CN105085433B - Substituted amide phenol compound and preparation method thereof, pharmaceutical composition and purposes - Google Patents

Abstract

The invention discloses a kind of substituted amide phenol compound and preparation method thereof, pharmaceutical composition and purposes, such compound has structure shown in following general formula I, and wherein the definition of Z, L and Q are as described in specification and claims.The compound of the present invention and its pharmaceutical composition can be used for preparing prevention and/or treat the drug of ribonucleotide reductase related neoplasms.

Description

Substituted amide phenol compound and its preparation method, pharmaceutical composition and use

technical field

The present invention relates to the fields of medicinal chemistry and pharmacotherapy, and more particularly to substituted amide phenol compounds and their preparation methods, pharmaceutical compositions and uses. The compounds can be used to prepare medicines for treating ribonucleotide reductase-related tumors.

Background technique

Ribonucleotide reductase is the rate-limiting enzyme in cellular DNA synthesis. Its function is to catalyze the reduction of the hydroxyl group at the C2 position of the ribose sugar in ribonucleotides (NDPs) to hydrogen to generate deoxyribonucleotides (dNDPs). In cells, dNDPs are kinased to generate deoxynucleoside triphosphates (dNTPs), which provide raw materials for DNA synthesis. Ribonucleotide reductase is a multi-subunit complex consisting of a large subunit R1 and a small subunit R2. R1 (also known as M1 in human ribonucleotide reductase) represents the α2 moiety, R2 (also known as M2 in human ribonucleotide reductase) represents the β2 moiety, there is another ribonucleotide reduction in mammals Enzyme small subunit p53R2 (also known as M2B in human ribonucleotide reductase). It has been proved that the high expression of ribonucleotide reductase, or the resulting disorder of the intracellular dNTPs pool, is closely related to the occurrence and development of tumors. Moreover, high expression of ribonucleotide reductase can enhance chemoresistance in tumor therapy. At present, targeting ribonucleotide reductase to treat related tumors has gradually become a hot spot and focus.

Ribonucleotide reductase is an established drug target. For ribonucleotide reductase, there are currently two drugs on the market, gemcitabine and hydroxyurea. The ribonucleotide reductase inhibitor 3-aminopyridine-2-carbaldehyde thiosemicarbazone (3-AP) is in phase II clinical study. In addition, there are a number of ribonucleotide reductase inhibitors in preclinical or clinical studies. There is still a need in the art to develop more inhibitors of ribonucleotide reductase drug targets.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a substituted amide phenol compound, a pharmaceutical composition and a preparation method thereof targeting ribonucleotide reductase, which can inhibit the activity of ribonucleotide reductase and have the ability to kill tumor cells. ability.

Another object of the present invention is to provide the use of the above-mentioned substituted amide phenol compounds as ribonucleotide reductase inhibitors in the preparation of medicaments for preventing and/or treating ribonucleotide reductase-related tumors.

The substituted amide phenol compounds involved in the present invention can be used as small molecule inhibitors of ribonucleotide reductase, and can inhibit the growth of tumor cells by inhibiting ribonucleotide reductase. Therefore, it can be developed into a new anti-tumor drug for the prevention or treatment of various tumors related to abnormal ribonucleotide reductase, such as oral epidermoid carcinoma, colon cancer, non-small cell lung cancer, glioma, chronic myeloid leukemia Wait.

A first aspect of the present invention provides a compound of general formula I and a pharmaceutically acceptable salt thereof:

in:

Q is hydrogen, C1-C6 alkyl, halogen or hydroxyl;

L is no connecting atom or group, -O-, -S-, -NH-, unsubstituted or substituted -(CH ₂ ) _m -, unsubstituted or substituted -C(O)(CH ₂ ) _m - , unsubstituted or substituted -(CH ₂ ) _m C(O)-, unsubstituted or substituted -(CH ₂ ) _m O-, unsubstituted or substituted -(CH ₂ ) _m S-, unsubstituted or substituted -(CH ₂ ) _m N(H)-, unsubstituted or substituted -O(CH ₂ ) _m -, unsubstituted or substituted -S-(CH ₂ ) _m -, or unsubstituted or substituted -NH (CH ₂ ) _m -, wherein each m is independently an integer from 1 to 6;

Z is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted ferrocene, unsubstituted or substituted C6-C20 aryl , or an unsubstituted or substituted C3-C14 heteroaryl group having a heteroatom selected from the group consisting of O, N, S;

Each of said substitutions is independently substituted with a substituent selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, amino, -NH(C1-C6 alkane base), -N(C1-C6 alkyl) (C-C6 alkyl), nitro, C2-C6 alkenyl, halogenated C1-C6 alkyl, oxo, thio, carboxyl, cyano, methylol group, halogenated C1-C6 alkoxy group, mercapto group, or sulfamoyl group, phenyl group, phenoxy group.

In another preferred embodiment, Z is:

in, Indicates a connection.

In another preferred embodiment, the compound is:

In each formula, the definitions of Z and L are as described above.

In another preferred example, L is: -CHF-, -CF ₂ -, -CH ₂ CF ₂ -, -C(=O)-CF ₂ -, or -C(OH)-CF ₂ -; and/ or

Z is an unsubstituted or substituted C6-C14 aryl group, or an unsubstituted or substituted C3-C10 heteroaryl group having a heteroatom selected from the group consisting of O, N, S; each of the Said substitution is independently substituted by a substituent selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, amino, -NH(C1-C6 alkyl) , -N(C1-C6 alkyl) (C-C6 alkyl), nitro, C2-C6 alkenyl, halogenated C1-C6 alkyl, oxo, thio, carboxyl, cyano, hydroxymethyl, Halogenated C1-C6 alkoxy, mercapto, or sulfamoyl, phenyl, phenoxy.

In another preferred embodiment, the compound has one or more of the following characteristics:

(1) Q is hydrogen or hydroxyl;

(2) L is no connecting atom or group, unsubstituted or substituted -(CH ₂ ) _m -, unsubstituted or substituted -CO(CH ₂ ) _m -, or unsubstituted or substituted -( CH ₂ ) _m CO-,

Wherein, each m is independently an integer from 1 to 6;

The substituent is substituted by a substituent selected from the group consisting of -OH, halogen, amino, halogenated C1-C6 alkyl, C1-C6 alkoxy;

(3) Z is unsubstituted or substituted C6-C20 aryl, unsubstituted or substituted ferrocene, or unsubstituted or substituted C3-C14 heteroaryl,

Wherein, the substitution is substituted by a substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, -OH, -NH ₂ , cyano, -NH(C1 -C6 alkyl), -N(C1-C6 alkyl) (C-C6 alkyl), nitro, C2-C6 alkenyl, halogenated C1-C6 alkyl, halogen, oxo, thio, cyano .

In another preferred embodiment, the aryl group is selected from: phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, phenanthryl, pyrenyl; and/or

The heteroaryl group is selected from: pyridyl, benzothiazolyl, furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrimidinyl, quinazolinyl, quinolinyl, Isoquinolinyl, indolyl.

In another preferred embodiment, the compound is:

In another preferred example, when the compound represented by the general formula I is L is a no-connecting atom or group formula, Z is not or in, Indicates a connection.

Through the in vitro recombinant ribonucleotide reductase activity inhibition test, it was confirmed that the compounds of the present application have strong ribonucleotide reductase activity inhibition ability, and can be used as ribonucleotide reductase inhibitors. And further detection at the cell level shows that the compound of the present invention has obvious anti-tumor activity, and can be developed into a tumor preventive and therapeutic drug.

The second aspect of the present invention provides a preparation method of the compound represented by the general formula I, which can optionally be conveniently prepared by combining various synthesis methods described in this specification or known in the art.

In a preferred embodiment, the method includes the following steps:

In an organic solvent, under the action of a base, the compound of formula A and the compound of formula B are reacted to obtain the compound shown in general formula I,

Wherein, X is hydroxyl or halogen;

The definitions of Z, L and Q are as previously described.

In another preferred embodiment, the preparation method has one or more of the following features:

(1) The organic solvent is N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, trichloromethane One or more mixtures of methane;

(2) The base is one or a mixture of two or more selected from diisopropylethylamine, triethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene ;

(3) the reaction is carried out under the action of a catalyst, and the catalyst is the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole one or a mixture of both;

(4) reaction temperature is 15-40 ℃;

(5) The reaction time is 5-48 hours.

In another preference, the preparation method of the compound shown in general formula I comprises the following steps:

Compound A and compound B are subjected to the action of a catalyst, a base and an organic solvent to obtain a compound having the general formula I, wherein the definitions of Z, L and Q are as described above.

The organic solvent is a suitable aprotic solvent, including but not limited to N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, One or more mixtures of acetonitrile, preferably N,N-dimethylformamide; the base is a suitable organic base, including but not limited to diisopropylethylamine, triethylamine, pyridine, One or more mixtures of 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably diisopropylethylamine; the catalyst is 1-(3-diisopropylethylamine methylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, or a combination thereof. The reaction temperature is 15-40°C, and the reaction time is 5-48 hours.

In another preference, the preparation method of the compound shown in general formula I comprises the following steps:

Compound A and compound B are subjected to the action of a base and an organic solvent to obtain a compound having the general formula I, wherein Z, L and Q are as defined above.

The organic solvent is a suitable aprotic solvent, including but not limited to one or more mixtures of dichloromethane, tetrahydrofuran and chloroform, preferably dichloromethane; the base is a suitable organic base , including but not limited to one or a mixture of two or more of diisopropylethylamine, triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably Triethylamine. The reaction temperature is 15-40°C, and the reaction time is 5-48 hours.

The compounds of the present invention may be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art.

A third aspect of the present invention provides a pharmaceutical composition, comprising: (1) the compound described in the first aspect or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof, for (a) preparing a ribonucleotide reductase inhibitor; or (b) preparing a prophylactic and/or Drugs for the treatment of tumors associated with abnormal ribonucleotide reductase.

The tumor associated with abnormal ribonucleotide reductase is selected from: oropharyngeal cancer, colorectal cancer, non-small cell lung cancer, glioma, leukemia, liver cancer, thyroid cancer, esophageal cancer, lymphoma, thoracic cancer, digestive Tract cancer, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, bile duct cancer, central nervous system cancer, testicular cancer, bladder cancer, prostate cancer, skin cancer, melanoma, sarcoma, brain cancer, cervical cancer carcinoma, glioma, gastric cancer, or ascites tumor.

In another preferred embodiment, the oropharyngeal carcinoma is oral epidermoid carcinoma.

In another preferred embodiment, the leukemia is chronic myeloid leukemia.

The fourth aspect of the present invention provides the use of the pharmaceutical composition described in the third aspect, for (a) preparing a ribonucleotide reductase inhibitor; or (b) preparing a preventive and/or therapeutic ribonucleotide reduction Drugs for tumors associated with enzyme abnormalities.

The tumor associated with abnormal ribonucleotide reductase is selected from: oropharyngeal cancer, colorectal cancer, non-small cell lung cancer, glioma, leukemia, liver cancer, thyroid cancer, esophageal cancer, lymphoma, thoracic cancer, digestive Tract cancer, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, bile duct cancer, central nervous system cancer, testicular cancer, bladder cancer, prostate cancer, skin cancer, melanoma, sarcoma, brain cancer, cervical cancer carcinoma, glioma, gastric cancer, or ascites tumor.

In another preferred embodiment, the oropharyngeal carcinoma is oral epidermoid carcinoma.

In another preferred embodiment, the leukemia is chronic myeloid leukemia.

The fifth aspect of the present invention provides an in vitro non-therapeutic method for inhibiting tumor cell proliferation or inducing tumor cell apoptosis, comprising the compound of the first aspect or a pharmaceutically acceptable salt thereof or the third aspect The pharmaceutical composition contacts the tumor cells, thereby inhibiting the proliferation of the tumor cells or inducing the apoptosis of the tumor cells.

In another preferred embodiment, the contact is culture contact.

The sixth aspect of the present invention provides a method for treating tumors, wherein a safe and effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in the third aspect is administered to a subject in need.

In another preferred embodiment, the treatment is photothermal treatment.

In another preferred embodiment, the subject in need is a non-human mammal or a human, preferably a human, a mouse or a rat.

The present invention discovers a new type of substituted amide phenol compounds. Through the in vitro recombinant ribonucleotide reductase activity inhibition test, it is confirmed that the compounds of the present application have strong ribonucleotide reductase activity inhibition ability, and can As an inhibitor of ribonucleotide reductase. And further detection at the cell level shows that the compound of the present invention has obvious anti-tumor activity, and can be developed into a tumor preventive and therapeutic drug.

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 in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the inventors of the present application have unexpectedly developed a substituted amide phenol compound with a novel structure for the first time, which can be used as an inhibitor of ribonucleotide reductase, has obvious anti-tumor activity, and can be developed into Cancer prevention and treatment drugs. On this basis, the present invention has been completed.

the term

In the context of the present invention, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, eg _-CH3 or -CH( _CH3 ) ₂ . The term "alkoxy" refers to a -O-(C1-6 alkyl) group. The term "alkenyl" refers to a straight or branched chain hydrocarbon moiety containing at least one double bond, eg -CH=CH- _CH3 . The term "cycloalkyl" refers to a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "aryl" refers to a hydrocarbyl moiety containing one or more aromatic rings. Examples of aryl moieties include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl. The term "heteroaryl" refers to a moiety comprising one or more aromatic rings having at least one heteroatom (eg, N, O, or S). Examples of heteroaryl moieties include furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, and indium dolyl.

Unless otherwise specified, alkyl, alkenyl, cycloalkyl, aryl, and heteroaryl groups described herein include both substituted and unsubstituted moieties. Possible substituents on alkyl, alkenyl, cycloalkyl, aryl and heteroaryl groups include, but are not limited to: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkane base, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, heteroaryl, heteroaryloxy, amino, C1-C10 alkane amino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfo Imino, arylsulfoimino, hydroxyl, halogen, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, Urea group, cyano group, nitro group, acyl group, thioacyl group, acyloxy group, carboxyl group and carboxylate group. On the other hand, cycloalkyl groups, heterocycloalkyl groups, heterocycloalkenyl groups, aryl groups and heteroaryl groups can also be condensed with each other.

In the present invention, the substitution is monosubstitution or polysubstitution, and the polysubstitution is disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution. The disubstituted refers to having two substituents, and so on.

The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate acid, glutamate, glucuronate, lactate, glutamate and maleate. Similarly, salts can be formed from cations with negatively charged groups (eg carboxylate) on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salt" refers to salts formed with the following acids: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, Salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, tartaric acid, succinic acid, oxalic acid, malic acid, glutamic acid.

pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising the active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.

The "active ingredient" of the present invention refers to the compound of formula I (the compound represented by general formula I) of the present invention.

The "active ingredients" and pharmaceutical compositions of the present invention can be used as ribonucleotide reductase inhibitors.

In another preferred example, it is used to prepare a medicament for preventing and/or treating tumors.

In another preferred embodiment, it is used to prepare a medicament for preventing and/or treating ribonucleotide reductase-related diseases. In another preferred embodiment, the ribonucleotide reductase-related disease is selected from the group consisting of: oropharyngeal cancer, colorectal cancer, non-small cell lung cancer, glioma, leukemia, liver cancer, thyroid cancer, esophageal cancer, and lymphoma , thoracic cancer, gastrointestinal cancer, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, bile duct cancer, central nervous system cancer, testicular cancer, bladder cancer, prostate cancer, skin cancer, melanoma, sarcoma cancer , brain cancer, cervical cancer, glioma, gastric cancer, or ascites tumor.

A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose. Preferably, the "one dose" is one tablet.

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

In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or macromolecule through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked with a macromolecular compound or a macromolecule through chemical bonds. The macromolecular compounds can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, and the like.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

The solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, 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, and the like. Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents such as chemotherapeutic agents.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All features disclosed in this specification may be used in combination with any composition, and each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

The benefits of the present invention are:

(1) To provide a substituted amide phenol compound with a novel structure and a preparation method thereof.

(2) The compounds have strong ribonucleotide reductase enzymatic activity inhibition ability, and can be used as ribonucleotide reductase inhibitors.

(3) The compounds have obvious anti-tumor activity, and can be developed into preventive and therapeutic drugs for tumors.

The present invention will be further described below in conjunction with specific embodiments. 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 method of unreceipted specific conditions in the following examples, usually according to normal conditions such as people such as Sambrook, molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor LaboratoryPress, 1989), or according to manufacturer's recommended conditions. Unless otherwise stated, percentages and parts are by weight and masses are in grams.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

Preparation Examples:

Thin-layer analysis (TLC) plate model is HSGF-254 (thickness 0.15-0.2mm, produced by Yantai Chemical Experiment Factory); column chromatography silica gel is 200-300 mesh commercial silica gel produced by Qingdao Ocean Chemical Factory; ¹ H-NMR, ¹³ C-NMR was recorded using a Bruker AM-300, Varian Mercury-400 or Varian Mercury-500 nuclear magnetic resonance apparatus, the internal standard was tetramethylsilane (TMS); chemical shifts were (ppm, δ), proton couplings were labeled as singlets (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br); low-resolution mass spectrometry (EI-MS or ESI) and high-resolution mass spectrometry ( HR-MS or ESI) was recorded using Finningan/MAT-95 instrument or Agilent6110 mass spectrometer, Orbitrap mass spectrometer; microwave reaction was carried out with CEM microwave reactor; melting point was determined with Büchi 510 melting point apparatus, and the thermometer was not calibrated. The drugs used in the experiments were all commercially available analytical grade or chemical grade, and all reagents were not purified before use unless otherwise stated.

Example 1N-(3,4-Dihydroxyphenyl)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetamide (Compound 1 ) preparation

(1) Preparation of 2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetic acid

2.45g (25mmol) of maleic anhydride was dissolved in 15mL of toluene and placed in a 100mL reaction flask, 3.12g (25mmol) of 15mL toluene solution of o-thiophenol was added dropwise at room temperature, and the reaction was stirred at room temperature for 3 hours, and white precipitated The solid was filtered, and the crude product was recrystallized with 15 mL of ethanol to obtain 1.6 g of a white solid with a yield of 29%.

¹ H NMR (400MHz, d ₆ -DMSO) δ 12.59 (s, 1H), 10.69 (s, 1H), 7.33 (dd, J=8.1, 1.5Hz, 1H), 7.20 (td, J=7.5, 1.5 Hz,1H),7.08-6.81(m,2H),3.79(dd,J=7.9,6.2Hz,1H),2.85(dd,J=16.4,6.2Hz,1H),2.43(dd,J=16.4, 7.9Hz, 1H); MS(ESI)(M+Na) ⁺ : m/z 246.1.

(2) Preparation of N-(3,4-dimethoxyphenyl)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)ethyl Amide

223mg (1mmol) 2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetic acid and 153mg (1mmol) 3,4-dimethoxyaniline In a 50mL reaction flask, add 10mL anhydrous DMF (N,N-dimethylformamide) as a solvent, then add 286mg (1.5mmol) EDCI (1-(3-dimethylaminopropyl)-3-ethyl) successively carbodiimide hydrochloride), 202 mg (1.5 mmol) HOBT (1-hydroxybenzotriazole), 193 mg (1.5 mmol) DIPEA (diisopropylethylamine), stirred at room temperature (RT) overnight, and then 30 mL of saturated sodium chloride solution was added daily, extracted with 50 mL of ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated by rotary evaporation, and 120 mg of white powder was obtained by column chromatography on silica gel with a yield of 34%.

¹ H NMR(300MHz,d ₆ -DMSO)δ10.69(s,1H),9.94(s,1H),7.34(d,J=8.0Hz,1H),7.30(d,J=2.3Hz,1H) ,7.26-7.16(m,1H),7.07(dd,J＝8.7,2.3Hz,1H),7.04-6.96(m,2H),6.87(d,J＝8.8Hz,1H),3.92(dd,J =8.7,5.4Hz,1H),3.71(s,6H),2.93(dd,J=15.4,5.4Hz,1H),2.55-2.52(m,1H); MS(ESI)(M+Na) ⁺ : m/z381.2.

(3) N-(3,4-Dihydroxyphenyl)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetamide (compound 1) Preparation

50mL reaction flask, add 143mg (0.4mmol) N-(3,4-dimethoxyphenyl)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazine) -2-yl)acetamide, 20 mL of anhydrous dichloromethane, after stabilization at -78 °C, 0.25 mL of 4M boron tribromide in dichloromethane solution was added dropwise, and the reaction was kept at low temperature for one hour, and saturated sodium bicarbonate solution was added. Washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (dichloromethane/methanol=20:1) to obtain 55 mg of white powder with a yield of 42%.

¹ H NMR(300MHz,d ₆ -DMSO)δ10.68(s,1H),9.69(s,1H),8.96(s,1H),8.59(s,1H),7.33(d,J=7.5Hz, 1H), 7.26-7.17(m, 1H), 7.13(d, J=2.3Hz, 1H), 7.06-6.95(m, 2H), 6.76(dd, J=8.4, 2.3Hz, 1H), 6.61(d , J=8.6Hz, 1H), 3.90 (dd, J=8.9, 5.3Hz, 1H), 2.88 (dd, J=15.4, 5.2Hz, 1H), 2.53-2.45 (m, 1H); MS (ESI) (M+H) ⁺ :m/z331.1.

Example 2 Preparation of N-(4-hydroxyphenyl)-2-ferroceneacetamide (compound 2)

Using 122 mg (0.5 mmol) of ferrocene acetic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 80 mg of yellow powder was obtained with a yield of 53%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.71(s,1H),9.15(s,1H),7.37(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H) , 4.24(t, J=1.4Hz, 2H), 4.13(s, 5H), 4.09(t, J=1.4Hz, 2H), 3.24(s, 2H); MS(ESI)(M+H) ⁺ : m/z336.1.

Example 3 Preparation of N-(4-hydroxyphenyl)-4-ethylbenzamide (compound 3)

Using 150 mg (1 mmol) of p-ethylbenzoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 150 mg of white powder was obtained with a yield of 62%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.88(s,1H),9.16(s,1H),7.86(d,J=8.1Hz,2H),7.51(d,J=8.8Hz,2H) ,7.33(d,J=8.0Hz,2H),6.73(d,J=8.8Hz,2H),2.67(q,J=7.5Hz,2H),1.21(t,J=7.6Hz,3H); MS (ESI)(M+H) ⁺ :m/z242.2.

Example 4 Preparation of N-(4-hydroxyphenyl)-4-methyl-1-naphthalenecarboxamide (compound 4)

Using 186 mg (1 mmol) of 4-methyl-1-naphthoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 180 mg of white powder was obtained with a yield of 65%.

¹ H NMR (300MHz, d ₆ -DMSO) δ 10.24 (s, 1H), 9.25 (s, 1H), 8.22 (dd, J=6.1, 2.2 Hz, 1H), 8.10 (dd, J=6.6, 2.8 Hz,1H),7.64-7.57(m,5H),7.44(d,J=7.3Hz,1H),6.75(d,J=8.8Hz,2H),2.70(s,3H); MS(ESI)( M+H) ⁺ :m/z278.1.

Example 5 Preparation of N-(4-hydroxyphenyl)-4-trifluoromethylbenzamide (compound 5)

Using 190 mg (1 mmol) of 4-trifluoromethylbenzoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 130 mg of white powder was obtained with a yield of 46%.

¹ H NMR (300 MHz, d ₆ -DMSO) δ 10.24 (s, 0H), 9.31 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H) ,7.53(d,J=8.8Hz,2H),6.75(d,J=8.8Hz,2H); MS(ESI)(M+H) ⁺ :m/z282.1.

Example 6 Preparation of N-(4-hydroxyphenyl)-2,3-dimethylbenzamide (compound 6)

Using 150 mg (1 mmol) of 2,3-dimethylbenzoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 160 mg of white powder was obtained with a yield of 66%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.96(s,1H),9.16(s,1H),7.50(d,J=8.8Hz,2H),7.25-7.13(m,3H),6.71( d, J=8.9Hz, 2H), 2.28(s, 3H), 2.24(s, 3H); MS(ESI)(M+H) ⁺ : m/z242.1.

Example 7 Preparation of N-(4-hydroxyphenyl)-4-ethyl-1-naphthalenecarboxamide (compound 7)

Using 150 mg (0.75 mmol) of 4-ethyl-1-naphthoic acid and 82 mg (0.75 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 60 mg of white powder was obtained with a yield of 21%.

¹ H NMR(300MHz,d ₆ -DMSO)δ10.23(s,1H),9.22(d,J=1.3Hz,1H),8.35-7.95(m,2H),7.78-7.51(m,5H), 7.45(d,J=7.3Hz,1H),6.76(d,J=8.8Hz,2H),3.13(q,J=7.5Hz,2H),1.32(t,J=7.5Hz,3H); MS( ESI)(M+H) ⁺ :m/z292.1.

Example 8 Preparation of N-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (Compound 8)

Using 176 mg (1 mmol) of 5,6,7,8-tetrahydro-1-naphthoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 110 mg of white powder was obtained with a yield of 41%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.98(s,1H),9.21(s,1H),7.50(d,J=8.9Hz,2H),7.28-7.05(m,3H),6.71( d, J=8.9Hz, 2H), 2.77(s, 4H), 1.72(s, 4H); MS(ESI)(M+H) ⁺ : m/z 268.2.

Example 9 Preparation of N-(4-hydroxyphenyl)-4-trifluoromethyl-2-aminobenzamide (compound 9)

Using 153 mg (0.75 mmol) of 4-trifluoromethyl-2-aminobenzoic acid and 82 mg (0.75 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 100 mg of white powder was obtained with a yield of 45%.

¹ H NMR (300MHz,d ₆ -DMSO)δ9.99(s,1H),9.27(s,1H),7.74(d,J=8.1Hz,1H),7.46(d,J=8.8Hz,2H) , 7.08(s, 1H), 6.84(d, J=8.9Hz, 1H), 6.73(d, J=8.8Hz, 2H), 6.57(s, 2H); MS(ESI)(M+H) ⁺ : m/z297.1.

Example 10 Preparation of N-(4-hydroxyphenyl)-4-trifluoromethyl-2-fluorobenzamide (compound 10)

Using 156 mg (0.75 mmol) of 4-trifluoromethyl-2-fluorobenzoic acid and 82 mg (0.75 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 140 mg of white powder was obtained with a yield of 62%.

¹ HNMR(300MHz,d ₆ -DMSO)δ10.35(s,1H),9.34(s,1H),7.91-7.81(m,2H),7.71(d,J=8.1Hz,1H),7.49(d , J=8.9Hz, 2H), 6.75 (d, J=8.9Hz, 2H); MS(ESI)(M+H) ⁺ : m/z300.1.

Example 11 Preparation of N-(4-hydroxyphenyl)-4-ethyl-2-fluorobenzamide (Compound 11)

(1) Methyl 4-ethyl-2-fluorobenzoate

A 25-mL reaction flask was placed into 94 mg (0.5 mmol) of methyl 2-fluoro-4-chlorobenzoate, 8.8 mg (0.025 mmol) of iron triacetylacetonate Fe(acac) ₃ , and 3 mL of anhydrous was injected into 3 mL of anhydrous by evacuating and changing nitrogen three times. Tetrahydrofuran THF, 0.3 mL of anhydrous N-methylpyrrolidone NMP, then injected with 0.6 mL of 1M Ethyl Grignard reagent (0.6 mmolEtMgBr), stirred at room temperature for half an hour, added 10 mL of dilute hydrochloric acid to quench the reaction, and extracted with 30 mL of ethyl acetate. Washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and separated by silica gel column chromatography (petroleum ether/ethyl acetate = 150:1) to obtain 60 mg of colorless liquid, yield 66% .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.85 (t, J=7.9Hz, 1H), 7.02 (ddt, J=8.0, 1.7, 0.7Hz, 1H), 6.96 (dtd, J=11.9, 1.0, 0.5 Hz, 1H), 3.91 (s, 3H), 2.68 (q, J=7.6Hz, 2H), 1.24 (t, J=7.6Hz, 4H); MS (ESI) (M+H) ⁺ : m/z183 .2.

(2) N-(4-hydroxyphenyl)-4-ethyl-2-fluorobenzamide (Compound 11)

25 mL reaction flask, put 60 (0.33 mmol) mg of methyl 4-ethyl-2-fluorobenzoate, 3 mL of methanol, 3 mL of water, 92 mg (1.6 mmol) of potassium hydroxide, and after stirring at room temperature for two hours, the methanol was removed by rotary evaporation. , the pH value of the aqueous layer was adjusted to 2 with hydrochloric acid, and a white solid was precipitated, which was washed with filtered water until neutral, and dried in vacuo to obtain 33 mg of 4-ethyl-2-fluorobenzoic acid as a white solid in a yield of 60%. Using 30 mg (0.18 mmol) of 4-ethyl-2-fluorobenzoic acid and 20 mg (0.18 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 27 mg of white powder was obtained with a yield of 58%.

¹ H NMR (400MHz, d ₆ -DMSO) δ 10.02 (s, 1H), 9.28 (s, 1H), 7.71 (ddd, J=12.9, 9.5, 1.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.45(t, J＝7.8Hz, 1H), 6.73(d, J＝8.8Hz, 2H), 2.69(q, J＝7.6Hz, 2H), 1.20(t, J＝7.6Hz, 3H); MS (ESI) (M+H) ⁺ : m/z 260.1.

Example 12 Preparation of N-(4-hydroxyphenyl)-4-cyclopropyl-2-fluorobenzamide (compound 12)

(1) Methyl 4-cyclopropyl-2-fluorobenzoate

25 mL reaction flask, put 94 mg (0.5 mmol) of methyl 2-fluoro-4-chlorobenzoate, 8.8 mg (0.025 mmol) of iron triacetylacetonate, vacuum and change nitrogen three times and inject 3 mL of anhydrous tetrahydrofuran into a syringe, 0.3 mL of no Water N-methylpyrrolidone, and then 1.5mL syringe with a concentration of 0.5M cyclopropyl Grignard reagent (0.75mmol cyclopropylmagnesium bromide), stir at room temperature for half an hour, add 10mL of dilute hydrochloric acid to quench the reaction, and extract with 30mL of ethyl acetate , washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio = 150:1) to obtain 50 mg of a colorless liquid, which was collected rate 52%.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.81 (t, J=7.9Hz, 1H), 6.88 (dd, J=8.1, 1.7Hz, 1H), 6.77 (dd, J=12.3, 1.7Hz, 1H) ,3.90(s,3H),1.90(ddd,J=13.4,8.6,5.0Hz,1H),1.15–0.98(m,2H),0.80–0.68(m,2H); MS(ESI)(M+H ) ⁺ :m/z195.2.

(2) Preparation of N-(4-hydroxyphenyl)-4-cyclopropyl-2-fluorobenzamide (Compound 12)

25 mL reaction flask, put 35 mg (0.18 mmol) of methyl 4-ethyl-2-fluorobenzoate, 3 mL of methanol, 3 mL of water, 50 mg (0.90 mmol) of potassium hydroxide, stirred at room temperature for two hours, and evaporated by rotary evaporation Methanol MeOH, the aqueous layer was adjusted to pH 2 with hydrochloric acid, extracted with 20 mL of ethyl acetate, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 4-cyclopropyl-2-fluoro. The white solid of benzoic acid was 31 mg, which was directly used in the next reaction, and the yield was 95%. Using 15 mg (0.08 mmol) of 4-cyclopropyl-2-fluorobenzoic acid and 9 mg (0.08 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 13 mg of white powder was obtained with a yield of 56%.

¹ H NMR(400MHz,d ₆ -DMSO)δ9.99(s,1H),9.26(s,1H),7.66-7.34(m,3H),7.03(s,1H),7.02-6.99(m,1H) ), 6.72 (d, J=9.1Hz, 1H), 2.00 (td, J=8.3, 4.3Hz, 1H), 1.07–1.00 (m, 2H), 0.80–0.74 (m, 2H); MS (ESI) (M+H) ⁺ :m/z272.1.

Example 13 Preparation of N-(4-hydroxyphenyl)-4-methylbenzamide (compound 13)

Using 136 mg (1.0 mmol) of 4-methylbenzoic acid and 109 mg (1 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 180 mg of white powder was obtained with a yield of 79%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.90(s,1H),9.21(s,1H),7.83(d,J=8.2Hz,2H),7.50(d,J=8.8Hz,2H) ,7.29(d,J=7.9Hz,2H),6.71(d,J=8.9Hz,2H),2.36(s,3H); MS(ESI)(M+H) ⁺ :m/z228.1.

Example 14 Preparation of N-(4-hydroxyphenyl)-4-methyl-2-methoxybenzamide (compound 14)

Using 83 mg (0.5 mmol) of 4-methyl-2-methoxybenzoic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 115 mg of white powder was obtained with a yield of 90%.

¹ H NMR (300MHz,d ₆ -DMSO)δ9.75(s,1H),9.20(s,1H),7.59(d,J=7.7Hz,1H),7.48(d,J=8.4Hz,2H) ,6.98(s,1H),6.86(d,J=7.7Hz,1H),6.70(d,J=8.5Hz,2H),3.89(s,3H),2.35(s,3H); MS(ESI) (M+H) ⁺ :m/z258.1.

Example 15 Preparation of N-(4-hydroxyphenyl)-5-ethylpyridine-2-carboxamide (Compound 15)

Using 75.5 mg (0.5 mmol) of 5-ethylpyridine-2-carboxylic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 102 mg of white powder was obtained with a yield of 84%.

¹ HNMR(300MHz,d ₆ -DMSO)δ10.32(s,1H),9.27(s,1H),8.56(s,1H),8.05(d,J=8.2Hz,1H),7.89(dd,1H) =8.0,2.0Hz,1H),7.66(d,J=8.8Hz,2H),6.74(d,J=8.9Hz,2H),2.74(q,J=7.6Hz,2H),1.24(t,J =7.6Hz,3H); MS(ESI)(M+H) ⁺ : m/z243.1.

Example 16 Preparation of N-(4-hydroxyphenyl)-4-dimethylaminobenzamide (compound 16)

Using 82.5 mg (0.5 mmol) of 4-dimethylaminobenzoic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 71 mg of light yellow powder was obtained with a yield of 56%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.63(s,1H),9.15(s,1H),7.83(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,2H) , 6.72(t, J=9.0Hz, 3H), 2.98(s, 6H); MS(ESI)(M+H) ⁺ : m/z257.1.

Example 17 Preparation of N-(4-hydroxyphenyl)-4-methylaminobenzamide (compound 17)

Using 75.5 mg (0.5 mmol) of 4-methylaminobenzoic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 90 mg of white powder was obtained with a yield of 74%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.55(s,1H),9.14(s,1H),7.75(d,J=8.8Hz,2H),7.48(d,J=8.9Hz,2H) ,6.70(d,J=8.9Hz,2H),6.56(d,J=8.8Hz,2H),6.25(s,1H),2.73(s,3H); MS(ESI)(M+H) ⁺ : m/z243.1.

Example 18 Preparation of N-(4-hydroxyphenyl)-4-ethyl-3-fluorobenzamide (compound 18)

(1) Methyl 4-ethyl-3-fluorobenzoate

25 mL reaction flask, put 94 mg (0.5 mmol) of methyl 3-fluoro-4-chlorobenzoate, 8.8 mg (0.025 mmol) of iron triacetylacetonate, evacuated and changed nitrogen three times and injected into 3 mL of anhydrous tetrahydrofuran, 0.3 mL of no Water N-methylpyrrolidone, then 0.6 mL of syringe with a concentration of 1 M ethyl Grignard reagent (0.6 mmolEtMgBr), after stirring at room temperature for half an hour, 10 mL of dilute hydrochloric acid was added to quench the reaction, extracted with 30 mL of ethyl acetate, washed with water, and saturated with sodium chloride The solution was washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio = 150:1) to obtain 75 mg of a colorless liquid with a yield of 62%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (dd, J=7.9, 1.8 Hz, 1H), 7.65 (dd, J=10.4, 1.7 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H) ,3.90(s,3H),2.71(d,J=7.2Hz,2H),1.24(d,J=7.2Hz,3H); MS(ESI)(M+H) ⁺ :m/z183.2.

(2) Preparation of N-(4-hydroxyphenyl)-4-ethyl-3-fluorobenzamide (Compound 18)

25 mL reaction flask, put 60 mg (0.33 mmol) methyl 4-ethyl-3-fluorobenzoate, 3 mL methanol, 3 mL water, 92 mg (1.6 mmol) potassium hydroxide, stir at room temperature for two hours, and remove by rotary evaporation Methanol, the pH value of the aqueous layer was adjusted to 2 with hydrochloric acid, and a white solid was precipitated, which was washed with filtered water until neutral, and dried under vacuum to obtain 35 mg of 4-ethyl-3-fluorobenzoic acid as a white solid, which was directly used in the next step. The yield was 63 %. Using 26 mg (0.16 mmol) of 4-ethyl-3-fluorobenzoic acid and 17 mg (0.16 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 30 mg of white powder was obtained with a yield of 75%.

¹ H NMR (400MHz, d ₆ -DMSO) δ 10.02 (s, 1H), 9.28 (s, 1H), 7.71 (ddd, J=12.9, 9.5, 1.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.45(t, J＝7.8Hz, 1H), 6.73(d, J＝8.8Hz, 2H), 2.69(q, J＝7.6Hz, 2H), 1.20(t, J＝7.6Hz, 3H); MS (ESI) (M+H) ⁺ : m/z 242.2.

Example 19 Preparation of N-(4-hydroxyphenyl)-4-ethyl-2,6-difluorobenzamide (compound 19)

(1) Methyl 4-ethyl-2,6-difluorobenzoate

25 ml reaction flask, put 50 mg (0.24 mmol) of methyl 2,6-difluoro-4-chlorobenzoate, 4.4 mg (0.013 mmol) of iron triacetylacetonate, evacuated and changed nitrogen three times and injected into 2 mL of anhydrous tetrahydrofuran, 0.2 mL of anhydrous N-methylpyrrolidone, then 0.35 mL of a syringe with a concentration of 1 M ethyl Grignard reagent (0.35 mmol), after stirring at room temperature for half an hour, 10 mL of dilute hydrochloric acid was added to quench the reaction, extracted with 30 mL of ethyl acetate, washed with water, saturated Washed with sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether/ethyl acetate=150:1) to obtain 20 mg of a colorless liquid with a yield of 41%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.79 (d, J=9.6 Hz, 2H), 3.93 (s, 3H), 2.65 (q, J=7.8 Hz, 2H), 1.23 (t, J=7.8 Hz) ,3H); MS(ESI)(M+H) ⁺ :m/z201.

(2) N-(4-hydroxyphenyl)-4-ethyl-2,6-difluorobenzamide (Compound 19)

A 25 mL reaction flask was placed in 46 mg (0.23 mmol) of methyl 4-ethyl-2,6-difluorobenzoate, 3 mL of methanol, 3 mL of water, 64 mg (1.15 mmol) of potassium hydroxide, stirred at room temperature for two hours, and then rotated. The methanol was removed, the pH value of the aqueous layer was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain a white solid 4-ethyl-2,6-difluoro 40 mg of benzoic acid was directly used in the next reaction, and the yield was 94%. Using 30 mg (0.16 mmol) of 4-ethyl-2,6-difluorobenzoic acid and 17 mg (0.16 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 26 mg of white powder was obtained with a yield of 58%.

¹ H NMR(500MHz,d ₆ -DMSO)δ10.42(s,1H),9.29(s,1H),7.45(d,J=8.9Hz,2H),7.08(d,J=8.6Hz,2H) ,6.72(d,J=8.8Hz,2H),2.65(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H); MS(ESI)(M+H) ⁺ :m/ z278.1.

Example 20 Preparation of N-(4-hydroxyphenyl)-4-cyclopropyl-2,6-difluorobenzamide (compound 20)

(1) Methyl 4-cyclopropyl-2,6-difluorobenzoate

A 25-mL reaction flask was placed into 100 mg (0.48 mmol) of methyl 2,6-difluoro-4-chlorobenzoate, 8.8 mg (0.026 mmol) of iron triacetylacetonate, and 3 mL of anhydrous tetrahydrofuran was injected into 3 mL of anhydrous tetrahydrofuran by vacuuming and changing nitrogen three times. 0.3mL of anhydrous N-methylpyrrolidone, then 1.16mL of a syringe with a concentration of 0.5M cyclopropyl Grignard reagent (0.58mmol of cyclopropylmagnesium bromide), after stirring at room temperature for half an hour, add 10mL of dilute hydrochloric acid to quench the reaction, ethyl acetate The ester was extracted with 30 mL, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether/ethyl acetate=150:1) to obtain 48 mg of colorless liquid, Yield 47%.

¹ H NMR (300MHz, CDCl ₃ ) δ 6.62 (d, J=9.5Hz, 2H), 3.91 (s, 3H), 1.88 (tt, J=8.4, 4.9Hz, 1H), 1.15-1.02 (m, 2H), 0.78–0.70 (m, 2H); MS (ESI) (M+H) ⁺ : m/z 213.

(2) N-(4-hydroxyphenyl)-4-cyclopropyl-2,6-difluorobenzamide (Compound 20)

A 25 mL reaction flask was placed into 37 mg (0.17 mmol) of methyl 4-cyclopropyl-2,6-difluorobenzoate, 3 mL of methanol, 3 mL of water, 49 mg (0.87 mmol) of potassium hydroxide, and after stirring at room temperature for two hours, Methanol was removed by rotary evaporation, the aqueous layer was adjusted to pH 2 with hydrochloric acid, extracted with 20 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain a white solid 4-cyclopropyl-2 , 33 mg of 6-difluorobenzoic acid was directly used in the next reaction with a yield of 96%. Using 28 mg (0.14 mmol) of 4-cyclopropyl-2,6-difluorobenzoic acid and 15 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 25 mg of white powder was obtained with a yield of 61%.

¹ H NMR(400MHz,d ₆ -DMSO)δ10.39(s,1H),9.30(s,1H),7.46(d,J=8.9Hz,2H),6.95(d,J=9.0Hz,2H) ,6.73(d,J=8.9Hz,2H),2.08-1.93(m,1H),1.08-0.97(m,2H),0.83-0.72(m,2H); MS(ESI)(M+H) ⁺ :m/z290.1.

Example 21 Preparation of N-(4-hydroxyphenyl)-4-vinylbenzamide (compound 21)

Using 296 mg (2 mmol) of 4-vinyl benzoic acid and 218 mg (2 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 216 mg of white powder was obtained with a yield of 45%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.98(s,1H),9.22(s,1H),7.91(d,J=8.3Hz,2H),7.59(d,J=8.4Hz,2H) ,7.54-7.41(m,2H),6.89-6.66(m,3H),5.96(d,J=17.6Hz,1H),5.37(d,J=11.2Hz,1H); MS(ESI)(M+ H) ⁺ :m/z240.1.

Example 22 Preparation of N-(4-hydroxyphenyl)-4-ethyl-2-nitrobenzamide (compound 22)

(1) 1-(3-nitro-4-bromophenyl)ethanol

1.5g (6.15mmol) of 3-nitro-4-bromoacetophenone was placed in a 50ml reaction flask, 30mL of methanol was added to dissolve, 351mg (9.22mmol) of sodium borohydride was added under an ice bath, stirred at room temperature for one hour, and the solvent was spin-dried , 50 mL of ethyl acetate was added, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio = 5:1) to obtain 1.42 g of yellow liquid , the yield is 94.0%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, J=2.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.44 (dd, J=8.3, 2.1 Hz, 1H), 4.96 (m, 1H), 1.51 (d, J=6.5Hz, 3H); MS (ESI) (M-OH) ⁺ : m/ _z 228.0.

(2) 5-ethyl-2-bromonitrobenzene

1.9g (7.7mmol) 1-(3-nitro-4-bromophenyl)ethanol was placed in a 50ml reaction flask, 20mL of dichloromethane was added to dissolve, 3.0g (11.5mmol) of triphenylphosphine was added, 790mg (11.5 mmol) imidazole, 3.0g (11.5mmol) iodine, stirred at room temperature for half an hour, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation to obtain a brown liquid, added 20mL of dimethyl sulfoxide DMSO, 588mg (15.5g) mmol) sodium borohydride, after stirring at room temperature for half an hour, 50 mL of ethyl acetate was added, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether) to obtain a yellow liquid 1.28 g, the yield is 72%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.27 (dd, J=8.3, 1.8 Hz, 1H), 2.69 (q, J=7.6Hz, 2H), 1.26 (t, J=7.6Hz, 3H); MS(ESI)(M+H) ⁺ : m/z 230.1

(3) 4-Ethyl-2-nitrobenzonitrile

506mg (2.2mmol) of 5-ethyl-2-bromonitrobenzene was placed in a 25ml reaction flask, 5mL of N-methylpyrrolidone NMP, 236mg (2.65mmol) of cuprous cyanide were added, and the reaction was carried out at 140°C overnight, and the temperature decreased the next day. At room temperature, 50 mL of ethyl acetate was added, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and separated by silica gel column chromatography (petroleum ether:ethyl acetate=50:1) to obtain 330 mg of yellow solid, Yield 85%.

¹ H NMR (300MHz, CDCl ₃ ) δ 8.18 (d, J=1.5Hz, 1H), 7.82 (d, J=7.9Hz, 1H), 7.63 (dd, J=8.3, 1.5Hz, 1H), 2.87 (q, J=7.6Hz, 2H), 1.33 (t, J=7.6Hz, 3H); MS(ESI)(M+H) ⁺ :m/z; MS(ESI)(M+H) ⁺ :m /z176.9.

(4) N-(4-hydroxyphenyl)-4-ethyl-2-nitrobenzamide (Compound 22)

3 mg (0.3 mmol) of 4-ethyl-2-nitrobenzonitrile was placed in a 25 mL reaction flask, 1 mL of concentrated sulfuric acid, 2 mL of water, 1 mL of glacial acetic acid AcOH was added, and the reaction was carried out at 110°C under reflux overnight, and 50 mL of ethyl acetate was added, saturated It was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 53 mg of 4-ethyl-2-nitrobenzoic acid as a white solid, which was directly used in the next reaction with a yield of 91%. Using 45 mg (0.23 mmol) of 4-ethyl-2-nitrobenzoic acid and 25 mg (0.23 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 37 mg of white powder was obtained with a yield of 56%.

¹ H NMR (500MHz, d ₆ -DMSO) δ 10.33(s, 1H), 9.27(s, 1H), 7.94(s, 1H), 7.67(d, J=7.9Hz, 1H), 7.63(d, J=7.8Hz, 1H), 7.42(d, J=8.8Hz, 2H), 6.72(d, J=8.9Hz, 2H), 2.75(q, J=7.6Hz, 2H), 1.21(t, J= 7.6Hz, 3H); MS(ESI)(M+H) ⁺ : m/z 287.1.

Example 23 Preparation of N-(4-hydroxyphenyl)-4-ethyl-2-aminobenzamide (compound 23)

25 ml reaction flask, put 28 mg (0.1 mmol) of N-(4-hydroxyphenyl)-4-ethyl-2-nitrobenzamide, add 8 mg of palladium on carbon, replace with hydrogen, stir at room temperature for two hours, and rotate evaporation The solvent was evaporated, and 22 mg of white powder was obtained by silica gel column chromatography (dichloromethane/methanol volume ratio=140:1) with a yield of 88%.

¹ H NMR(500MHz,d ₆ -DMSO)δ9.66(s,1H),9.17(s,1H),7.51(d,J=8.1Hz,1H),7.42(d,J=8.8Hz,2H) ,6.69(d,J＝8.8Hz,2H),6.54(s,1H),6.41(d,J＝8.1Hz,1H),6.28(s,2H),2.46(d,J＝7.6Hz,2H) , 1.14(t, J=7.6Hz, 3H); MS(ESI)(M+H) ⁺ : m/z 257.1.

Example 24 Preparation of N-(4-hydroxyphenyl)-4-cyclopropylbenzamide (compound 24)

Using 12 mg (0.07 mmol) of 4-cyclopropylbenzoic acid and 8 mg (0.07 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 13 mg of white powder was obtained with a yield of 69%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.88(s,1H),9.20(s,1H),7.80(d,J=8.4Hz,1H),7.49(d,J=8.8Hz,1H) ,7.17(d,J＝8.4Hz,1H),6.71(d,J＝8.8Hz,1H),1.98(tt,J＝8.7,4.8Hz,1H),1.16–0.91(m,2H),0.81– 0.57 (m, 2H); MS (ESI) (M+H) ⁺ : m/z 254.2.

Example 25 Preparation of N-(4-hydroxyphenyl)-2-(benzothiazol-2-yl)acetamide (Compound 25)

(1) Ethyl 2-benzothiazole acetate

100mL reaction flask, add 3.75g (30mmol) o-aminothiophenol, 3.39g (30mmol) o-aminothiophenol, reflux reaction under nitrogen protection for 3 hours, the reaction is complete, mix sample silica gel column chromatography (petroleum ether/ethyl acetate) Ester volume ratio=50:1) to obtain 3.16 g of yellow liquid, with a yield of 48%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 7.86 (ddd, J=7.9, 1.3, 0.6 Hz, 1H), 7.46 (ddd, J=8.1 ,7.2,1.4Hz,1H),7.37(ddd,J=7.8,7.2,1.3Hz,1H),4.24(q,J=7.2Hz,2H),4.17(s,2H),1.29(t,J= 7.1Hz,3H); MS(ESI)(MH) ⁺ :m/z200.0.

(2) N-(4-Hydroxyphenyl)-2-(benzothiazol-2-yl)acetamide (Compound 25)

A 50 mL reaction flask was placed into 442 mg (2 mmol) of ethyl 2-benzothiazole acetate, 20 mL of methanol, 20 mL of water, 840 mg (20 mmol) of lithium hydroxide monohydrate, and after stirring at room temperature for two hours, the methanol was removed by rotary evaporation. The pH value was adjusted to 5 with hydrochloric acid, and a white solid was precipitated, which was immediately filtered, washed to neutrality, and dried in vacuo to obtain 200 mg of 2-benzothiazoleacetic acid as a white powder, which was directly used in the next reaction with a yield of 52%. Using 96.5 mg (0.5 mmol) of 2-benzothiazole acetic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 78 mg of white powder was obtained with a yield of 55%.

¹ H NMR(400MHz,d ₆ -DMSO)δ10.19(s,1H),9.25(s,1H),8.07(d,J=8.0Hz,1H),7.96(d,J=8.1Hz,1H) ,7.49(t,J=7.6Hz,1H),7.46-7.33(m,3H),6.71(dd,J=8.8,1.9Hz,2H),4.22(s,2H); MS(ESI)(M+ H) ⁺ :m/z285.1.

Example 26 Preparation of N-(4-hydroxyphenyl)-benzothiazole-2-carboxamide (compound 26)

(1) Ethyl 2-benzothiazole formate

100mL reaction flask, add 1.25g (10mmol) o-aminothiophenol, 2.92g (20mmol) diethyl oxalate, react at 140 DEG C for 4 hours, after the reaction is completed, it is lowered to room temperature, and the reaction system is poured into concentrated hydrochloric acid: water: ethanol ( 5mL: 15mL: 5mL) in the ice-cold solution, the precipitated solid particles were filtered and dried in vacuo overnight, and the next day, the samples were mixed with silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain 1.5 g of white solid with a yield of 73%.

¹ H NMR (300MHz, CDCl ₃ ) δ 8.35-8.17 (m, 1H), 8.04-7.87 (m, 1H), 7.68-7.43 (m, 1H), 4.55 (q, J=7.2Hz, 2H), 1.48 (t, J=7.1 Hz, 3H); MS(ESI)(M+H) ⁺ : m/z 208.1.

(2) N-(4-Hydroxyphenyl)-benzothiazole-2-carboxamide (Compound 26)

Using 89.5 mg (0.5 mmol) of 2-benzothiazolecarboxylic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 78 mg of white powder was obtained with a yield of 58%.

¹ H NMR(500MHz,d ₆ -DMSO)δ10.87(s,1H),9.37(s,1H),8.21(dd,J=28.6,7.8Hz,1H),7.73-7.54(m,4H), 6.75(d, J=8.9Hz, 2H); MS(ESI)(M+H) ⁺ : m/z 271.1.

Example 27 Preparation of N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionamide (Compound 27)

(1) 3-(4-ethylphenyl)-22-difluoro-3-hydroxypropionic acid ethyl ester

A 25mL reaction flask was added with 490mg (7.5mmol) of activated zinc powder. After vacuuming and changing nitrogen for three times, the syringe was injected with 10mL of anhydrous tetrahydrofuran, 670mg (5mmol) of p-ethylbenzaldehyde, and 1.26g (6.2mmol) of ethyl bromodifluoroacetate. (BrF ₂ CCOOEt), refluxed for 5 hours, cooled to room temperature to quench the reaction with dilute hydrochloric acid, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate volume ratio=15:1) to obtain 1.04 g of a colorless liquid with a yield of 83%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 5.13 (dd, J=15.5, 8.0 Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 2.66 (q, J=7.6Hz, 2H), 1.28 (t, J=7.1Hz, 3H), 1.23 (t, J=7.6Hz, 3H); MS (ESI) )(M+Na) ⁺ :m/z281.2.

(2) 3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionic acid

100 mL reaction flask, put 516 mg (2 mmol) 3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionic acid ethyl ester, 10 mL methanol, 10 mL water, 560 mg (10 mmol) potassium hydroxide After stirring at room temperature for two hours, the methanol was evaporated by rotary evaporation, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, a white solid was precipitated, filtered, washed until neutral, and dried in vacuo to obtain 140 mg of white powder with a yield of 30%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32 (d, J=7.6 Hz, 2H), 7.14 (d, J=7.7 Hz, 2H), 5.04 (dd, J=17.4, 7.4 Hz, 1 H), 2.59 (q, J=7.6Hz, 2H), 1.17 (t, J=7.6Hz, 3H); MS(ESI)(M+Na) ⁺ : m/z 253.1.

(3) N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionamide (Compound 27)

Using 69 mg (0.3 mmol) 3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionic acid and 33 mg (0.3 mmol) p-aminophenol as raw materials, referring to the preparation method of compound 1, white powder 40 was obtained mg, yield 42%.

¹ H NMR (300MHz, d ₆ -DMSO) δ 10.17(s, 1H), 9.34(s, 1H), 7.42(d, J=8.8Hz, 2H), 7.34(d, J=7.9Hz, 2H) ,7.20(d,J＝7.9Hz,2H),6.71(d,J＝8.8Hz,2H),6.40(d,J＝5.5Hz,1H),5.23-5.02(m,1H),2.58(q, J=7.5Hz, 2H), 1.17 (t, J=7.5Hz, 3H); MS(ESI)(M+H) ⁺ : m/z322.2.

Example 28 Preparation of N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoropropionamide (Compound 28)

(1) 3-(4-ethylphenyl)-2,2-difluoro-3-chloropropionic acid ethyl ester

A 50 mL reaction flask was placed with 774 mg (3 mmol) of ethyl 3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionate, 260 mg (3.3 mmol) of pyridine, and 4 mL of thionyl chloride, A drop of DMF was added dropwise, and after refluxing for 5 hours, the solvent was spin-dried, extracted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, spin-dried and mixed with silica gel column chromatography ( Petroleum ether/ethyl acetate=150:1) to obtain 580 mg of colorless liquid, yield 70%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J=8.0 Hz, 2H), 7.22 (dd, J=8.0 Hz, 2H), 5.29 (dd, J=15.0, 10.3 Hz, 0H), 4.31 (q,J=7.1Hz,2H),2.66(q,J=7.6Hz,2H),1.30(q,J=7.6Hz,3H),1.24(t,J=7.2Hz,3H).MS(ESI )(M+Na) ⁺ :m/z299.1.

(2) Ethyl 3-(4-ethylphenyl)-2,2-difluoropropionate

A 50 ml reaction flask was placed into 451 mg (1.6 mmol) of 3-(4-ethylphenyl)-2,2-difluoro-3-chloropropionic acid ethyl ester, 40 mg of palladium carbon was added, and the reaction was stirred at room temperature overnight after replacing hydrogen. , filtered, spin-dried the solvent, and separated by silica gel column chromatography (petroleum ether/ethyl acetate=150:1) to obtain 360 mg of a colorless liquid with a yield of 91%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.16 (s, 4H), 4.24 (q, J=6.9 Hz, 2H), 3.34 (t, J=13.8 Hz, 2H), 2.62 (q, J=7.5 Hz) ,2H),1.22(m,6H).MS(ESI)(M+Na) ⁺ :m/z265.2.

(3) N-(4-Hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoropropionamide (Compound 28)

100 mL reaction flask, put 260 mg (1.07 mmol) 3-(4-ethylphenyl)-2,2-difluoropropionic acid ethyl ester, methanol 10 mL, water 10 mL, 300 mg (5.4 mmol) potassium hydroxide, room temperature After stirring for two hours, spin off methanol, adjust the pH of the aqueous layer to 5 with hydrochloric acid, and precipitate a white solid, filter, wash to neutrality, and vacuum dry to obtain a white powder 3-(4-ethylphenyl)-2,2- Difluoropropionic acid 128 mg, yield 55.7%. Using 64.2 mg (0.3 mmol) of 3-(4-ethylphenyl)-2,2-difluoropropionic acid as the raw material, 37 mg of white powder was obtained with a yield of 40%.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 7.34 (d, J=8.9 Hz, 2H), 7.16 (d, J= 2.3Hz, 4H), 6.70 (d, J=8.8Hz, 2H), 3.43 (t, J=17.5Hz, 2H), 2.56 (q, J=7.6Hz, 2H), 1.14 (t, J=7.6Hz) ,3H).MS(ESI)(M+H) ⁺ :m/z306.0.

Example 29 Preparation of N-(4-hydroxyphenyl)-2-(4-ethylphenyl)-2-hydroxyacetamide (compound 29)

296mg (2mmol) 4-ethylacetophenone was placed in a 50ml reaction flask, 444mg (4mmol) selenium dioxide, 124mg (0.2mmol) ytterbium trifluoromethanesulfonate Yb(OTf) ₃ were added, and 6mL dioxane was added Ring, 2mL of water, 90 ℃ oil bath reaction overnight, the next day to room temperature, diatomaceous earth filtration, the filtrate is adjusted to pH 11 with dilute sodium hydroxide solution, washed with dichloromethane three times, the water layer is adjusted to pH 2 with dilute hydrochloric acid , extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 253 mg of 2-hydroxy-2-(4-ethylphenyl)acetic acid as a brown oil, which was all used for In the next step of condensation reaction, 153 mg (1.4 mmol) of p-aminophenol was reacted, and 109 mg of white powder was obtained by referring to the preparation method of compound 1, and the two-step yield was 20%.

¹ H NMR(400MHz,d ₆ -DMSO)δ9.64(s,1H),9.19(s,1H),7.45(d,J=8.9Hz,2H),7.39(d,J=8.0Hz,2H) ,7.17(d,J＝8.0Hz,2H),6.67(d,J＝8.9Hz,2H),6.27(d,J＝4.7Hz,1H),5.00(d,J＝4.7Hz,1H),2.57 (q, J=7.6Hz, 2H), 1.15 (t, J=7.6Hz, 3H); MS(ESI)(M+H) ⁺ : m/z 272.1.

Example 30 Preparation of N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-3-oxopropionamide (compound 30)

(1) 3-(4-ethylphenyl)-3-oxopropionic acid ethyl ester

25mL round bottom flask, add 592mg (4mmol) p-ethylacetophenone, after vacuuming and changing nitrogen three times, add 320mg (8mmol) 60% sodium hydrogen, inject 6mL diethyl carbonate with syringe, react in oil bath at 120°C for 5 hours, The temperature was lowered to room temperature, extracted with 50 mL of ethyl acetate, washed with dilute hydrochloric acid solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) 576 mg of yellow liquid were obtained, the yield was 66%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.00 (s , 2H), 2.71(q, J=7.6Hz, 2H), 1.32-1.20(m, 6H); MS(ESI)(M+H) ⁺ : m/z221.1.

(2) N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-3-oxopropionamide (Compound 30)

A 50 mL reaction flask was placed in 295 mg (1.3 mmol) of ethyl 3-(4-ethylphenyl)-3-oxopropionate, 10 mL of methanol, 10 mL of water, 290 mg (5.2 mmol) of potassium hydroxide, and stirred at room temperature for two hours. After one hour, the methanol was evaporated by rotary evaporation, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotated to dryness to obtain a white powder 3-(4-ethylphenyl)-3-oxo 200 mg of propionic acid was directly used in the next condensation reaction, reacted with 113 mg (1.04 mmol) of p-aminophenol, and 100 mg of white powder was obtained by referring to the preparation method of compound 1, and the two-step yield was 26%.

¹ H NMR(300MHz,d ₆ -DMSO)δ9.90(s,1H),9.19(s,1H),7.51-7.45(m,5H),7.25(d,J=8.1Hz,2H),6.75- 6.95(m, 3H), 3.31(s, 2H), 2.61(q, J=7.8Hz, 2H), 1.17(t, J=7.8Hz, 3H); MS(ESI)(M+H) ⁺ :m /z284.1.

Example 31 Preparation of N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-3-hydroxypropionamide (compound 31)

(1) Ethyl 3-(4-ethylphenyl)-3-hydroxypropionate

250mg (1.2mmol) of ethyl 3-(4-ethylphenyl)-3-oxopropionate was placed in a 50ml reaction flask, 10ml of methanol was added to dissolve, 95mg (2.5mmol) of sodium borohydride was added under ice bath, room temperature Stir for one hour, remove the solvent by rotary evaporation, add 50 mL of ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 237 mg of a colorless liquid, which was shown as a mixture by ¹ HNMR, which was directly used In the next step hydrolysis reaction.

(2) N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-3-hydroxypropionamide (Compound 31)

A 50 mL reaction flask was placed into a mixture of 220 mg (0.99 mmol) of ethyl 3-(4-ethylphenyl)-3-hydroxypropionate, 10 mL of methanol, 10 mL of water, 250 mg (4.5 mmol) of potassium hydroxide, and stirred at room temperature for two hours. After one hour, the methanol was evaporated by rotary evaporation, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain a pale yellow liquid 3-(4-ethylphenyl)- 194 mg of 3-hydroxypropionic acid was directly used in the next step to react with 109 mg (1 mmol) of p-aminophenol, and 100 mg of white powder was obtained by referring to the preparation method of compound 1, and the two-step yield was 35%.

¹ H NMR(400MHz,d ₆ -DMSO)δ9.61(s,1H),9.14(s,1H),7.34(d,J=8.9Hz,2H),7.26(d,J=8.0Hz,2H) ,7.14(d,J＝8.0Hz,2H),6.65(d,J＝8.9Hz,2H),5.36(d,J＝4.4Hz,1H),4.98(dt,J＝8.8,4.5Hz,1H) , 2.61–2.44 (m, 4H), 1.14 (t, J=7.6Hz, 3H); MS (ESI) (M+H) ⁺ : m/z 308.1.

Example 322 Preparation of 2-(4-ethylphenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 32)

(1) Ethyl 2-(4-ethylphenyl)-2,2-difluoroacetate

25mL reaction flask, add 360mg (5.6mmol) copper powder, after vacuuming and changing nitrogen three times, inject 10mL dimethyl sulfoxide, 464mg (2mmol) p-ethyl iodobenzene, 406mg (2mmol) ethyl bromodifluoroacetate, 50 mL The reaction was carried out at ℃ overnight, and the next day was lowered to room temperature, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-ethylphenyl)-2,2- Ethyl difluoroacetate mixture yellow liquid 400 mg.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 2.69 (q , J=7.5Hz, 2H), 1.31 (t, J=7.1Hz, 3H), 1.25 (t, J=7.6Hz, 3H); MS(ESI)(M+Na) ⁺ : m/z251.2.

(2) 2-(4-ethylphenyl)-2,2-difluoroacetic acid

300 mg of ethyl 2-(4-ethylphenyl)-2,2-difluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, and 490 mg (8.7 mmol) of potassium hydroxide. After stirring at room temperature for two hours, the methanol was removed by rotary evaporation. , the aqueous layer was adjusted to pH 5 with hydrochloric acid, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-ethylphenyl)-2,2-difluoroacetic acid mixture as a brown liquid 270mg.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 2.69 (q, J=7.6 Hz, 2H), 1.25 (t ,J=7.6Hz,3H).

(3) 2-(4-Ethylphenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 32)

Using 167 mg (0.83 mmol) 2-(4-ethylphenyl)-2,2-difluoroacetic acid and 90 mg (0.83 mmol) p-aminophenol as raw materials, referring to the preparation method of compound 1, 80 mg of white powder was obtained in a yield of 33 %.

¹ H NMR(300MHz,d ₆ -DMSO)δ10.50(s,1H),9.39(s,1H),7.57(d,J=7.9Hz,2H),7.43(d,J=8.6Hz,2H) ,7.38(d,J=7.8Hz,2H),6.72(d,J=8.5Hz,2H),2.65(q,J=7.5Hz,2H),1.18(t,J=7.5Hz,3H); MS (ESI)(M+H) ⁺ :m/z292.2.

Example 33 Preparation of N-(4-hydroxyphenyl)-4-difluoromethylbenzamide (compound 33)

(1) p-difluoromethylbenzonitrile

50mL round-bottom flask, add 262mg (2mmol) p-cyanobenzaldehyde, after vacuuming and changing nitrogen three times, inject 25mL dichloromethane into the syringe, after stirring in ice bath for half an hour, add 644mg (4mmol) diethylamino trifluoro into the syringe dropwise Sulfur (DAST), react at room temperature for 28 hours, extract with 50 mL of ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin dry and mix with silica gel column chromatography (petroleum ether/ethyl acetate=20:1) 174 mg of colorless liquid were obtained, the yield was 56.9%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 6.69 (t, J=55.8 Hz, 1 H); MS (ESI) )(M+H) ⁺ :m/z154.2.

(2) N-(4-hydroxyphenyl)-4-difluoromethylbenzamide (Compound 33)

137 mg (0.90 mmol) of p-difluoromethylbenzonitrile was placed in a 25 mL reaction flask, 2 mL of concentrated sulfuric acid, 4 mL of water, and 2 mL of glacial acetic acid were added, and the reaction was carried out at 110° C. for 4 hours, followed by the addition of 50 mL of ethyl acetate and saturated sodium chloride solution. Washed, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 75 mg of p-difluoromethylbenzoic acid pale yellow solid, which was directly used in the next step reaction, reacted with 47 mg (0.44 mmol) of p-aminophenol, with reference to the preparation method of compound 1 40 mg of white powder were obtained, and the two-step yield was 16%.

¹ H NMR (500MHz, d ₆ -DMSO) δ 10.13 (s, 1H), 9.27 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H) ,7.52(d,J=8.7Hz,2H),7.11(t,J=55.7Hz,1H),6.73(d,J=8.8Hz,2H); MS(ESI)(M+H) ⁺ :m/ z263.9.

Example 34 Preparation of N-(4-hydroxyphenyl)-4-difluoromethyl-2-fluorobenzamide (compound 34)

(1) Methyl 4-difluoromethyl-2-fluorobenzoate

25mL round bottom flask, add 218mg (1.2mmol) methyl 4-formyl-2-fluorobenzoate, after vacuuming and changing nitrogen three times, inject 10mL dichloromethane into the syringe, after stirring in ice bath for half an hour, dropwise add 386mg ( 2.4 mmol) diethylaminosulfur trifluoride (DAST), reacted at room temperature for 28 hours, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to remove the solvent by rotary evaporation, and subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate=70:1) to obtain 131 mg of colorless liquid, yield 54%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08-7.99 (m, 1H), 7.39-7.28 (m, 2H), 6.65 (t, J=55.9 Hz, 1H), 3.95 (s, 3H); MS ( ESI)(M+H) ⁺ :m/z205.1.

(2) N-(4-hydroxyphenyl)-4-difluoromethyl-2-fluorobenzamide (Compound 34)

100mg (0.49mmol) methyl 4-difluoromethyl-2-fluorobenzoate was placed in a 50 mL reaction flask, 10 mL methanol, 10 mL water, 130 mg (2.3 mmol) potassium hydroxide were added, and after stirring at room temperature for two hours, the solution was rotated. Methanol was evaporated and the aqueous layer was adjusted to pH 5 with hydrochloric acid, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried to obtain 75 mg of 4-difluoromethyl-2-fluorobenzoic acid as a white powder, which was directly used in the next step. In the first step, it was reacted with 88 mg (0.81 mmol) of p-aminophenol, and 83 mg of white powder was obtained by referring to the preparation method of compound 1, and the two-step yield was 60%.

¹ H NMR (400MHz, d ₆ -DMSO) δ 10.25 (s, 1H), 9.29 (s, 1H), 7.76 (t, J=7.4Hz, 1H), 7.54 (dd, J=20.1, 9.2Hz, 2H), 7.47(d, J=8.0Hz, 2H), 7.10(t, J=56Hz, 1H), 673(d, J=8.0Hz, 2H); MS(ESI)(M+H) ⁺ :m /z282.2.

Example 35 Preparation of N-(4-hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoro-3-oxopropionamide (Compound 35)

(1) 3-(4-ethylphenyl)-2,2-difluoro-3-oxopropionic acid ethyl ester

100 mL reaction flask, put 516 mg (2 mmol) of 3-(4-ethylphenyl)-2,2-difluoro-3-hydroxypropionic acid ethyl ester, 10 mL of dichloromethane, and add 2.2 g (5.2 mmol) of Dess -Martin oxidant DMP, stirred at room temperature for two days, washed with saturated sodium bicarbonate solution, washed with saturated sodium thiosulfate solution, dried with anhydrous sodium sulfate, spin-dried and mixed with silica gel column chromatography (petroleum ether/ethyl acetate = 50:1 ) to obtain 105 mg of colorless liquid, yield 7.4%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 2.73 (q , J=7.6Hz, 2H), 1.42-1.18 (m, 6H); MS (ESI) (M+H) ⁺ : m/z 257.1.

(2) N-(4-Hydroxyphenyl)-3-(4-ethylphenyl)-2,2-difluoro-3-oxopropionamide (Compound 35)

A 50 mL reaction flask was placed with 82 mg (0.32 mmol) of 3-(4-ethylphenyl)-2,2-difluoro-3-oxopropionic acid ethyl ester, 10 mL of methanol, 10 mL of water, 90 mg (1.6 mmol) Potassium hydroxide, after stirring at room temperature for two hours, the methanol was evaporated, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried to obtain 3-(4-ethylphenyl) as a colorless liquid )-2,2-difluoro-3-oxopropionic acid 64mg, directly used in the next step reaction, reacted with 31mg (0.28mmol) p-aminophenol, referring to the preparation method of compound 1 to obtain 27 mg of white powder, two-step yield 27%.

¹ H NMR(300MHz,d ₆ -DMSO)δ10.90(s,1H),9.44(s,1H),7.96(d,J=8.4Hz,2H),7.46(d,J=8.5Hz,2H) ,7.41(d,J=8.9Hz,2H),6.73(d,J=8.9Hz,2H),2.69(q,J=7.5Hz,2H),1.18(t,J=7.6Hz,3H); (ESI)(M+H) ⁺ :m/z.MS(ESI)(M+H) ⁺ :m/z320.1.

Example 36 Preparation of 2-(4-chlorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (compound 36)

(1) Ethyl 2-(4-chlorophenyl)-22-difluoroacetate

50mL reaction flask, add 360mg (5.6mmol) copper powder, after vacuuming and changing nitrogen three times, inject 10mL dimethyl sulfoxide, 477mg (2mmol) p-chloroiodobenzene, 609mg (3mmol) ethyl bromodifluoroacetate, 80 ℃ The reaction was overnight, and the next day, it was cooled to room temperature, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-chlorophenyl)-2,2-difluoro. Ethyl acetate mixture yellow liquid 500 mg. used directly in the next reaction.

(2) 2-(4-Chlorophenyl)-2,2-difluoroacetic acid

500 mg of ethyl 2-(4-chlorophenyl)-2,2-difluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, 560 mg (10 mmol) of potassium hydroxide, and after stirring at room temperature for two hours, the methanol was removed by rotary evaporation, and the water The pH of the layer was adjusted to 5 with hydrochloric acid, and a white solid was precipitated, which was filtered and dried under vacuum to obtain 270 mg of 2-(4-chlorophenyl)-2,2-difluoroacetic acid as a white powder. used directly in the next reaction.

(3) 2-(4-Chlorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 36)

Using 103 mg (0.5 mmol) of 2-(4-chlorophenyl)-2,2-difluoroacetic acid and 55 mg (0.5 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 41 mg of white powder was obtained, and the yield was 28%. .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.66 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.42–7.28 (m, 2H), 6.82–6.71 (m ,2H); MS(ESI)(M+H) ⁺ :m/z298.1.

Example 37 Preparation of 2-(4-ethylphenyl)-N-(4-hydroxyphenyl)-2-fluoroacetamide (compound 37)

(1) Ethyl 2-(4-ethylphenyl)-2-fluoroacetate

25mL two-necked flask, add 450mg (3mmol) p-ethylphenylboronic acid, 17mg (0.075mmol) palladium acetate, 78mg (0.3mmol) triphenylphosphorus, 1.2g (4.5mmol) potassium phosphate trihydrate, after vacuuming and changing nitrogen three times , inject 10 mL of toluene, 278 mg (1.5 mmol) of ethyl bromofluoroacetate into a syringe, react at 100° C. overnight, drop to room temperature the next day, evaporate the solvent by rotary evaporation, and perform silica gel column chromatography (petroleum ether/ethyl acetate=10:1) 450 mg of ethyl 2-(4-chlorophenyl)-2,2-difluoroacetate mixture was obtained as a yellow liquid.

(2) 2-(4-Ethylphenyl)-2-fluoroacetic acid

300 mg of ethyl 2-(4-ethylphenyl)-2-fluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, and 280 mg (5 mmol) of potassium hydroxide. After stirring at room temperature for two hours, the methanol was removed by rotary evaporation, and the aqueous layer was washed with hydrochloric acid. The pH value was adjusted to 5, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 190 mg of 2-(4-ethylphenyl)-2-fluoroacetic acid as a colorless liquid. used directly in the next reaction.

(3) 2-(4-Ethylphenyl)-N-(4-hydroxyphenyl)-2-fluoroacetamide (Compound 37)

Using 134 mg (0.74 mmol) of 2-(4-ethylphenyl)-2-fluoroacetic acid and 81 mg (0.74 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 130 mg of white powder was obtained with a yield of 64%.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.43 (d, J=6.9 Hz, 2H), 7.36 (d, J=8.7 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 6.74 ( d, J=8.7Hz, 2H), 5.82 (d, J=48.0Hz, 1H), 2.65 (q, J=7.5Hz, 2H), 1.21 (t, J=7.6Hz, 3H).MS(ESI) (M+H) ⁺ :m/z274.2.

Example 38 Preparation of 2-(4-isopropylphenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 38)

(1) Ethyl 2-(4-isopropylphenyl)-2,2-difluoroacetate

25mL reaction flask, add 360mg (5.6mmol) copper powder, after vacuuming and changing nitrogen three times, inject 10mL dimethyl sulfoxide, 500mg (2mmol) p-ethyl iodobenzene, 609mg (3mmol) ethyl bromodifluoroacetate, 80 mL The reaction was carried out at ℃ overnight, and the next day was lowered to room temperature, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-ethylphenyl)-2,2- 360 mg of yellow liquid of ethyl difluoroacetate mixture. used directly in the next reaction.

(2) 2-(4-Isopropylphenyl)-2,2-difluoroacetic acid

300 mg of ethyl 2-(4-isopropylphenyl)-2,2-difluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, 490 mg (8.7 mmol) of potassium hydroxide, stirred at 60°C for two hours, and evaporated by rotary evaporation. Methanol was removed, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 2-(4-isopropylphenyl)-2,2-difluoroacetic acid The mixture is a colorless liquid 240 mg. used directly in the next reaction.

(3) 2-(4-Isopropylphenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 38)

Using 72 mg (0.34 mmol) 2-(4-isopropylphenyl)-2,2-difluoroacetic acid and 37 mg (0.34 mmol) p-aminophenol as raw materials, referring to the preparation method of compound 1, 27 mg of white powder was obtained in a yield of 27 mg. 26%.

¹ H NMR (500 MHz, CD ₃ OD) δ 7.61 (d, J=8.4 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 6.78 ( d, J=9.0Hz, 2H), 2.96 (hept, J=6.9Hz, 1H), 1.27 (d, J=6.9Hz, 6H); MS (ESI) (M+H) ⁺ : m/z306.2 .

Example 39 Preparation of 2-(4-methyl-2-fluorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 39)

(1) Ethyl 2-(4-methyl-2-fluorophenyl)-2,2-difluoroacetate

25mL reaction flask, add 360mg (5.6mmol) copper powder, after vacuuming and changing nitrogen three times, inject 10mL dimethyl sulfoxide, 472mg (2mmol) 4-methyl-2-fluoroiodobenzene, 609mg (3mmol) bromodifluoro into the syringe Ethyl acetate, reacted at 80°C overnight, cooled to room temperature the next day, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-methyl 2-fluoro). Phenyl)-2,2-difluoroethyl acetate mixture Yellow liquid 310 mg. used directly in the next reaction.

(2) 2-(4-Methyl-2-fluorophenyl)-2,2-difluoroacetic acid

310 mg of ethyl 2-(4-methyl-2-fluorophenyl)-2,2-difluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, 450 mg (8 mmol) of potassium hydroxide, stirred at 60°C for two hours, and rotated The methanol was evaporated and the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 2-(4-methyl-2-fluorophenyl)-2, 2-Difluoroacetic acid mixture colorless liquid 19 mg. used directly in the next reaction.

(3) 2-(4-Methyl-2-fluorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 39)

Using 19mg (0.1mmol) 2-(4-methyl-2-fluorophenyl)-2,2-difluoroacetic acid and 11mg (0.1mmol) p-aminophenol as raw materials and referring to the preparation method of compound 1 to obtain 5 mg of white solid , the yield is 17%.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 7.55 (t, J=7.9 Hz, 1H), 7.39 (d, J=9.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.06 (d, J=11.9Hz, 1H), 6.77 (d, J=9.0Hz, 2H), 2.39 (s, 3H); MS (ESI) (M+H) ⁺ : m/z 296.2.

Example 40 Preparation of 2-(4-Chloro-2-fluorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 40)

(1) ethyl 2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetate

25mL reaction flask, add 360mg (5.6mmol) copper powder, after vacuuming and changing nitrogen three times, inject 10mL dimethyl sulfoxide, 512mg (2mmol) 4-chloro-2-fluoroiodobenzene, 609mg (3mmol) bromodifluoroacetic acid into the syringe Ethyl ester was reacted at 80°C overnight, then cooled to room temperature the next day, extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent by rotary evaporation to obtain 2-(4-chloro-2-fluorobenzene). ethyl)-2,2-difluoroacetate mixture as a yellow liquid, 350 mg. used directly in the next reaction.

(2) 2-(4-Chloro-2-fluorophenyl)-2,2-difluoroacetic acid

350 mg of ethyl 2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetate mixture was added with 10 mL of methanol, 10 mL of water, 388 mg (7 mmol) of potassium hydroxide, and after stirring at 60°C for two hours, rotary evaporation The methanol was evaporated, the pH value of the aqueous layer was adjusted to 5 with hydrochloric acid, extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain 2-(4-chloro-2-fluorophenyl)-2,2- Difluoroacetic acid mixture colorless liquid 150mg. used directly in the next reaction.

(3) 2-(4-Chloro-2-fluorophenyl)-N-(4-hydroxyphenyl)-2,2-difluoroacetamide (Compound 40)

Using 150 mg (0.67 mmol) of 2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetic acid and 73 mg (0.67 mmol) of p-aminophenol as raw materials and referring to the preparation method of compound 1, 105 mg of white solid were obtained, Yield 50%.

¹ H NMR (500 MHz, MeOD) δ 7.72 (t, J=8.0 Hz, 1H), 7.53–7.14 (m, 4H), 6.79 (d, J=8.9 Hz, 2H); MS (ESI) (M+ H) ⁺ :m/z315.2.

Example 41 Preparation of N-(4-hydroxyphenyl)-4-ethyl-2-hydroxybenzamide (compound 41)

(1) 4-ethyl-2-hydroxybenzoic acid

According to the literature method (Zhang Y H, Yu J Q. Journal of the American Chemical Society, 2009, 131(41): 14654-14655.): add p-ethylbenzoic acid (75mg, 0.5mmol) to a 50mL two-necked flask, Palladium acetate (11mg, 0.05mmol), p-phthaloquinone BQ (54mg, 0.5mmol), potassium acetate (98mg, 1mmol), N,N-dimethylacetamide (DMA) (1.5mL), vacuum for oxygen exchange Three times, stirred at 115°C for 15 hours and cooled to room temperature. The reaction solution was diluted with ethyl acetate and water, filtered with suction, the filter cake was washed with hydrochloric acid (1.0N, 5 mL) and saturated brine (5 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (PE:EtOAc=5:3) to give 4-ethyl-2-hydroxybenzoic acid (38 mg, 46%, white solid).

(2) N-(4-hydroxyphenyl)-4-ethyl-2-hydroxybenzamide (Compound 41)

Using 30 mg (0.18 mmol) of 4-ethyl-2-hydroxybenzoic acid and 22 mg (0.18 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 23 mg of yellow solid was obtained with a yield of 50%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 12.18(s, 1H), 10.12(s, 1H), 9.32(s, 1H), 7.90(d, J=8.5Hz, 1H), 7.42(d, J=8.8Hz, 2H), 6.86–6.67 (m, 4H), 2.58 (q, J=7.6Hz, 2H), 1.16 (t, J=7.6Hz, 3H); MS (ESI) (M+H) ⁺ :m/z258.2.

Example 42 Preparation of N-(4-hydroxyphenyl)-2,4-dihydroxybenzamide (compound 42)

Using 500 mg (3.25 mmol) of 2,4-dihydroxybenzoic acid and 390 mg (3.25 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 315 mg of yellow solid was obtained with a yield of 40%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.14(s, 1H), 9.93(s, 1H), 9.32(s, 1H), 7.84(d, J=9.1Hz, 1H), 7.37(d, J=8.3Hz, 2H), 6.72(d, J=8.0Hz, 2H), 6.33(d, J=9.7Hz, 1H), 6.27(s, 1H); MS(ESI)(M+H) ⁺ : m/z246.2.

Example 43 Preparation of N-(4-hydroxyphenyl)-4-isopropyl-2-hydroxybenzamide (compound 43)

(1) 4-isopropyl-2-hydroxybenzoic acid

Using p-isopropylbenzoic acid (82 mg, 0.5 mmol) as raw material, the target product (23 mg, 26%, yellow solid) was obtained according to the synthesis method of compound 4-ethyl-2-hydroxybenzoic acid.

(2) N-(4-hydroxyphenyl)-4-isopropyl-2-hydroxybenzamide (Compound 43)

Using 23 mg (0.13 mmol) of 4-ethyl-2-hydroxybenzoic acid and 15 mg (0.14 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 13 mg of brown solid was obtained with a yield of 37%.

¹ H NMR (300MHz, Chloroform-d) δ 12.04(s, 1H), 7.81(s, 1H), 7.40(m, 3H), 6.89(d, J=1.6Hz, 1H), 6.85(d, J =8.8Hz,2H),6.78(dd,J=8.2,1.7Hz,1H),2.89(p,J=6.8Hz,1H),1.25(d,J=6.9Hz,6H); MS(ESI)( M+H) ⁺ :m/z272.3.

Example 44 Preparation of N-(4-hydroxyphenyl)-4-cyclopropyl-2-hydroxybenzamide (compound 44)

(1) 4 _- Cyclopropyl _- 2 _- hydroxybenzoic acid

Using p-cyclopropylbenzoic acid (81 mg, 0.5 mmol) as raw material, the target product (18 mg, 20%, yellow solid) was obtained according to the synthesis method of compound 4-ethyl-2-hydroxybenzoic acid.

(2) N-(4-hydroxyphenyl)-4-cyclopropyl-2-hydroxybenzamide (Compound 44)

Using 18 mg (0.10 mmol) of 4-cyclopropyl-2-hydroxybenzoic acid and 12 mg (0.11 mmol) of p-aminophenol as raw materials, referring to the preparation method of compound 1, 5 mg of a brown solid was obtained with a yield of 67%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.10(s, 1H), 9.34(s, 1H), 7.86(d, J=8.2Hz, 1H), 7.41(d, J=8.6Hz, 2H) ,6.73(d,J＝8.7Hz,2H),6.63(d,J＝8.6Hz,1H),6.60(s,1H),1.89(m,1H),0.99(m,2H),0.72(m, 2H); MS (ESI) (M+H) ⁺ : m/z 270.3.

Example 45 Inhibitory effect on ribonucleotide reductase activity

(I) Experimental materials and instruments

Experimental material: Hydroxyurea (Hydroxyurea, HU, Sigma).

Apparatus: high performance liquid analyzer (Shimadzu LC-10ATVP, Japan), liquid scintillation counter (Backman LS6500).

(II) Inhibitory effect on ribonucleotide reductase activity

(1) Recombinant ribonucleotide reductase sample preparation and activity assay

1) Prepare reaction samples: E. coli expresses and purifies recombinant human ribonucleotide reductase large subunit M1 (see SEQ ID NO.1 for the sequence) and small subunit M2 protein (see SEQ ID NO.2 for the sequence) in vitro (the protein The dosage is that the ribonucleotide reductase activity reaches 65-95%), add double distilled water to adjust the volume to 80 μL, add 10 μL of test compounds of different concentrations; mix well, incubate at room temperature for 30-60 min;

2) Add reaction buffer to each tube to a volume of 100 μL (final concentration: 50 mM HEPES, pH 7.2, 6 mM DTT, 4 mM magnesium acetate, 2 mM ATP, 0.05 mM CDP, 100 mM KCl, 0.125 μM [3H]CDP); incubate at 37°C for 20 -30min; inactivated by boiling water for 10min;

3) Add 5 μL of 20 mg/mL PDE (phosphodiesterase), incubate at 37° C. for 30 min-60 min; inactivate with boiling water for 10 min; centrifuge at 16000 rpm for 15 min, and take the supernatant.

(2) HPLC determination

1) Chromatographic conditions: mobile phase: ammonium dihydrogen phosphate, pH 3-5; flow rate: 1 mL/min. Chromatographic column: C18 column.

2) Sample determination: 20 μL of the above supernatant was injected into the sample; 50 μL/tube of HPLC separation samples was collected, and 4 mL of scintillation fluid was added to each tube. The samples were placed in a scintillation counter to determine the CPM (instrument detected count rate).

3) Calculate ribonucleotide reductase activity (%) = CPM of the product dCDP of the experimental group/CPM of the blank control group×100%.

(3) Determination of the half effective inhibitory concentration (IC ₅₀ ) of ribonucleotide reductase activity

Compounds were diluted with DMSO at equal times, and the enzyme activity test was carried out as described in the above method. The inhibition rate of each concentration of the compound was calculated, and the IC ₅₀ value of the compound was calculated by GraphPad Prism5. Table 1 shows the inhibitory IC ₅₀ values of some compounds against ribonucleotide reductase.

IC ₅₀ values of some compounds in Table 1 for ribonucleotide reductase activity

Among them, HU (Hydroxyurea) is a positive control drug, and its IC ₅₀ for ribonucleotide reductase is 80 μM.

It can be seen from Table 1 that the compounds of the present invention have a strong inhibitory effect on ribonucleotide reductase. It shows that the compound of the present invention can be used as an anti-tumor lead compound or further developed into an anti-tumor drug.

Example 46 Killing activity against human pharyngeal cancer cells

(1) Experimental materials:

Cell line: Human oral epidermoid carcinoma cells (KB cells) (ATCC, USA, passaged and preserved in our laboratory), cultured in RPMI-1640 medium (containing 10% fetal bovine serum)

Main reagents: RPMI-1640 medium (Gibco, USA), fetal bovine serum (Gibco, USA), hydroxyurea (Hydroxyurea, HU, Sigma), CCK-8 kit.

Main instruments: carbon dioxide incubator (Thermo Forma, USA), automatic microplate reader (Bio-TEK, Elx800).

(2) Experimental method:

1) Cell culture

KB cells were cultured in RPMI-1640 medium (containing 10% fetal bovine serum, pH 7.2), the medium was supplemented with 2 mmol/L glutamine, and placed in a cell culture incubator at 37° C., 5% CO ₂ .

2) The inhibitory effect of each compound on tumor cell growth was determined by CCK-8 kit

The KB cells were digested with trypsin and prepared into a single cell suspension, and the cell concentration was adjusted to 6×10 ⁴ cells/mL after counting. Add 50 μL of the above cell suspension to each well of a 96-well culture plate, and place it in a CO ₂ incubator at 37 °C for 24 hours. After the cells adhere to the wall and grow well, add 50 μL of drugs prepared with different concentrations of culture medium, and the control group is added with the corresponding volume of Medium, 3 parallel wells were set in each group. The culture was continued for 72 h, and 2 h before the end of the cultivation, 10 μL of CCK-8 reagent was added to each well, and the culture was continued in a CO ₂ incubator. After 2 h, the OD value of each well at 490 nm was detected by an automatic microplate reader. Calculate the cell viability: cell inhibition rate (%)=[1-(mean OD of experimental well/mean OD of control well)]×100%. The fitting function was used to obtain the IC50 of the drug concentration that inhibited cell growth by ₅₀ %. The experiment was repeated three times.

Example 47 Killing activity against human colon cancer cells

Experimental materials: human colon cancer cells (RKO cells) (ATCC, USA, passaged and preserved in our laboratory), cultured in RPMI-1640 medium (containing 10% fetal bovine serum). Others are the same as in Example 46.

Experimental method: see Example 46.

Example 48 Killing activity against human non-small cell lung cancer cells

Experimental materials: human non-small cell lung cancer cells (A549 cells) (ATCC, USA, passaged and preserved in our laboratory), cultured in RPMI-1640 medium (containing 10% fetal bovine serum). Others are the same as in Example 46.

Experimental method: see Example 46.

Example 49 Killing activity against human glioma cells

Experimental materials: human glioma cells (U251 cells) (Shanghai Cell Bank, Chinese Academy of Sciences, passaged and preserved in our laboratory), cultured in DMEM medium (containing 10% fetal bovine serum), and others are the same as in Example 46.

Experimental method: see Example 46.

Example 50 Killing activity against human chronic myeloid leukemia cells

Experimental materials: human chronic myelogenous leukemia cells (K-562 cells) (ATCC, USA, passaged and preserved in our laboratory), cultured in RPMI-1640 medium (containing 10% fetal bovine serum), and others are the same as in Example 46.

Experimental method: see Example 46.

Table 2 _IC50 values (μM) of some compounds on tumor cell growth

*: Low solubility, unable to increase concentration

Among them, HU is a positive drug, which is a ribonucleotide reductase inhibitor with broad-spectrum anti-tumor activity.

It can be seen from Table 2 that the compounds of the present invention can inhibit the growth of various tumor cells, and are significantly better than the positive control, indicating that the compounds of the present invention have broad-spectrum anti-tumor activity.

Industrial Applicability

The preparation method of the substituted amide phenol compound of the present invention has mild reaction conditions, abundant and readily available raw materials, and simple operation and post-processing.

The substituted amide compounds of the present invention show positive results in both the ribonucleotide reductase activity inhibition test and the tumor cell growth inhibition test, which proves its pharmacological action mechanism. Therefore, the compounds of the present invention, as inhibitors of ribonucleotide reductase, have the ability to inhibit the growth of tumor cells, and can be developed into preventive and/or therapeutic drugs for tumors.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (7)

1. a compound shown in general formula I and a pharmaceutically acceptable salt thereof: Wherein: the compound is: 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt refers to a salt formed by an anion and a positively charged group on the compound, and the anion is chlorine Ion, Bromide, Iodide, Sulfate, Nitrate, Phosphate, Citrate, Methanesulfonate, Trifluoroacetate, Acetate, Malate, Tosylate, Tartrate, Fumarate, Glutamate , glucuronate, lactate, glutarate or maleate; Or it refers to a salt formed by a cation and a negatively charged group on a compound, and the cation is one or more of sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion. 3. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: (1) The compound of claim 1 or a pharmaceutically acceptable salt thereof; and (2) A pharmaceutically acceptable carrier. 4. the purposes of a compound shown in general formula I and a pharmaceutically acceptable salt thereof, in: L is unsubstituted or substituted -(CH ₂ ) _m -, unsubstituted or substituted -C(O)(CH ₂ ) _m -, or unlinked atom or group, wherein each m is independently 1-6 An integer of ; the substitution is to be substituted by a substituent selected from the group consisting of -OH, halogen; Z is ferrocenyl, unsubstituted or substituted C6-C20 aryl, or unsubstituted or substituted C3-C14 heteroaryl; each said substitution is independently substituted with a substituent selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, -OH, -NH ₂ , -NH(C1-C6 alkyl), -N(C1-C6 alkyl) (C1-C6 alkyl), nitro, C2-C6 alkenyl, halogenated C1-C6 alkyl, halogen; the C6-C20 aryl group is selected from: phenyl, naphthyl, tetrahydronaphthyl; the C3-C14 hetero Aryl is pyridyl or benzothiazolyl; Used for: (a) preparing a ribonucleotide reductase inhibitor; or (b) preparing a medicament for preventing and/or treating a tumor associated with abnormal ribonucleotide reductase. 5. The use according to claim 4, wherein the tumor associated with abnormal ribonucleotide reductase is selected from the group consisting of: oropharyngeal cancer, colorectal cancer, non-small cell lung cancer, glioma, leukemia, Liver cancer, thyroid cancer, esophagus cancer, lymphoma, thoracic cancer, gastrointestinal cancer, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, bile duct cancer, central nervous system cancer, testicular cancer, bladder cancer, prostate cancer cancer, skin cancer, melanoma, sarcoma, brain cancer, cervical cancer, stomach cancer, or ascites tumor. 6. The use according to claim 4, wherein L is: -CHF-, _-CF2- , _-CH2CF2- , _-C (=O) _-CF2- , or -C(OH )-CF ₂ -. 7. purposes as claimed in claim 4, is characterized in that, described compound is: