Example 5: preparation of Compound 5
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-bromosalicylaldehyde (98mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (3-bromo-2-hydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (5,171.1mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.63(s,1H),12.53(s,1H),10.36(s,1H),8.68(s,1H),7.63(d,J＝7.9Hz,1H),7.47(d,J＝7.6Hz,1H),7.29(t,J＝8.1Hz,1H),7.05(d,J＝8.3Hz,1H),6.92(t,J＝7.7Hz,1H),6.69(d,J＝8.0Hz,1H),2.75(s,3H)。
Example 6: preparation of Compound 6
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3,4, 5-trimethoxybenzaldehyde (96mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (3,4, 5-trimethoxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (6,169.3mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),10.29(s,1H),8.45(s,1H),7.26(t,J＝8.1Hz,1H),7.02(d,J＝13.9Hz,2H),7.00(s,1H),6.68(d,J＝7.9Hz,1H),3.85(s,6H),3.71(s,3H),2.71(s,3H)。
Example 7: preparation of Compound 7
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2, 4-dihydroxybenzaldehyde (67.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2, 4-dihydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (7,143.8mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.05(s,1H),11.55(s,1H),10.30(s,1H),10.00(s,1H),8.59(s,1H),7.26(dt,J＝8.1,3.9Hz,2H),7.02(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),6.41–6.30(m,2H),2.72(s,3H)。
Example 8: preparation of Compound 8
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-bromo-2-hydroxybenzaldehyde (98mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (4-bromo-2-hydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (8,171.1mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.29(s,1H),11.58(s,1H),10.34(s,1H),8.71(s,1H),7.58–7.45(m,1H),7.27(t,J＝8.1Hz,1H),7.18–7.08(m,2H),7.03(d,J＝8.3Hz,1H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 9: preparation of Compound 9
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3, 4-dihydroxybenzaldehyde (67.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (3, 4-dihydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (9,143.8mg, yield: 90%). 1 H NMR(400MHz,dmso)δ11.64(s,1H,NH),10.25(s,1H,OH),9.34(s,2H,OH),8.32(s,1H,CH＝N),7.31–7.15(m,2H,ArH),6.99(d,J＝8.2Hz,1H,ArH),6.90(d,J＝7.4Hz,1H,ArH),6.77(d,J＝8.1Hz,1H,ArH),6.64(d,J＝7.9Hz,1H,ArH),2.67(d,J＝11.4Hz,3H,CH 3 )。
Example 10: preparation of Compound 10
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-hydroxy-5-methylbenzaldehyde (66.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (2-hydroxy-5-methylbenzylidene) benzofuran-2-carbohydrazide (10,142.9mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.23(s,1H),11.12(s,1H),10.34(s,1H),8.69(s,1H),7.28(dd,J＝10.5,5.3Hz,2H),7.12(dd,J＝8.5,2.3Hz,1H),7.04(d,J＝8.3Hz,1H),6.84(d,J＝8.3Hz,1H),6.69(d,J＝8.0Hz,1H),2.74(s,3H),2.26(s,3H)。
Example 11: preparation of Compound 11
Reacting 4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-hydroxy-5-nitrobenzaldehyde (81.8mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2-hydroxy-5-nitrophenylmethylene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (11,156.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.36(s,0H),10.30(s,1H),8.78(s,1H),8.49(s,1H),8.12(dd,J＝9.2,2.8Hz,1H),7.25(t,J＝8.0Hz,1H),7.07(d,J＝9.0Hz,1H),7.00(d,J＝8.2Hz,1H),6.65(d,J＝7.9Hz,1H),2.70(s,3H)。
Example 12: preparation of Compound 12
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 5-fluoro-2-hydroxybenzaldehyde (68.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (5-fluoro-2-hydroxybenzaldehyde benzylidene) benzofuran-2-carbohydrazide (12,144.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.29(s,1H),11.04(s,1H),10.31(s,1H),8.69(s,1H),7.48–7.33(m,1H),7.25(t,J＝8.1Hz,1H),7.13(td,J＝8.6,3.3Hz,1H),7.01(d,J＝8.3Hz,1H),6.92(dd,J＝9.0,4.6Hz,1H),6.66(d,J＝8.0Hz,1H),2.71(s,3H)。
Example 13: preparation of Compound 13
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-fluoro-2-hydroxybenzaldehyde (68.6mg,0.49mmol) were uniformly dispersed in ethanol (5)mL), the system was reacted at 80 ℃ for 24 hours. An equal volume of water was added to the mixture and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (3-fluoro-2-hydroxybenzylidene) benzofuran-2-carbohydrazide (13,144.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.41(s,1H),11.70(s,1H),10.36(s,1H),8.76(s,1H),7.38–7.25(m,3H),7.05(d,J＝8.2Hz,1H),6.94(td,J＝8.0,4.8Hz,1H),6.70(d,J＝7.9Hz,1H),2.75(s,3H)。
Example 14: preparation of Compound 14
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3, 5-dihydroxybenzaldehyde (67.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (3, 5-dihydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (14,143.8mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.78(s,1H),10.29(s,1H),9.47(s,2H),8.34(s,1H),7.26(t,J＝8.1Hz,1H),7.02(d,J＝8.3Hz,1H),6.68(d,J＝8.0Hz,1H),6.62–6.57(m,2H),6.27(t,J＝2.3Hz,1H),2.71(s,3H)。
Example 15: preparation of Compound 15
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-chloro-6-hydroxybenzaldehyde (76.4mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. Filtering and collecting the precipitated solid, washing with petroleum ether, and dryingTo give (E) -4-hydroxy-3-methyl-N' - (2-chloro-6-hydroxybenzylidene) benzofuran-2-carbohydrazide (15,151.7mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.63(s,1H),12.56(s,1H),10.37(s,1H),9.18(s,1H),7.31(dt,J＝10.7,8.1Hz,2H),7.08–7.01(m,2H),6.95(d,J＝8.4Hz,1H),6.70(d,J＝8.0Hz,1H),2.75(s,3H)。
Example 16: preparation of Compound 16
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 5-chloro-2-hydroxybenzaldehyde (76.4mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (5-chloro-2-hydroxybenzylidene) benzofuran-2-carbohydrazide (16,151.7mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.33(s,1H),11.32(s,1H),10.34(s,1H),8.72(s,1H),7.63(s,1H),7.30(q,J＝9.1,8.5Hz,2H),7.00(dd,J＝28.5,8.6Hz,2H),6.69(d,J＝8.1Hz,1H),2.74(s,3H)。
Example 17: preparation of Compound 17
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-hydroxy-3, 5-dimethoxybenzaldehyde (89.2mg,0.49mmol) were uniformly dispersed in ethanol (5mL) to obtain a raw material mixture.
The raw material mixture was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (4-hydroxy-3, 5-dimethoxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (17,163.2mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.80(s,1H),10.28(s,1H),8.94(s,1H),8.42(s,1H),7.25(q,J＝8.0Hz,1H),7.01(d,J＝24.1Hz,3H),6.68(d,J＝8.0Hz,1H),3.83(s,6H),2.72(s,3H)。
Example 18: preparation of Compound 18
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-furaldehyde (47mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (furan-2-methylene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (18,125.2mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),10.37(s,1H),8.48(s,1H),7.91(d,J＝1.8Hz,1H),7.31(t,J＝8.1Hz,1H),7.07(d,J＝8.2Hz,1H),6.97(d,J＝3.5Hz,1H),6.77–6.66(m,2H),2.77(s,3H)。
Example 19: preparation of Compound 19
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-methoxybenzaldehyde (66.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (3-methoxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (19,142.9mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),10.31(s,1H),8.51(s,1H),7.38(t,J＝8.0Hz,1H),7.26(t,J＝6.0Hz,3H),7.03(dd,J＝7.6,3.1Hz,2H),6.68(d,J＝7.9Hz,1H),3.82(s,3H),2.72(s,3H)。
Example 20: preparation of Compound 20
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3, 5-dichloro-2-hydroxybenzaldehyde (93.1mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (3, 5-dichloro-2-hydroxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (20,166.7mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.62(s,1H),12.53(s,1H),10.35(s,1H),8.65(s,1H),7.57(s,2H),7.28(t,J＝8.1Hz,1H),7.03(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),2.73(s,3H)。
Example 21: preparation of Compound 21
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-methoxybenzaldehyde (66.6mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2-methoxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (21,142.9mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),10.30(s,1H),8.90(s,1H),7.87(d,J＝7.6Hz,1H),7.49–7.38(m,1H),7.26(t,J＝8.1Hz,1H),7.11(d,J＝8.4Hz,1H),7.08–6.98(m,2H),6.67(d,J＝7.9Hz,1H),3.87(s,3H),2.71(s,3H)。
Example 22: preparation of Compound 22
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3, 4-dimethoxybenzaldehyde (81.3mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (3, 4-dimethoxybenzylidene) benzofuran-2-carbohydrazide (22,156.1mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.80(s,1H),10.28(s,1H),8.46(s,1H),7.33(d,J＝1.9Hz,1H),7.25(t,J＝8.1Hz,1H),7.18(dd,J＝8.3,1.9Hz,1H),7.03(dd,J＝8.3,2.9Hz,2H),6.67(d,J＝8.0Hz,1H),3.82(d,J＝5.9Hz,6H),2.72(s,3H)。
Example 23: preparation of Compound 23
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-trifluoromethylbenzaldehyde (85.3mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (4-trifluoromethylbenzylidene) benzofuran-2-carbohydrazide (23,159.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.12(s,1H),10.32(s,1H),8.62(s,1H),7.93(d,J＝8.3Hz,2H),7.82(d,J＝8.1Hz,2H),7.27(t,J＝8.1Hz,1H),7.04(d,J＝8.2Hz,1H),6.69(d,J＝8.1Hz,1H),2.73(s,3H)。
Example 24: preparation of Compound 24
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-fluorobenzaldehyde (60.8 m)g,0.49mmol) was dispersed homogeneously in ethanol (5mL) and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (2-fluorobenzylidene) benzofuran-2-carbohydrazide (24,137.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.10(s,1H),10.31(s,1H),8.80(s,1H),7.95(t,J＝7.5Hz,1H),7.54–7.45(m,1H),7.36–7.22(m,3H),7.03(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 25: preparation of Compound 25
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-thiophenecarboxaldehyde (55mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (thiophene-2-methylene) -3-methylbenzofuran-2-carbohydrazide (25,132.3mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),10.34(s,1H),8.78(s,1H),7.73(d,J＝5.1Hz,1H),7.57–7.46(m,1H),7.31(t,J＝8.1Hz,1H),7.20(dd,J＝5.0,3.5Hz,1H),7.08(d,J＝8.4Hz,1H),6.73(d,J＝7.9Hz,1H),2.77(s,3H)。
Example 26: preparation of Compound 26
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and benzaldehyde (52mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid is collected by filtration, washed with petroleum ether and driedThus, (E) -N' -benzylidene-4-hydroxy-3-methylbenzofuran-2-carbohydrazide (26,129.7mg, yield: 90%) was obtained. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),10.31(s,1H),8.55(s,1H),7.72(d,J＝7.1Hz,2H),7.47(d,J＝7.0Hz,3H),7.26(t,J＝8.1Hz,1H),7.03(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 27: preparation of Compound 27
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-fluorobenzaldehyde (60.8mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (4-fluorobenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (27,137.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),10.31(s,1H),8.54(s,1H),7.77(t,J＝7.0Hz,2H),7.28(dt,J＝17.0,8.4Hz,3H),7.03(d,J＝8.3Hz,1H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 28: preparation of Compound 28
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-hydroxybenzaldehyde (59.8mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (4-hydroxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (28,136.7mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),10.30(s,1H),9.98(s,1H),8.44(s,1H),7.56(d,J＝8.3Hz,2H),7.26(t,J＝8.0Hz,1H),7.03(d,J＝8.2Hz,1H),6.86(d,J＝8.2Hz,2H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 29: preparation of Compound 29
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-trifluoromethylbenzaldehyde (85.3mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. An equal volume of water was added to the mixture and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (2-trifluoromethylbenzylidene) -3-methylbenzofuran-2-carbohydrazide (29,159.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.15(s,1H),10.34(s,1H),8.62(s,1H),8.09–7.96(m,2H),7.79(d,J＝7.8Hz,1H),7.70(t,J＝7.8Hz,1H),7.27(t,J＝8.1Hz,1H),7.04(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),2.73(s,3H)。
Example 30: preparation of Compound 30
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2, 3-dihydroxybenzaldehyde (68mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -N' - (2, 3-dihydroxybenzylidene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (30,143.8mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.28(s,1H),11.25(s,1H),10.35(s,1H),9.24(s,1H),8.68(s,1H),7.28(t,J＝8.1Hz,1H),7.04(d,J＝8.2Hz,1H),6.92(d,J＝7.6Hz,1H),6.86(dd,J＝7.9,1.5Hz,1H),6.75(t,J＝7.8Hz,1H),6.68(d,J＝8.0Hz,1H),2.73(s,3H)。
Example 31: preparation of Compound 31
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-hydroxy-3-methoxybenzaldehyde (74.5mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (4-hydroxy-3-methoxybenzylidene) -3-methylbenzofuran-2-carbohydrazide (31,150mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H,NH),10.25(s,1H,OH),9.58(s,1H),8.40(s,1H,CH＝N),7.31–7.18(m,2H,ArH),7.09–6.96(m,2H,ArH),6.83(d,J＝8.1Hz,1H,ArH),6.65(d,J＝8.0Hz,1H,ArH),3.36(s,3H,CH 3 ),2.69(s,3H,CH 3 )。
Example 32: preparation of Compound 32
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-fluorobenzaldehyde (60.8mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-N' - (3-fluorobenzylidene) -3-methylbenzofuran-2-carbohydrazide (32,137.6mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.05(s,1H),10.32(s,1H),8.55(s,1H),7.61–7.45(m,3H),7.33–7.22(m,2H),7.03(d,J＝8.3Hz,1H),6.68(d,J＝7.9Hz,1H),2.72(s,3H)。
Example 33: preparation of Compound 33
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-hydroxybenzaldehyde (59.8mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (3-hydroxybenzylidene) benzofuran-2-carbohydrazide (33,136.7mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ11.88(s,1H),10.32(s,1H),9.67(s,1H),8.46(s,1H),7.27(t,J＝8.0Hz,2H),7.20(t,J＝1.9Hz,1H),7.06(dd,J＝22.7,7.9Hz,2H),6.84(dd,J＝8.1,2.6Hz,1H),6.68(d,J＝8.0Hz,1H),2.72(s,3H)。
Example 34: preparation of Compound 34
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 2-pyridinecarboxaldehyde (52.4mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. An equal volume of water was added to the mixture and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether, and dried to obtain (E) -N' - (pyridine-2-methylene) -4-hydroxy-3-methylbenzofuran-2-carbohydrazide (34,130mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.23(s,1H),10.35(s,1H),8.68–8.56(m,2H),7.98(d,J＝7.7Hz,1H),7.90(td,J＝7.7,1.8Hz,1H),7.43(ddd,J＝7.4,4.9,1.3Hz,1H),7.28(t,J＝8.1Hz,1H),7.06(d,J＝8.2Hz,1H),6.69(d,J＝8.0Hz,1H),2.74(s,3H)。
Example 35: preparation of Compound 35
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 3-pyrazinePyridinecarboxaldehyde (52.4mg,0.49mmol) was uniformly dispersed in ethanol (5mL) and the system was reacted at 80 ℃ for 24 hours. An equal volume of water was added to the mixture and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (pyridine-3-methylene) benzofuran-2-carbohydrazide (35,130mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.13(s,1H),10.35(s,1H),8.86(d,J＝10.2Hz,1H),8.66–8.58(m,2H),8.14(dt,J＝8.1,1.9Hz,1H),7.55–7.44(m,1H),7.28(t,J＝8.1Hz,1H),7.04(d,J＝8.3Hz,1H),6.69(d,J＝8.0Hz,1H),2.73(s,3H)。
Example 36: preparation of Compound 36
4-hydroxy-3-methylbenzofuran-2-carbohydrazide (1-d,100mg,0.49mmol) and 4-pyridinecarboxaldehyde (52.4mg,0.49mmol) were uniformly dispersed in ethanol (5mL), and the system was reacted at 80 ℃ for 24 hours. To the mixture was added an equal volume of water and a solid was observed to precipitate. The precipitated solid was collected by filtration, washed with petroleum ether and dried to give (E) -4-hydroxy-3-methyl-N' - (pyridine-4-methylene) benzofuran-2-carbohydrazide (36,130mg, yield: 90%). 1 H NMR(400MHz,DMSO-d 6 )δ12.23(s,1H),10.36(s,1H),8.70–8.63(m,2H),8.53(s,1H),7.71–7.62(m,2H),7.28(t,J＝8.1Hz,1H),7.04(d,J＝8.2Hz,1H),6.69(d,J＝8.0Hz,1H),2.73(s,3H)。
Test example 1 determination of inhibitory Activity of the Compound of the present invention against LSD1 enzyme
1. Prepare 1 × test buffer: 50mM Tris-HCl; 0.01% Tween-20; 10mM NaCl
2. Sample preparation for testing:
1) compound stocks were prepared in 100% DMSO at 100 times the maximum working concentration of compound. 50 μ L of the compound stock was added to the first well of a 384 well plate. The mother liquor of the compound in the first well was then diluted 5-fold in 100% DMSO in the second well and the dilutions were made 5-fold in sequence in this way to obtain 7 concentrations of compound. Such as: if the highest working concentration required for the experiment is 5. mu.M, then a 500. mu.M solution of compound in DMSO needs to be prepared at this step.
2) Two empty wells of the same 384-well plate were selected and 50. mu.L of 100% DMSO solution was added. Both wells contained DMSO alone and no enzyme or compound.
3) From the 384 well plate containing the sample, 100nL of the solution was taken per well and transferred to a new 384 well plate for testing. Two replicates were made for each sample. Such as: 100nL of sample was taken from well A1 of the sample plate and added to well A1 and A2 of the test plate, respectively. 100nL of sample was taken from well A2 of the sample plate and transferred to wells A3 and A4. And so on.
3.1) make up a solution of LSD1 with 1 Xbuffer, ensuring that the concentration of LSD1 is twice the concentration of all reagents in the final working concentration. (final working concentration of LSD1 was 2 nM).
2) mu.L of the prepared LSD1 solution was added to each test well of the test plate for each drug to be tested. To control wells containing DMSO alone, 5 μ L of 1x buffer was added. 3) Test panel after shaking the mixture.
4.1) A solution of substrate GL-48(H3K4me2) was prepared with 1 Xbuffer, ensuring that the concentration of GL-48(H3K4me2) was twice the concentration of all reagents in the final working concentration. (GL-48(H3K4me2) at a final working concentration of 100 nM). 2) mu.L of a prepared solution of substrate GL-48(H3K4me2) was added to each test well of the test plate. 3) Test panel after shaking the mixture.
5. Incubate at room temperature for 60 minutes.
6. Prepare 1 × Alphalisa buffer.
7. Recipient and donor solutions were prepared with 1x Alphalisa buffer. 1) The solution of the acceptor and donor beads was prepared with 1x Alphalisa buffer, ensuring that the concentration of the acceptor and donor beads was 1.67 times the concentration of all reagents in the final working concentration. 2) Each test well was assayed by adding 15. mu.L of a solution of acceptor and donor microbeads to the test plate. 3) The test plate after the mixture was shaken and incubated for 60 minutes at room temperature in the dark.
8. Reading of the end point was performed using an ensspire instrument using the Alpha method.
9. And (6) data processing.
Fitting the data in Excel with formula (a) yields inhibition values:
inh% ((Max-Signal)/(Max-Min) × 100)
Fitting data in XL-Fit with formula (b) to obtain IC 50 The value:
y ═ Bottom + (Top-Bottom)/(1+ (IC) 50 /X)*HillSlope)
Y is the inhibition rate%; and X is the sample concentration.
Table 1 percentage inhibition of LSD1 enzyme levels at a single concentration point for the compounds of the invention. The results show that most compounds have strong inhibitory effect on LSD1 enzyme at this concentration.
Table 1.
Selecting the above partial compounds, and performing LSD1 enzyme level inhibition IC 50 The test of (1). The results are shown in Table 2. Compounds 1, 2,3,4, 5, 7, 8, 9, 10, 12, 13, 15, 16, 20, 30 inhibit IC of LSD1 enzyme 50 Below 100 nM.
TABLE 2 inhibition IC of LSD1 enzyme levels by compounds 50 Measurement of (2)
Test example 2: measurement of inhibitory Activity on proliferation of tumor cell line
Cell culture: cells were cultured in RPMI-1640 medium, supplemented with 10% FBS and 1% double antibody. Placing at 37 deg.C and 5% CO 2 Culturing under the condition.
Cell plating: 1) the cells are cultured until the saturation degree of the cells is 80% -90% and when the quantity reaches the requirement, the cells are collected. 2) And (4) resuspending the cells in a corresponding culture medium, counting the cells, and preparing a cell suspension with a proper density. 3) The cell suspension was added to 384-well plates at 30. mu.L/well, 700 cells/well.
Preparation of the compound: 1) compounds were diluted 4-fold with DMSO starting from 2mM at 8 concentrations. 2) Blank control wells were cells plus 0.1% DMSO as high reading control wells.
Compound treatment of cells: 1) 30nL of compound was added to the corresponding wells using Echo. 2) Cells were incubated at 37 ℃ with 5% CO 2 Incubated under conditions for 96 hours.
And (3) CTG method detection: 1) mu.L of CTG reagent (CelltiterGlo kit) was added to each well, and the mixture was left for 30 minutes at room temperature in the dark. 2) Chemiluminescence signal values were read using Envision instruments.
And (3) data analysis: IC calculation Using GraphPad Prism 6software 50 . The IC of the compound was obtained using the following non-linear fit equation 50 (median inhibitory concentration): y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC) 50 -X) × HillSlope)). X is the log value of the concentration of the compound; y is inhibition ratio (% inhibition); inhibition (% inhibition) × (high read control reading-compound well reading)/(high read control reading-low read control reading) × 100. The test data are shown in table 3. The results show that the compounds 4 and 7 have strong inhibition effect on the proliferation of HT-29 and MCF-7 cell lines.
TABLE 3 inhibitory Effect of Compounds on different tumor cell lines
Note: the incubation time was 96 hours.
Claims (8)
1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a LSD1 inhibitor:
wherein the content of the first and second substances,
ring A is phenyl, furyl, thienyl, pyridyl or naphthyl;
each R is 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-8 Alkyl or C 1-8 Alkoxy radical, said C 1-8 Alkyl radical, C 1-8 Alkoxy is optionally substituted by 1, 2 or 3R a Substitution;
each R is 2 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-8 Alkyl radical, C 1-8 Alkoxy radical, said C 1-8 Alkyl radical, C 1-8 Alkoxy is optionally substituted by 1, 2 or 3R b Substitution;
m is 0,1, 2 or 3;
n is 0,1, 2,3 or 4;
each R is a 、R b Each independently F, Cl, Br, I, OH, NO 2 Or CN;
when the structural unit
Is composed of
Time, structural unit
Is different from
2. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of an LSD1 inhibitor, wherein R is 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-3 Alkyl or C 1-3 Alkoxy radical, said C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted by 1, 2 or 3R a And (4) substitution.
3. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 2 for the preparation of an LSD1 inhibitor, wherein R is 1 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH(CH 3 ) 2 、-CF 3 、-CH 2 CF 3 or-CH 2 CH 2 CF 3 。
4. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of an LSD1 inhibitor, wherein said building block
Is composed of
5. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of an LSD1 inhibitor, wherein R is 2 Each independently is H, F, Cl, Br, I, OH, NO 2 、CN、C 1-3 Alkyl or C 1-3 Alkoxy radical, said C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted by 1, 2 or 3R b And (4) substitution.
6. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in the preparation of a LSD1 inhibitor, wherein the compound of formula (I) is:
7. use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is according to any one of claims 1 to 6, for the preparation of a LSD1 inhibitor.
8. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a tumour associated with aberrant expression of LSD1, wherein said compound of formula (I) or pharmaceutically acceptable salt thereof is according to any of claims 1 to 6.
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