WO2018068357A1 - Novel sirt2 protein inhibitor and pharmaceutical use thereof - Google Patents

Abstract

Disclosed are a compound as shown in formula I, or a pharmaceutically acceptable salt, a crystal form, a solvate thereof, wherein Z is selected from (II), (III), (IV) or (V); R1 is selected from H or (VI); R2 is selected from (VII) or (VIII); and R3 is selected from halogen, C1-C4 alkyl, C1-C4 alkoxyl or (IX). The novel compound as shown in formula I of the present invention not only has a good inhibitory activity on SIRT2, but also has an excellent inhibitory effect on tumours, thus having good medicinal potential and providing a new potential option for clinical medications. Furthermore, the preparation method for the novel compound of the present invention is simple and convenient, features mild reaction conditions, convenient operation and control, low energy-consumption, high productivity and low cost, and is suitable for industrialized production.

Description

A new class of SIRT2 protein inhibitors and their use in pharmaceuticals Technical field

The invention belongs to the field of compound medicines, and in particular relates to a novel class of SIRT2 protein inhibitors and their use in pharmacy.

Background technique

The reversible acetylation modification of protein translation is one of the important means of protein function regulation. Histone acetyltransferase (HAT) catalyzes the acetylation of substrate histones or non-histone lysine residues. In contrast, histone deacetylase (HDAC) catalyzes the corresponding substrate protein lysine. Deacetylation of acid residues, the above-mentioned acetylation/deacetylation protein post-translational modification jointly regulates the functions of various proteins in the body and participates in important physiological processes such as gene expression and cell cycle progression. Up to now, 18 HDACs have been discovered and classified into two classes according to their catalytic mechanisms: Zn2+-dependent histone deacetylase (HDAC1-11) and NAD+-dependent histone deacetylase (Sirtuin1-7, SIRT1- 7). SIRT is highly conserved from bacteria to humans and is found in many tissues and organs such as the liver, heart, brain and pancreas. SIRT1-7 has diverse physiological functions due to its different subcellular structures and its action on substrate proteins that are not identical.

In SIRT1-7, SIRT2 is mainly located in the cytoplasm, and it is found that SIRT2 can continuously shuttle into the nucleus and cytoplasm. Therefore, it can catalyze histones and non-histone lysine residues such as α-tubulin, P53, p65 and FOXO1. Deacetylation regulates gene expression, microtubule stability and cell cycle progression. Due to the involvement of SIRT2 in many important biological processes, recent studies have revealed abnormal expression of SIRT2 and various diseases including neurodegenerative diseases (Parkinson, Alzheimer's disease, Huntington, etc.), tumors (lung cancer, breast cancer, liver cancer). Etc. etc. are closely related, therefore, SIRT2 is considered to be a potential therapeutic target for these diseases.

In view of this, the development of new selective high-activity SIRT2 inhibitors is a hot spot in drug research, and has attracted great attention from domestic and foreign scholars, research institutions and pharmaceutical companies.

A large number of novel SIRT2 inhibitors have been reported so far, including Sirtinol (IC ₅₀ = 46 μM), Salermide (IC ₅₀ = 25 μM), EX-527 (IC ₅₀ = 20 μM), AK-7 (IC ₅₀ = 15.5 μM). ), AGK2 (IC ₅₀ = 3.5 μM), etc., which have different inhibitory activities and selectivity for SIRT2 protein, and only a few inhibitors exhibit certain anti-tumor or neurodegenerative diseases in vivo, except There are almost no inhibitors of SIRT2 in clinical studies for the treatment of related diseases.

Therefore, the development of truly effective SIRT2 inhibitors in vitro and in vivo for the treatment of related diseases is still an urgent task. In particular, the number of existing SIRT2 inhibitors is still small, it is difficult to meet the needs of the majority of patients, and a new class of inventions needs to be invented. Inhibitors of sir-regulatory factor 2-related proteins provide more medication options for a wide range of patients.

Summary of the invention

It is an object of the present invention to provide a new class of compounds of pharmaceutically useful form: compounds of formula I.

A compound of formula I, or a pharmaceutically acceptable salt, crystalline form, or solvate thereof, provided by the invention:

among them,

Z is selected from

R _{1 is} selected from H or

X is selected from

R _{4 is} selected from aryl, heteroaryl, substituted aryl, substituted heteroaryl or

The substituents of the substituted aryl group and the substituted heteroaryl group are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group,

Halogen, hydroxy, thiol, ether, ester, amino or nitro;

R _4a and R _4b are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, aryl, heteroaryl or C ₃ -C ₆ cycloalkyl ;

R _{2 is} selected from

R _2a to R _2f are each independently selected from H, a hydroxyl group, a halogen, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group or a phenyl group;

R _{3 is} selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or

Y is selected from

R _{5 is} selected from aryl, heteroaryl, substituted aryl or substituted heteroaryl, and the substituents of the substituted aryl and substituted heteroaryl are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, halogen, hydroxy, decyl, ether, ester, amino, nitro, amido or aminoacyl.

Further, the compound is

further,

In R ₄ , the aryl group is a phenyl group or a naphthyl group, and the heteroaryl group is a pyridyl group, a furyl group, a thienyl group, a quinolyl group, a carbazolyl group or a quinolyl group, the substituted aryl group and the substituent. The substituents of the heteroaryl group are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group,

R _4a and R _4b are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl, phenyl or thienyl;

In R ₂ , R _2a , R _2c and R _2f are each independently selected from H, a hydroxyl group, a halogen, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group or a phenyl group. , R _2b , R _2d , and R _2e are each H.

further,

R _{5 is} selected from the group consisting of phenyl, pyridyl, furyl, thienyl, substituted phenyl, substituted pyridyl, substituted furyl or substituted thienyl; substituted phenyl, substituted pyridyl, substituted furanyl and substituted thienyl The substituents are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group or a C ₁ -C ₄ haloalkyl group.

Further, the compound is

The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt, crystal form, or solvate thereof, for the preparation of an inhibitor of a sirtuin-2 related protein.

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt, crystal form, or solvate thereof for the preparation of a medicament for treating and/or preventing a tumor.

Further, the tumor is liver cancer, hepatoblastoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer or leukemia.

The present invention also provides a pharmaceutical composition for treating and/or preventing tumors, which comprises the above compound or a pharmaceutically acceptable salt, a crystal form thereof, a solvate thereof as an active ingredient, and a pharmaceutically-acceptable auxiliary ingredient. The resulting preparation was prepared.

The novel compound of the formula I of the present invention not only has good inhibitory activity against SIRT2, but also has a good inhibitory effect on tumors, has good medicinal potential, and provides a new potential choice for clinical use; The preparation method of the novel compound of the invention is simple, the reaction condition is mild, the operation and the control are convenient, the energy consumption is small, the yield is high, the cost is low, and the product can be suitable for industrial production.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definitions of terms used in connection with the present invention: initial definitions provided by groups or terms herein unless otherwise indicated This group or terminology is applicable to the entire specification; for terms that are not specifically defined herein, the meanings that those skilled in the art can give to them should be given in light of the disclosure and context.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix C _a to C _b alkyl group indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C ₁ -C ₄ alkyl means an alkyl group containing from 1 to 4 carbon atoms, in other words, C ₁ -C ₄ alkyl includes methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, tert-butyl.

The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.

The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. An acid salt, an oxalate salt, a malate salt, a succinate salt, a fumarate salt, a maleate salt, a tartrate salt or a trifluoroacetate salt.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

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

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form can comprise 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-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ Oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.

The pharmaceutically acceptable excipient of the present invention means a substance which is contained in a dosage form in addition to the active ingredient.

The pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component does not change the dominant position of the above pharmaceutical composition in the course of disease treatment, but only plays an auxiliary effect, and the auxiliary effects are only It is the utilization of the known activity of the component, and is an auxiliary treatment method conventionally used in the medical field. It is still within the scope of the present invention to use the above auxiliary ingredients in combination with the pharmaceutical composition of the present invention.

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

DRAWINGS

Figure 1 is a ¹ H NMR chart of Compound 28 of the present invention.

Figure 2 is a ¹³ C NMR chart of Compound 28 of the present invention.

Figure 3 is a ¹ H NMR chart of the compound 33 of the present invention.

Figure 4 is a ¹³ C NMR chart of the compound 33 of the present invention.

detailed description

The raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.

Example 1. Synthesis of N-(3-benzylphenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 1)

First, LiAlH ₄ (10 mmol, 379.5 mg) was added to the reaction flask, and after being placed at 0 ° C for about 15 minutes, a solution of AlCl ₃ (10 mmol, 1333 mg) in diethyl ether (15 ml) was added dropwise to the reaction, and the mixture was at 0. Stir at °C for 5 min. Then, a solution of m-aminobenzophenone (1a, 1 mmol, 197.2 mg) in diethyl ether (15 ml) was added dropwise to the reaction, and the reaction was allowed to react to room temperature for 3 h. After the reaction was completed by TLC, the reaction solution was taken with 6 M HCl. dried diluted with saturated NaHCO ₃ and the aqueous layer was with ethyl acetate (20ml × 3), the organic layers were combined, dried over anhydrous Na ₂ SO _4, and concentrated by column chromatography to give intermediate 1b.

Then, intermediate 1b (1 mmol, 183 mg) and bromoacetic acid (1.2 mmol, 166.8 mg) were dissolved in DCM (16 ml), and stirred at 0 ° C, and then added at 0 ° C, 1-(3-di) Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.2 mmol, 230.4 mg), 1-hydroxybenzotriazole (HOBT, 1.2 mmol, 162 mg), N,N-diisopropyl Ethylethylamine (DIEA, 2 mmol, 331 μl) was added and the reaction was taken to room temperature and stirred overnight. After the reaction was completed by TLC (Thin Layer Chromatography), the excess solvent was removed under reduced pressure, and the residue was purified by column chromatography.

Further, the compound 4,6-dimethyl-2-mercaptopyrimidine (1.2 mmol, 168.2 mg) was dissolved in DMF (3 ml), and potassium t-butoxide (2 mmol, 224.4 mg) was added at room temperature and stirred at room temperature After 30 min, the compound 1c (1 mmol, 302 mg) was dissolved in DMF (1 ml) and slowly added to the reaction. After the reaction was stirred for 4-5 h at room temperature, after the reaction was completed by TLC, ice water (40 ml) was added to the reaction, and acetic acid was used. drying extracted with ethyl (20ml × 3 Finally the organic layer was dried over anhydrous over MgSO _4, and concentrated to give compound 1 (168mg by column chromatography, the three-step overall yield ^{38%) 1 H NMR (400MHz} , DMSO):. δ10. 17(s,1H), 7.43-7.41 (m, 2H), 7.31-7.27 (m, 2H), 7.24-7.19 (m, 4H), 7.00-6.94 (m, 2H), 4.01 (s, 2H), 3.91 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9, 142.3, 141.5, 139.6, 129.2, 129.1, 128.8, 125.5, 124.2, 119.9, 117.4, 116.5, 41.6, 35.9, 23.8 ppm.

Example 2 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(phenylamino)phenyl)acetamide (Compound 2)

First, m-nitroaniline (2 mmol, 276.3 mg), phenylboronic acid (1 mmol, 121.9 mg), NiCl ₂ .6H ₂ O (0.2 mmol, 47.5 mg), 2,2-dipyridine (0.2 mmol, 31.2 mg) And 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU, 2 mmol, 304.4 mg) was dissolved in acetonitrile (10 ml) and stirred at room temperature for 28 h, and the reaction was completely confirmed by TLC. after addition of ethyl acetate (10ml) and water (10ml) to the reaction mixture, the aqueous layer (10ml × 3) and extracted with ethyl acetate, the organic layers were combined, dried over anhydrous Na ₂ SO _4, and concentrated to give the intermediate column chromatography Body 2b. Then, 2b (0.2 mmol, 42 mg) was dissolved in EtOH (2 ml) / H ₂ O (1 ml), and NH ₄ Cl (0.1 mmol, 5.4 mg) and Fe (1 mmol, 56 mg) were added and reacted at 80 ° C for 30 min. After the reaction was completed by TLC, the insoluble material was removed by hot filtration, then NaHCO ₃ was added to adjust the pH to basicity, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, concentrated, and then purified by column chromatography. Finally, the target compound 2 was synthesized by the synthesis method of the target compound 1 using the intermediate 2c in a four-step total yield of 26%. ^{1 H NMR (400MHz, DMSO)} : δ10.12 (s, 1H), 8.18 (s, 1H), 7.46 (s, 1H), 7.24 (t, J = 8.0Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 (dd, J = 1.6 Hz, J = 5.6 Hz, 1H), 4.02 (s, 2H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.2, 140.8, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 36.0, 23.8 ppm.

Example 3, 2-((4-Methyl-6-carbonyl-1,6-dihydropyrimidin-2-yl)thio)-N-(3-(anilino)phenyl)acetamide (Compound 3 )Synthesis

First, 3a was synthesized by the synthesis of 2c intermediate and bromoacetic acid according to 1c, and the target compound 3 was synthesized by the synthesis method of compound 1 using 3a and the starting material methylthiouracil, and the yield was 45%. ^{1 H NMR (400MHz, DMSO)} : δ12.56 (br s, 1H), 10.16 (s, 1H), 8.20 (s, 1H), 7.46 (s, 1H), 7.24 (t, J = 8.0Hz, 2H ), 7.15 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.75 (dd, J = 1.6 Hz, J = 7.6 Hz, 2H), 6.01 (br s, 1H), 4.06 (s, 2H), 2.15 (s, 3H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169 .8, 167.5, 167.1, 160.5, 150.2, 140.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 35.9, 22.6 ppm.

Example 4 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(phenoxy)phenyl)acetamide (Compound 4)

Using Compound 4a, Compound 4 was synthesized according to the synthesis method of Target Compound 1, and the total yield in two steps was 58%. _{^{1 H NMR (400MHz, CDCl 3}} ): δ9.60 (s, 1H), 7.35 (t, J = 8.0Hz, 2H), 7.27-7.25 (m, 2H), 7.14 (t, J = 7.2Hz, 1H ), 7.09 (s, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.82 (s, 1H), 6.76-6.73 (m, 1H), 3.88 (s, 2H), 2.46 (s, 6H) ¹³ C NMR (100 MHz, DMSO): δ 169.7, 167.3, 167.0, 140.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 36.0, 23.8 ppm.

Example 5 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(phenylthio)phenyl)acetamide (Compound 5)

First, m-iodoaniline (5a, 2 mmol, 438 mg), CuSO ₄ .5H ₂ O (0.1 mmol, 25 mg), KOH (10 mmol, 561 mg) and DMSO (4 ml) / H ₂ O (0.4 ml) were added to the reaction flask. Then, 1,2-ethanedithiol (2 mmol, 180 μl) was added and reacted at 100-110 ° C for 8 h. After the reaction solution was cooled to room temperature, iodobenzene (2.6 mmol, 530.4 mg) was dissolved in DMF (2 ml). After adding to the reaction, the reaction was continued at 120 ° C for 18 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, water and ethyl acetate were added, and ethyl acetate (10 ml × 3) was evaporated, and the organic phase was combined, dried over anhydrous Na ₂ SO ₄ and concentrated. Body 5b. The target compound 5 was synthesized by the synthesis method of Compound 1 using 5b in a three-step total yield of 46%. ^{1 H NMR (400MHz, DMSO)} : δ10.32 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.46-7.30 (m, 6H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.02 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.7, 167.4, 167.2, 140.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 35.9, 23.8 ppm.

Example 6. Synthesis of N-(3-benzoylphenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 6)

The synthesis of the title compound 6 was carried out according to the synthesis method of the compound 1, and the total yield of the two steps was 46%. _{^{1 H NMR (400MHz, CDCl 3}} ): δ9.84 (s, 1H), 8.02 (t, J = 8.0Hz, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.66 (s, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.52-7.43 (m, 4H), 6.85 (s, 1H), 3.91 (s, 2H), 2.50 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO) ): δ 196.0, 169.7, 167.4, 139.6, 138.0, 137.5, 133.1, 130.0, 129.6, 129.0, 124.9, 123.5, 120.6, 116.5, 35.9, 23.8 ppm.

Example 7. Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(hydroxy(phenyl)methyl)phenyl)acetamide (Compound 7)

First, LiAlH ₄ (5 mmol, 189.8 mg) was added to the reaction flask, and after stirring at 0 ° C for 15 min, a solution of AlCl ₃ (5 mmol, 666.7 mg) in diethyl ether (8 ml) was added dropwise to the reaction, and the mixture was Stir at 0 ° C for 5 min. Then, a solution of m-aminobenzophenone (6a, 1 mmol, 197.2 mg) in diethyl ether (8 ml) was added dropwise to the reaction, and then the reaction was allowed to react to room temperature for 3 h, and after the reaction was completed by TLC, the reaction solution was firstly used. dilute HCl, ₃ and the aqueous layer was extracted with ethyl acetate (10ml × 3) and then with saturated NaHC03, the organic layers were combined, dried over anhydrous Na ₂ SO _4, and concentrated by column chromatography intermediate compound 7a. Finally, compound 7 was obtained by the synthesis method of the target compound 1 using 7a, and the total yield in three steps was 35%. ^{1 H NMR (400MHz, DMSO)} : δ10.20 (s, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.36 (d, J = 7.6Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (q, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 5.90 (d , J = 4.0 Hz, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.01 (s, 2H), 2.31 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9 , 146.9, 146.0, 139.3, 128.8, 128.5, 127.2, 125.7, 121.8, 118.1, 117.6, 116.5, 74.7, 35.9, 23.8 ppm.

Example 8. Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(1-phenylethyl)phenyl)acetamide (Compound 8)

First, m-nitroacetophenone (8a, 1 mmol, 165 mg) and p-methylbenzenesulfonylhydrazide (1 mmol, 185 mg) were dissolved in 10 ml of dioxane, and reacted at 80 ° C for 1.5 hours, and the reaction was detected by TLC. After completion, distillation under reduced pressure gave 8b crude product; then p-methoxyphenylboronic acid (1.5 mmol, 227 mg), K ₂ CO ₃ (1.5 mmol) and 15 ml of dioxane were added and refluxed at 110 ° C for 5 hours. After the TLC reaction was completed, the solvent was evaporated under reduced pressure, and then water and ethyl acetate (yield, 10 ml, 3), and the organic layer was combined, dried over anhydrous Na ₂ SO ₄ and concentrated to give compound intermediate 8c; The title compound 8 was synthesized according to the synthesis method of the compound 2 in a five-step total yield of 23%. ^{: 1 H NMR (400MHz, DMSO} ): δ10.18 (s, 1H), 7.42 (d, J = 7.6Hz, 2H), 7.30-7.28 (m, 2H), 7.24-7.19 (m, 4H), 7.00 - 6.94 (m, 2H), 4.01 (s, 2H), 3.93 (t, J = 7.6 Hz, 1H), 3.87 (s, 3H), 2.32 (s, 6H), 1.58 (d, J = 7.6 Hz, 3H)ppm; ¹³ C NMR (100MHz, DMSO): δ169.8,167.4,166.9,142.3,141.5,139.6,129.2,129.1,128.8,125.5,124.2,119.9,117.4,116.5,56.3,41.6,35.9,23.8,20.6 Ppm.

Example 9. Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(methyl(phenyl)amino)phenyl)acetamide (Compound 9)

First, the raw material 2b (1.0 eq.) is dissolved in DMF and catalytically dehydrogenated with NaH (0.5 eq.) and then reacted with methyl iodide to obtain intermediate 9a. The target compound 9 is synthesized according to the synthesis method of compound 2 using 9a. The rate is 19%. ^{1 H NMR (400MHz, DMSO)} : δ10.13 (s, 1H), 7.45 (s, 1H), 7.23 (t, J = 8.0Hz, 2H), 7.12 (t, J = 8.0Hz, 1H), 7.06 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 (dd, J = 1.6 Hz) , J = 5.6 Hz, 1H), 4.02 (s, 2H), 3.02 (s, 3H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 140.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 42.5, 35.9, 23.8 ppm.

Example 10 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(phenylsulfinyl)phenyl)acetamide (Compound 10)

The intermediate 10a was synthesized by the method of the synthesis of the compound 1b, and then 10a (590 mg, 1.85 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (335 mg, 1.94 mmol) was added with stirring at 0 ° C, and reacted at room temperature. After 45 min, the excess solvent was removed under reduced pressure by TLC. Then, the target compound 10 was synthesized by the synthesis method of the compound 1 using the intermediate 10b in a four-step total yield of 32%. ^{1 H NMR (400MHz, DMSO)} : δ10.32 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.46-7.30 (m, 6H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.02 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.7, 167.4, 167.2, 140.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 35.9, 23.8 ppm.

Example 11. Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(phenylsulfonyl)phenyl)acetamide (Compound 11)

The compound 10a (590 mg, 1.85 mmol) was dissolved in DCM (10 mL). EtOAc (EtOAc m. Column chromatography gave the white intermediate 11a. The target compound 11 was synthesized by the synthesis method of the target compound 1 using 11a. The total yield in two steps was 51%. ^{1 H NMR (400MHz, DMSO)} : δ10.33 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.46-7.31 (m, 6H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.02 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.2, 142.5, 135.9, 134.9, 131.4, 130.3, 130.1, 128.0, 125.7, 121.1, 118.5, 116.5, 36.0, 23.8 ppm.

Example 12 Synthesis of N-(3-(benzylamino)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 12)

The synthesis of the above intermediate 12b is carried out by the synthesis method of 1b using 12a, and then the intermediate 12c is synthesized by the synthesis method of the target compound 1 using 12b. Then, benzaldehyde (0.374 mmol, 39.6 mg) and compound 12c (0.34 mmol, 98.1 mg) were dissolved in DCM (6 ml), then dihydropyridyl ester (0.477 mmol, 120.1 mg) was added, and finally trifluoro Acetic acid (0.17 mmol, 12.7 μl) was refluxed at 45 ° C overnight. After the reaction was completed by TLC, the excess solvent was removed under reduced pressure, and the title compound 12 was obtained by column chromatography. The total yield of the three-step reaction was 29%. ^{1 H NMR (400MHz, DMSO)} : δ9.93 (s, 1H), 7.35-7.29 (m, 4H), 7.22 (t, J = 6.8Hz, 1H), 6.97-6.91 (m, 3H), 6.75 ( d, J = 8.0 Hz, 1H), 6.32-6.27 (m, 2H), 4.23 (d, J = 6.0 Hz, 2H), 3.99 (s, 2H), 2.33 (s, 6H) ppm; ¹³ C NMR ( 100 MHz, DMSO): δ 169.8, 167.4, 166.7, 149.3, 141.6, 139.6, 129.3, 129.1, 122.6, 118.2, 118.0, 116.5, 116.2, 112.7, 48.0, 36.0, 23.8 ppm.

Example 13, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((thien-2-ylmethyl)amino)phenyl)acetamide (Compound 13 )Synthesis

The title compound 13 was obtained by the method of synthesizing compound 12 using the important intermediate 12c and 2-thiophenecarbaldehyde in a yield of 68%. ^{1 H NMR (400MHz, DMSO)} : δ9.95 (s, 1H), 7.36 (dd, J = 0.8Hz, J = 4.0Hz, 1H), 7.03 (d, J = 2.4Hz, 1H), 6.99-6.95 (m, 4H), 6.77 (d, J = 8.8 Hz, 1H), 6.35-6.31 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.00 (s, 2H), 2.34 (s, 6H) ppm.

Example 14, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((1-phenylethyl)amino)phenyl)acetamide (Compound 14) synthesis

The title compound 14 was obtained by the method of synthesizing the compound 12 using the important intermediate 12c and acetophenone, yield 53%. ^{1 H NMR (400MHz, DMSO)} : δ9.92 (s, 1H), 7.35-7.29 (m, 4H), 7.22 (t, J = 7.2Hz, 1H), 6.97-6.91 (m, 3H), 6.75 ( d, J = 7.2 Hz, 1H), 6.32-6.27 (m, 2H), 4.20 (m, 1H), 3.99 (s, 2H), 2.33 (s, 6H), 1.38 (d, J = 6.0 Hz, 3H ) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.7, 149.3, 141.6, 139.6, 129.3, 129.1, 122.6, 118.2, 118.0, 116.5, 116.2, 112.7, 48.0, 36.0, 23.8 ppm.

Example 15. Synthesis of N-(3-(phenoxy)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 15)

First, m-aminophenol (15a, 0.5 mmol, 54.6 mg) was dissolved in dichloromethane (5 ml), triethylamine (1.5 mmol, 208 μl) was added, then acetic anhydride (0.55 mmol, 51.9 μl) was added at room temperature. The reaction was carried out overnight. The reaction was completely confirmed by TLC, and concentrated under reduced pressure. Next, the compound 15b (0.54 mmol, 81.6 mg) and potassium t-butoxide (0.81 mmol, 90.9 mg) were dissolved in DMF (5 ml), and the reaction was stirred at room temperature for 30 min, then benzyl bromide (0.59 mmol, 70.6 μl) was slowly Add and react overnight at room temperature. The reaction was completed by TLC, and water was added, and the aqueous layer was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous Na ₂ SO ₄ and concentrated to give intermediate 15c. Then, the compound 15c (0.26 mmol, 63.2 mg) was dissolved in methanol (2 ml), chlorosulfoxide (0.64 mmol, 45.3 μl) was added, and the reaction was stirred under reflux for 3 h. The reaction was completed by TLC, and then saturated NaHCO ₃ solution was added to adjust the pH to basicity. Methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous Na ₂ SO ₄ and concentrated. Important intermediate 15d. Finally, the target compound 15 was synthesized by the synthesis method of the compound 1 using 15d, and the total yield of the five steps was 18%. ^{1 H NMR (400MHz, DMSO)} : δ10.22 (s, 1H), 7.46-7.33 (m, 6H), 7.21 (d, J = 8.4Hz, 1H), 7.12 (d, J = 8.4Hz, 1H) , 6.98 (s, 1H), 6.72 (dd, J = 2.4 Hz, J = 5.6 Hz, 1H), 5.07 (s, 2H), 4.04 (s, 2H), 2.34 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.7, 149.3, 141.6, 139.6, 129.3, 129.1, 122.6, 118.2, 118.0, 116.5, 116.2, 112.7, 48.0, 36.0, 23.8 ppm.

Example 16. Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-((phenylamino)methyl)phenyl)acetamide (Compound 16)

m-Nitrobenzaldehyde (16a, 2mmol, 302.2mg) and aniline (2.2mmol, 201μl) were dissolved in DCM (16ml), then dihydropyridyl ester (2.8mmol, 708.4mg) was added, and finally added trifluoro Acetic acid (1 mmol, 74.6 μl) was refluxed at 45 ° C overnight. After the reaction was completely detected by TLC, excess solvent was removed under reduced pressure, and the residue was purified by column chromatography. The reductive amination product 16b (1.89 mmol, 427 mg) was dissolved in a mixed solvent of ethanol (10 ml) and water (5 ml), and then iron powder (9.44 mmol, 528.4 mg) and NH ₄ Cl (0.945 mmol, 50.6 mg) were added to the reaction. The mixture was refluxed at 80 ° C for 30 min, and the reaction was completed by TLC. After filtration, the insoluble material was removed by filtration. NaHCO _{3 was} added to adjust the pH to basicity. Ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Compound 16, the total yield in four steps was 45%. ¹ H NMR (400 MHz, DMSO): δ 10.21. (s, 1H), 7.55 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.06 -7.01 (m, 3H), 6.96 (s, 1H), 6.55-6.49 (m, 3H), 6.24 (d, J = 6.0 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 4.02 ( s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9, 149.1, 141.6, 139.6, 129.3, 129.1, 122.6, 118.2, 118.0, 116.5, 116.2, 112.7, 47.0, 35.9, 23.8 ppm.

Example 17, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(((4-methoxyphenyl)amino)methyl)phenyl)phenyl) Synthesis of amide (compound 17)

The aniline was changed to 4-methoxyaniline using 16a, and the title compound 17 was synthesized according to the synthesis of compound 16 in a four-step total yield of 46%. ^{1 H NMR (400MHz, DMSO)} : δ10.23 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.26 (t, J = 8.0Hz, 1H), 7.06 -7.00 (m, 3H), 6.96 (s, 1H), 6.55-6.49 (m, 3H), 6.24 (d, J = 6.0 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 4.02 ( s, 2H), 3.83 (s, 1H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9, 149.1, 141.6, 139.6, 129.3, 129.1, 122.6, 118.2, 118.0 , 116.5, 116.2, 112.7, 47.0, 58.0, 35.9, 23.8 ppm.

Example 18, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((3-(trifluoromethyl)phenyl)amino)methyl)benzene Synthesis of acetamide (Compound 18)

The title compound 18 was synthesized according to the synthesis method of the compound 16 using 16a and m-trifluoromethylaniline, with a total yield of 38% in four steps. ^{1 H NMR (400MHz, DMSO)} : δ10.22 (s, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.29-7.22 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 6.79 (t, J = 7.6 Hz, 3H), 4.29 (d, J = 6.0 Hz, 2H), 4.02 (s, 2H), 2.31 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.5, 166.9, 146.9, 146.1, 139.3, 133.3, 129.3, 128.8, 128.5, 127.2, 125.7, 121.8, 119.4, 118.1, 117.6, 116.5, 74.7, 35.9, 23.8 ppm.

Example 19, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(1-(phenylamino)ethyl)phenyl)acetamide (Compound 19) synthesis

m-Acetylaminoacetophenone (19a, 2mmol, 354.4mg) and aniline (2.4mmol, 219.2μl) were dissolved in toluene (30ml), followed by NaHCO ₃ (10mmol, 840mg) and appropriate molecular sieve and placed at 120 ° C The reaction was refluxed overnight. After the reaction was completed by TLC, the insoluble material was removed by filtration, concentrated under reduced pressure, and then subjected to column chromatography to give the imamine compound 19b. Then, compound 19b was dissolved in DCM (5 ml), a catalytic amount of DMF (0.2 mmol, 384 μl) was added, the reaction solution was placed at 0 ° C, and HMCl ₃ (2 mmol, 200 μl) of DCM (5 ml) was added at 0 °C. The solution was added to the reaction at 0 ° C overnight. After the reaction was completed by TLC, the excess HSiCl _{3 was} quenched by adding an appropriate amount of water. After stirring at room temperature for 10 min, the pH was adjusted to basic with NaHCO ₃ , DCM was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The product 19c was reduced. Next, the imine reduction product (19c, 0.5 mmol, 127 mg) was dissolved in methanol (2 ml), dichloromethane (1.2 mmol, 87 μl) was added, and refluxed at 65 ° C for 3-4 h. After the reaction was completely confirmed by TLC, an appropriate amount of saturated NaHCO ₃ was added to adjust the pH to basicity, and methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, and concentrated to give an intermediate 19d. Finally, the target compound 19 was synthesized according to the synthesis method of the compound 1 using 19d; the total yield of the five steps was 28%. ^{1 H NMR (400MHz, DMSO)} : δ10.19 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 8.0Hz, 1H), 7.23 (t, J = 7.6Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.99-6.95 (m, 3H), 6.48-6.44 (m, 3H), 6.13 (d, J = 6.0 Hz, 1H), 4.40-4.34 (m, 1H), 4.02 (s, 2H), 2.32 (s, 6H), 1.40 (d, J = 6.8 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.8 149.1, 141.6, 139.6, 129.3, 129.1 , 122.6, 118.2, 118.0, 116.5, 116.2, 112.7, 55.8, 35.9, 23.8, 21.0 ppm.

Example 20, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(1-((3-(trifluoromethyl)phenyl)amino)ethyl) Synthesis of phenyl)acetamide (Compound 20)

The title compound 20 was synthesized according to the synthesis method of the compound 19 using 19a and m-trifluoromethylaniline in a five-step total yield of 30%. ^{1 H NMR (400MHz, DMSO)} : δ10.20 (s, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.0Hz, 1H), 7.25 (t, J = 7.6Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.76-6.66 (m, 3H), 4.49-4.42 ( m,1H), 4.01 (s, 2H), 2.31 (s, 6H), 1.42 (d, J = 6.8 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9, 146.9, 146.0 , 139.3, 133.3, 129.9, 128.8, 128.5, 127.2, 125.7, 121.8, 118.6, 118.1, 117.6, 116.5, 74.7, 35.9, 23.8 ppm.

Example 21 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(phenoxymethyl)phenyl)acetamide (Compound 21)

First, phenol (1.0 equivalent) was dissolved in DMF, K ₂ CO _{3 (} 3.0 eq.) was added, and then a solution of m-nitrobenzyl bromide in DMF was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After the reaction was completed by TLC, an appropriate amount of water was added, the aqueous layer was extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous Na ₂ SO ₄ , and concentrated to give nucleophilic substituted product 21b by column chromatography. Then, 21b (1 mmol, 229 mg) was dissolved in a mixed solvent of ethanol (3 ml) and water (1.5 ml), and NH ₄ Cl (0.5 mmol, 26.8 mg) and Fe (5 mmol, 280 mg) were reacted at 80 ° C After 30 min, the reaction was completed by TLC, and the insoluble material was removed by hot filtration. Then, NaHCO ₃ was added to adjust the pH to basicity. The ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Finally, the target compound 21 was synthesized by the synthesis method of Compound 1 using 21c, and the total yield in four steps was 35%. ^{: 1 H NMR (400MHz, DMSO} ): δ10.29 (s, 1H), 7.69 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.35-7.28 (m, 3H), 7.14 (d , J = 7.6 Hz, 1H), 7.01-6.93 (m, 4H), 5.08 (s, 2H), 4.04 (s, 2H), 2.33 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169 .8, 167.4, 167.1, 158.7, 139.7, 138.3, 130.0, 129.3, 122.9, 121.2, 119.0, 118.5, 116.5, 115.2, 69.5, 35.9, 23.8 ppm.

Example 22, N-(3-((4-acetamidophenoxy)methyl)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (compound) 22) Synthesis

The phenol was replaced with acetaminophen, and the target compound 22 was synthesized according to the synthesis of Compound 21 in a four-step yield of 28%. ^{1 H NMR (400MHz, DMSO)} : δ10.29 (s, 1H), 9.78 (s, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.97 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 4.05 (s, 2H), 2.34 (s, 6H), 2.01 (s, 3H), ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 168.0, 167.4, 167.1, 158.7, 139.7, 138.3, 130.0, 129.3, 122.9, 121.2, 119.0, 118.5, 116.5, 115.2, 69.5, 35.9, 23.8, 22.9 ppm.

Example 23, N-(3-((3-acetamidophenoxy)methyl)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (compound) Synthesis of 23)

The phenol was replaced with m-cresol, and the target compound 23 was synthesized according to the synthesis method of the compound 21 in a four-step yield of 29%. ^{1 H NMR (400MHz, DMSO)} : δ10.30 (s, 1H), 9.92 (s, 1H), 7.68 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.37-7.32 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 2H), 6.98 (s, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.05 (s, 2H), 2.34 (s, 6H), 2.04 (s, 3H), ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 168.0, 167.4, 167.1, 154.1, 139.8, 138.3, 134.6 , 129.4, 128.0, 127.6, 127.0, 126.7, 125.9, 125.5, 122.7, 122.0, 120.7, 119.0, 118.7, 118.3, 116.5, 106.3, 69.8, 36.0, 23.8, 22.9 ppm.

Example 24, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((naphthyl-1-oxy)methyl)phenyl)acetamide (compound) 24) Synthesis

The target compound 24 was synthesized by the synthesis method of the compound 21 using 1-naphthol, and the yield in four steps was 33%. ^{1 H NMR (400MHz, DMSO)} : δ10.33 (s, 1H), 8.24 (d, J = 8.4Hz, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.81 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.58-7.49 (m, 3H), 7.45-7.36 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 5.30 (s, 2H), 4.06 (s, 2H), 2.33 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 154.1, 139.8 , 138.3, 134.6, 129.4, 128.0, 127.0, 126.7, 125.9, 125.5, 122.7, 122.0, 120.7, 119.0, 118.3, 116.5, 106.3, 69.8, 36.0, 23.8 ppm.

Example 25, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((naphthyl-2-oxy)methyl)phenyl)acetamide (compound) 25) Synthesis

The target compound 25 was synthesized according to the synthesis method of the compound 21 using 2-naphthol, and the yield in four steps was 35%. ^{1 H NMR (400MHz, DMSO)} : δ10.31 (s, 1H), 7.87-7.77 (m, 4H), 7.57 (d, J = 7.6Hz, 1H), 7.47 (t, J = 7.6Hz, 1H) , 7.42 (s, 1H), 7.36 (t, J = 8.0 Hz, 2H), 7.26-7.20 (m, 2H), 6.96 (s, 1H), 5.22 (s, 2H), 4.06 (s, 2H), 2.33 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 156.7, 139.7, 138.1, 134.7, 129.9, 129.4, 129.1, 128.0, 127.2, 125.9, 124.1, 123.0, 119.2, 119.1 , 118.7, 116.5, 107.8, 69.7, 36.0, 23.8 ppm.

Example 26, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((quinolinyl-8-oxy)methyl)phenyl)acetamide ( Synthesis of Compound 26)

The title compound 26 was synthesized according to the synthesis method of the compound 21 using 8-hydroxyquinoline in a four-step yield of 25%. ^{1 H NMR (400MHz, DMSO)} : δ10.32 (s, 1H), 8.80 (dd, J = 1.6Hz, J = 4.0Hz, 1H), 8.33 (dd, J = 1.6Hz, J = 8.0Hz, 1H ), 7.76 (s, 1H), 7.61 - 7.54 (m, 2H), 7.53 - 7.48 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 2H) , 6.96 (s, 1H), 5.30 (s, 2H), 4.05 (s, 2H), 2.32 (s, 6H) ppm.

Example 27, N-(4-((3-(2-((4,6-dimethylpyrimidin-2-yl))thio)acetamide)benzyl)oxy)phenyl)thiophene-2- Synthesis of Formamide (Compound 27)

The intermediate 22a (1.0 mmol, 286 mg) was dissolved in 5 ml of methanol, and then 0.5 ml of thionyl chloride was added dropwise thereto, followed by reflux for 0.5 hour, and then the solvent was distilled off under reduced pressure, and then NaHCO _{3 was} added to adjust the pH to 7-8 and then added. After extraction with water and ethyl acetate, the organic layer was dried over Na ₂ SO ₄ and then evaporated on a rotary evaporator. After condensing with thiophene-2-carbonyl chloride, the nitro group was reduced by iron powder to obtain intermediate 27b; Synthesis of Compound 1 The title compound 27 was synthesized in a five-step total yield of 28%. ^{1 H NMR (400MHz, DMSO)} : δ10.30 (s, 1H), 10.13 (s, 1H), 7.99 (d, J = 3.2Hz, 1H), 7.84 (dd, J = 0.8Hz, J = 4.0Hz , 1H), 7.71 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.22 (t , J=8.0Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 7.02-6.97(m,3H), 5.08(s,2H), 4.06(s,2H), 2.36(s,6H) ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 160.0, 155.1, 140.7, 139.7, 138.3, 132.4, 132.0, 129.2, 128.5, 122.9, 122.5, 119.0, 118.5, 116.5, 115.3, 69.8, 36.0 , 23.8ppm.

Example 28, N-(3((4-(cyclopropanesulfonamido)phenoxy)methyl)phenyl-2-((4,6-dimethylpyrimidin-2-yl)thio) Synthesis of amide (compound 28)

The title compound 28 was synthesized according to the synthesis method of the compound 27 using 27a and cyclopropylsulfonyl chloride, and the total yield of the four steps was 29%. ^{1 H NMR (400MHz, DMSO)} : δ10.30 (s, 1H), 9.38 (s, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 7.00-6.97 (m, 3H), 5.06 (s, 2H), 4.05 (s, 2H), 2.50-2.47 (m, 1H), 2.34 (s, 6H), 0.91 - 0.86 (m, 4H), ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 156.0, 139.6, 138.2, 131.5, 129.3, 124.2, 122.9 119.0, 118.6, 116.5, 115.7, 69.8, 36.3, 36.0, 23.8, 5.3 ppm.

Example 29, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((4-(phenylsulfonamido)phenoxy)methyl)phenyl) Synthesis of acetamide (Compound 29)

The target compound 29 was synthesized according to the synthesis method of the compound 27 using 27a and benzenesulfonyl chloride, and the total yield of the four steps was 30%. ^{1 H NMR (400MHz, DMSO)} : δ10.28 (s, 1H), 9.95 (s, 1H), 7.70 (d, J = 7.2Hz, 2H), 7.65 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.56-7.52 (m, 3H), 7.31 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.97 (d, J = 2.8 Hz, 2H), 6.89 (s, 1H), 6.87 (s, 1H), 4.98 (s, 2H), 4.04 (s, 2H), 2.36 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 167.1, 156.0, 139.9, 139.6, 138.1, 133.2, 130.8, 129.6, 129.3, 127.1, 123.8, 122.9, 119.0, 118.6, 116.5, 115.7, 69.8, 35.9, 23.8 ppm.

Example 30, N-(3(((1H-carbazol-5-yl)oxy)methyl)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio) Synthesis of acetamide (Compound 30)

Compound 30a (400mg, 2.99mmol) was dissolved with 5mL DMF was added with stirring _{K 2 CO 3 (3.19g, 23.1mmol} ), the mixture was cooled to 0 deg.] C, the m-nitro benzyl bromide (1g, 4.62mmol) with 5mL DMF was dissolved, slowly added dropwise to the mixture of compound 30a, reacted at 0 ° C for 2 h, and then reacted at room temperature for 3 h. The reaction was completely monitored by TLC. The reaction mixture was poured with water, extracted with EA, washed with saturated NaCl, dried and concentrated to give a crude product. The purified product (DCM) gave 420 mg of 30b pure product, yield 52%. Next, the compound 30b (200 mg, 0.74 mmol) was dissolved in 4 mL of ethanol, and 2 mL of H ₂ O was added, and NH ₄ Cl (20 mg, 0.37 mmol), iron powder (151 mg, 3.70 mmol), and refluxed at 80 ° C for 30 min. The mixture was filtered with EtOAc. EtOAc (EtOAc m. Compound 30c (170 mg, 0.71 mmol), 8 (108 mg, 0.78 mmol) was added to a reaction flask, dissolved in 8 mL DCM, and EDCI (164 mg, 0.85 mmol), HOBt (125 mg, 0.85 mmol), DIEA ( 235 μL, 1.42 mmol), and then reacted at room temperature overnight. The reaction mixture was dried and purified by column chromatography (PE: EA=3:1→PE: EA=1:1). Finally, compound 30d (130 mg, 0.36 mmol) was dissolved in 2 mL of DMF, and t-BuOK (48 mg, 0.43 mmol) was stirred at room temperature for 30 min, then 10 (73 mg, 0.43 mmol) was dissolved in 2 mL of DMF and added to the thiol group. The mixture of the imidazoles was reacted at room temperature overnight, added with water, extracted with EA, washed with saturated NaCI, and then evaporated to dryness to give a crude product which was obtained by column chromatography (PE:EA=3:1→PE:EA=1:1) (Compound 30) 105 mg, yield 71.9%. ^{1 H NMR (400MHz, DMSO)} : δ12.93 (s, 1H), 10.30 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.55 (d, J = 8.0Hz, 1H) , 7.47 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.8 Hz, J=2.0 Hz, 1H), 6.96 (s, 1H), 5.11 (s, 2H), 4.05 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169 .8, 167.4, 167.1, 153.2, 139.7, 138.5, 136.3, 133.3, 129.3, 123.5, 122.9, 118.9, 118.8, 118.5, 116.5, 111.6, 101.9, 70.1, 36.0, 23.8 ppm.

Example 31, N-(3-(Benzyloxy)-4-fluoro-phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 31) Synthesis

The title compound 31 was synthesized by the synthesis method of the compound 15 using 5-amino-2-fluorophenol (31a, 0.5 mmol, 65 mg). The five-step total yield was 26%. ¹ H NMR (400 MHz, DMSO): δ 10.21 (s, 1H), 7.44-7.30 (m, 6H), 7.22 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H) , 7.11 (s, 1H), 6.98 (s, 1H), 5.06 (s, 2H), 4.03 (s, 2H), 2.34 (s, 6H) ppm; LC-MS m/z: 398.1 [M+H] ⁺ .

Example 32, N-(3-(Benzyloxy)-4-methyl-phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 32) Synthesis

The title compound 32 was synthesized by the synthesis method of the compound 15 using 5-amino-2-methylphenol (32a, 0.5 mmol, 62 mg). The total yield of the five steps was 27%. ^{1 H NMR (400MHz, DMSO)} : δ10.22 (s, 1H), 7.45-7.31 (m, 6H), 7.24 (d, J = 8.4Hz, 1H), 7.10 (d, J = 8.4Hz, 1H) , 7.10 (s, 1H), 6.99 (s, 1H), 5.05 (s, 2H), 4.03 (s, 2H), 2.34 (s, 6H), 2.08 (s, 3H) ppm; LC-MS m/z :394.2[M+H] ⁺ .

Example 33 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-(phenylamino)phenyl)acetamide (Compound 33)

Compound 33a (1 mmol, 184 mg) was dissolved in dichloromethane (DCM, 3 ml), triethylamine (3 mmol, 416 μl) was added, and then the reaction was stirred at 0 ° C, and bromoacetyl bromide (1.1) at 0 ° C. A solution of mmol, 96 μl of DCM (1 ml) was slowly added to the reaction. The reaction was stirred to room temperature and stirred for 4-5 h. After the reaction was completed by TLC, excess solvent was removed under reduced pressure. Then, 4,6-dimethyl-2-mercaptopyrimidine (1.2 mmol, 168.2 mg) was dissolved in DMF (N,N-dimethylformamide, 3 ml), and potassium t-butoxide (2 mmol) was added at room temperature. After the reaction was stirred at room temperature for 30 min, the compound 33b (1 mmol, 305 mg) was dissolved in DMF (1 ml) and slowly added to the reaction, and the reaction was stirred at room temperature for 4-5 h. to the reaction was added ice-water (40ml), and extracted with ethyl acetate (20ml × 3), the organic layer was dried over anhydrous over MgSO _4, and concentrated to give compound 33 (142mg, yield 41%) by column chromatography. ^{1 H NMR (400MHz, DMSO)} : δ10.08 (s, 1H), 8.05 (s, 1H), 7.46 (d, J = 8.8Hz, 2H), 7.20 (t, J = 8.0Hz, 2H), 7.05 -6.98 (m, 5H), 6.77 (t, J = 7.2 Hz, 1H), 4.02 (s, 2H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.3, 144.5, 139.4, 132.3, 129.6, 121.0, 119.5, 118.3, 116.5, 116.3, 35.9, 23.8 ppm.

Example 34 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-phenoxyphenyl)acetamide (Compound 34)

The compound 34a (1 mmol, 185 mg) and bromoacetic acid (1.2 mmol, 166.8 mg) were dissolved in DCM (16 ml), and dissolved at 0 ° C, and then added at 0 ° C, 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (EDCI, 1.2 mmol, 230.4 mg), 1-hydroxybenzotriazole (HOBT, 1.2 mmol, 162 mg), N,N-diisopropylethylamine (DIEA, 2 mmol, 331 μl), after completion, the reaction was taken to room temperature and stirred overnight. After the reaction was completed by TLC, the excess solvent was removed under reduced pressure and the residue was purified to afford Intermediate 34b. Using the intermediate 34b as a starting material, the title compound 34 was obtained in a similar manner. ^{1 H NMR (400MHz, DMSO)} : δ10.27 (s, 1H), 7.60 (d, J = 8.8Hz, 2H), 7.37 (t, J = 8.0Hz, 2H), 7.11 (t, J = 7.6Hz , 1H), 7.01-6.96 (m, 5H), 4.04 (s, 2H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.8, 157.8, 152.3, 135.4, 130.4 , 123.5, 121.3, 119.9, 118.4, 116.5, 35.8, 23.8 ppm.

Example 35 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)sulfinyl)-N-(4-phenoxyphenyl)acetamide (Compound 35)

The compound 34 (70.0 mg, 0.185 mmol) was dissolved in DCM (4 mL), and m-chloro-peroxybenzoic acid (33.5 mg, 0.194 mmol) was added with stirring at 0 ° C, and reacted at room temperature for 45 min. Excess solvent was obtained by column chromatography to give white crystals Compound Compound Compound ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.32 (s, 1H), 7. 7. (d, J = 8.8 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 7.00-6.93 (m, 5H), 4.16 (d, J = 14.4 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 2.55 (s, 6H) ppm; ¹³ C NMR ( 100 MHz, DMSO): δ 171.5, 168.9, 162.9, 157.7, 152.7, 134.9, 130.4, 123.5, 121.9, 121.4, 119.9, 118.4, 60.5, 23.9 ppm.

Example 36, Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)sulfonyl)-N-(4-phenoxyphenyl)acetamide (Compound 36)

The compound 34 (70.0 mg, 0.185 mmol) was dissolved in DCM (4 mL), and m-chloro-peroxybenzoic acid (95.6 mg, 0.554 mmol) was added with stirring at 0 ° C, and reacted for 3 h at room temperature. Solvent, column chromatography gave the title compound 36 (44 mg, yield 71%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.33 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 7.00-6.95 (m, 5H), 4.16 (d, J = 14.4 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 2.55 (s, 6H) ppm; ¹³ C NMR ( 100 MHz, DMSO): δ 169.3, 164.5, 159.8, 157.6, 152.9, 134.6, 130.5, 123.7, 123.6, 121.4, 119.9, 118.5, 57.9, 23.8 ppm.

Example 37, Synthesis of N-(4-benzylphenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 37)

After adding LiAlH ₄ (10 mmol, 379.5 mg) to the reaction flask, a solution of AlCl ₃ (10 mmol, 1333 mg) in diethyl ether (15 ml) was added dropwise to the reaction mixture at 0 ° C for about 15 min, and the mixture was stirred at 0 ° C. 5min. Then, a solution of p-aminobenzophenone (37a, 1 mmol, 197.2 mg) in diethyl ether (15 ml) was added dropwise to the reaction, and the reaction was allowed to react to room temperature for 3 h. After the reaction was completed by TLC, the reaction solution was taken with 6 M HCl. dried diluted with saturated NaHCO ₃ and the aqueous layer was with ethyl acetate (20ml × 3), the organic layers were combined, dried over anhydrous Na ₂ SO _4, and concentrated by column chromatography to give intermediate 37b. Using the intermediate 37b as a starting material, the title compound 37 was obtained in a similar manner to the compound 34 of Example 34, with a three-step yield of 36%. ^{1 H NMR (400MHz, DMSO)} : δ10.17 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.28 (t, J = 7.6Hz, 2H), 7.22-7.15 (m, 5H) , 6.97 (s, 1H), 4.02 (s, 2H), 3.89 (s, 2H), 2.34 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.8, 141.9, 137.5, 136.7 , 129.4, 129.1, 128.8, 125.4, 119.8, 116.5, 40.0, 35.9, 23.8 ppm.

Example 38 Synthesis of N-(4-benzoylphenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 38)

Using the compound 37a as a starting material, the title compound 38 was obtained according to the similar compound of compound 34 of Example 34, with a total yield of 45% in two steps. ^{1 H NMR (400MHz, DMSO)} : δ10.65 (s, 1H), 7.79-7.74 (m, 4H), 7.72 (d, J = 8.0Hz, 2H), 7.67 (t, J = 4.4Hz, 1H) , 7.56 (t, J = 8.0 Hz, 2H), 6.98 (s, 1H), 4.10 (s, 2H), 2.34 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 195.00, 169.7, 167.7, 167.5, 143.6, 138.0, 132.7, 131.9, 131.7, 129.8, 128.9, 118.8, 116.6, 36.1, 23.8 ppm.

Example 39 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-(hydroxy(phenyl)methyl)phenyl)acetamide (Compound 39)

LiAlH ₄ (5 mmol, 189.8 mg) was added to the reaction flask, and the mixture was stirred at 0 ° C for 15 min, then a solution of AlCl ₃ (5 mmol, 666.7 mg) in diethyl ether (8 ml) was added dropwise to the reaction mixture at 0 ° C. Stir for 5 min. Then, a solution of p-aminobenzophenone (37a, 1 mmol, 197.2 mg) in diethyl ether (8 ml) was added dropwise to the reaction, then the reaction was allowed to react to room temperature for 3 h, and after completion of the reaction by TLC, the reaction solution was firstly taken with 6 M HCl. dilution, (10ml × 3) ₃ and extracted the aqueous layer with ethyl acetate, the organic layers were combined, dried over anhydrous Na ₂ SO _4, and concentrated to give compound intermediate 39a by column chromatography with saturated NaHCO. Using the intermediate 39a as a starting material, a compound 39 was obtained according to the compound of Example 34, to give compound 39 in a three-step yield of 32%. ^{1 H NMR (400MHz, DMSO)} : δ10.20 (s, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.36 (d, J = 7.2Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.25-7.19 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 5.89 (d, J = 4.0 Hz, 1H) , 5.65 (d, J = 4.0 Hz, 1H), 4.01 (s, 2H), 2.32 (s, 6H) ppm.

Example 40 Synthesis of N-(4-(Benzylamino)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 40)

The intermediate 40b was synthesized by the method of the synthesis of the intermediate 34b of Example 34 using 40a, and then the intermediate 40c was synthesized by the synthesis of the title compound 34 of Example 34 using 40b. Then benzaldehyde (0.374 mmol, 39.6 mg) and compound 40c (0.34 mmol, 98.1 mg) were dissolved in DCM (6 ml), then 2,6-dimethyl-1,4-dihydropyridine-3,5 Ethyl dicarboxylate (Hans, 0.477 mmol, 120.1 mg) was added, and finally trifluoroacetic acid (0.17 mmol, 12.7 μl) was added dropwise and refluxed at 45 ° C overnight. After completion of the reaction by TLC, excess solvent was removed under reduced pressure and the title compound 40 was obtained by column chromatography. The total yield of the three-step reaction was 27%. ^{1 H NMR (400MHz, DMSO)} : δ9.85 (s, 1H), 7.37-7.31 (m, 4H), 7.30-7.25 (m, 4H), 6.98 (s, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 3.97 (s, 2H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.9, 167.4, 166.0, 150.2, 149.9, 145.1, 129.0, 122.8, 121.4, 116.5, 112.7, 46.1, 35.7, 23.8 ppm.

Example 41, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-((3-methoxybenzyl)amino)phenyl)acetamide (Compound 41 )Synthesis

Using the intermediate 40c and 3-methoxybenzaldehyde, the title compound 41 was obtained in a similar manner to the compound 40 of Example 40, yield 75%. ^{1 H NMR (400MHz, DMSO)} : δ9.85 (s, 1H), 7.38-7.32 (m, 3H), 7.28-7.24 (m, 4H), 6.98 (s, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 3.97 (s, 2H), 3.83 (s, 3H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 170.0, 167.6, 166.2, 159.9 , 150.3, 149.9, 145.1, 129.0, 122.8, 121.4, 117.0, 116.5, 112.7, 54.2, 46.1, 35.7, 23.8 ppm.

Example 42, 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(4-((pyridin-4-yl-methyl)amino)phenyl)acetamide (compound) 42) Synthesis

Using the intermediate 40c and 4-pyridinecarboxaldehyde, the title compound 42 was obtained in a similar manner to the compound 40 of Example 40, yield 78%. ^{1 H NMR (400MHz, DMSO)} : δ9.83 (s, 1H), 8.48 (d, J = 5.6Hz, 2H), 7.33 (d, J = 6.0Hz, 2H), 7.24 (d, J = 8.8Hz , 2H), 6.97 (s, 1H), 6.50 (d, J = 8.8 Hz, 2H), 6.29 (t, J = 6.0 Hz, 1H), 4.29 (d, J = 6.4 Hz, 2H), 3.96 (s) 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.9, 167.4, 166.0, 150.2, 149.9, 145.1, 129.0, 122.8, 121.4, 116.5, 112.7, 46.1, 35.7, 23.8 ppm.

Example 43, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-((thiophen-2-yl-methyl)amino)phenyl)acetamide (compound) Synthesis of 43)

Using the important intermediate 40c and 2-thiophenecarboxaldehyde, the title compound 43 was obtained in a similar manner to the compound 40 of Example 40, yield 71%. ^{1 H NMR (400MHz, DMSO)} : δ9.80 (s, 1H), 7.32 (d, J = 3.2Hz, 1H), 7.24 (d, J = 5.6Hz, 2H), 7.01 (s, 1H), 6.93 (t, J = 3.2 Hz, 2H), 6.57 (d, J = 5.6 Hz, 2H), 6.07 (br s, 1H,), 4.39 (s, 2H), 3.95 (s, 2H), 2.32 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 170.8, 169.9, 167.4, 165.9, 145.1, 144.8, 129.2, 127.2, 125.2, 124.8, 121.3, 116.5, 113.0, 55.4, 35.8, 23.8 ppm.

Example 44, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-((furan-2-yl-methyl)amino)phenyl)acetamide (compound) 44) Synthesis

Using the intermediate 40c and furfural, the title compound 44 was obtained in a similar manner to the compound 40 of Example 40, yield 70%. ^{1 H NMR (400MHz, DMSO)} : δ9.89 (s, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.8Hz, 2H), 6.97 (s, 1H), 6.65 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 6.29 (s, 1H), 4.24 (s, 2H), 3.99 (s, 2H), 2.35 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO) : δ 169.9, 167.4, 166.0, 153.4, 144.2, 142.5, 129.8, 121.2, 116.5, 113.5, 110.8, 107.7, 41.0, 35.8, 24.1 ppm.

Example 45 Synthesis of N-(4-(Benzyloxy)phenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide (Compound 45)

The fluoronitrobenzene (45a, 0.5 mmol, 70.5 mg), benzyl alcohol (0.75 mmol, 72 mg) was dissolved in dioxane (5 ml), KOH (1.5 mmol, 84 mg) was added, and the reaction was stirred at room temperature overnight. After the TLC detection reaction was completed, the solvent dioxane was removed under reduced pressure, and an appropriate amount of water and ethyl acetate were added thereto, and the mixture was subjected to extraction, dried, and concentrated to give the intermediate 45b. Next, 45b (0.45 mmol, 103.5 mg) was dissolved in a mixed solvent of ethanol (3 ml) and water (1.5 ml), and NH ₄ Cl (0.225 mmol, 12 mg) and Fe (2.25 mmol, 126 mg) were added and reacted at 80 ° C. After 30 min, the reaction was complete by TLC, and then filtered to remove insoluble materials. NaHCO _{3 was} added to adjust pH to basicity, and then ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated to afford intermediate 45c. The title compound 45 was synthesized by a similar synthetic procedure to the compound 34 of Example 34 using 45c, with a four-step total yield of 41%. ^{1 H NMR (400MHz, DMSO)} : δ10.10 (s, 1H), 7.49 (d, J = 6.8Hz, 2H), 7.46-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.35- 7.31 (m, 1H), 7.00-6.95 (m, 3H), 5.07 (s, 2H), 4.01 (s, 2H), 2.34 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4 , 166.5, 154.8, 137.6, 132.9, 128.9, 128.2, 128.1, 121.1, 116.5, 115.3, 69.8, 35.8, 23.8 ppm.

Example 46, Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(4-(phenoxymethyl)phenyl)acetamide (Compound 46)

Phenol (46a, 1 mmol, 94 mg) was added to a reaction flask and dissolved with 2 ml of DMF, followed by potassium carbonate (5 mmol, 690 mg) and p-nitrobenzyl bromide (1 mmol, 216 mg) was dissolved in 2 ml of DMF and added dropwise. In the reaction bottle. The reaction was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the compound 46b was obtained by distillation under reduced pressure. Then, after dissolving compound 46b (1 mmol, 229 mg) in a mixed solvent of ethanol and water (10 ml, ethanol: water = 2:1), iron powder (5 mmol, 280 mg) and ammonium chloride (1 mmol, 53.5 mg) were added to 80. The mixture was stirred and refluxed for 0.5 hour at ° C. After the reaction was completed by TLC, the pH was adjusted to basic with sodium hydrogen carbonate. After suction filtration, ethanol was distilled off under reduced pressure, and then water was added thereto, and extracted with ethyl acetate. . Compound 46 was synthesized according to the synthesis of the title compound 34 of Example 34 using 46c, with a four-step total yield of 24%. ^{1 H NMR (400MHz, DMSO)} : δ10.30 (s, 1H), 7.61 (d, J = 8.4Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 7.30 (t, J = 7.2Hz , 2H), 7.01-6.98 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 5.04 (s, 2H), 4.05 (s, 2H), 2.34 (s, 6H) ppm.

Example 47, Synthesis of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(4-((phenylamino)methyl)phenyl)acetamide (Compound 47)

p-Nitrobenzaldehyde (47a, 2mmol, 302.2mg) and aniline (2.2mmol, 201μl) were dissolved in DCM (16ml), then 2,6-dimethyl-1,4-dihydropyridine-3, Ethyl 5-dicarboxylate (Hans, 2.8 mmol, 708.4 mg) was added, and finally trifluoroacetic acid (1 mmol, 74.6 μl) was added dropwise and refluxed at 45 ° C overnight. After the reaction was completely detected by TLC, excess solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give the reductive product 47b. The reductive amination product 47b (1.89 mmol, 427 mg) was dissolved in a mixed solvent of ethanol (10 ml) and water (5 ml), and then iron powder (9.44 mmol, 528.4 mg) and NH ₄ Cl (0.945 mmol, 50.6 mg) were added to the reaction. The mixture was refluxed at 80 ° C for 30 min, and the reaction was completed by TLC. After filtration, the insoluble material was removed by filtration. NaHCO _{3 was} added to adjust the pH to basicity. Ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Compound 47c. Compound 47 was synthesized according to the method for the synthesis of the title compound 34 of Example 34 using 47c. ^{1 H NMR (400MHz, DMSO)} : δ10.19 (s, 1H), 7.52 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 7.03 (t, J = 8.4Hz , 2H), 6.97 (s, 1H), 6.56 (d, J = 8.8 Hz, 2H), 6.51 (t, J = 7.2 Hz, 1H), 6.14 (t, J = 6.0 Hz, 1H), 4.20 (d) , J = 6.0 Hz, 2H), 4.03 (s, 2H), 2.34 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.8, 149.1, 138.0, 135.6, 129.2, 128.0, 119.6 , 116.5, 116.2, 112.7, 46.6, 35.9, 23.8 ppm.

Example 48, 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-((3-(trifluoromethyl)phenyl)amino)methyl)benzene Synthesis of acetamide (Compound 48)

The title compound 48 was synthesized according to the synthesis of the compound 47 of Example 47 using 3-trifluoromethylaniline in place of aniline, with a total yield of 38% in four steps. ¹ H NMR (400 MHz, DMSO): δ 10.21 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.6 Hz) , 1H), 6.97 (s, 1H), 6.84-6.79 (m, 3H), 6.69 (t, J = 6.0 Hz, 1H), 4.26 (d, J = 5.6 Hz, 2H), 4.03 (s, 2H) , 2.33 (s, 6H) ppm; ¹³ C NMR (100 MHz, DMSO): δ 169.8, 167.4, 166.9, 149.6, 138.2, 134.7, 130.2, 128.1, 125.4, 123.6, 119.7, 116.5, 116.0, 112.0, 108.6, 46.3, 35.9, 23.8 ppm.

Example 49 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-(phenylthio)phenyl)acetamide (Compound 49)

To the reaction flask was added p-iodoaniline (49a, 2 mmol, 438 mg), CuSO ₄ .5H ₂ O (0.1 mmol, 25 mg), KOH (10 mmol, 561 mg) and DMSO (dimethyl sulfoxide, 4 ml) / H ₂ O (0.4 ml), then 1,2-ethanedithiol (2 mmol, 180 μl) was added and reacted at 100-110 ° C for 8 h, then the reaction solution was cooled to room temperature and then iodobenzene (2.6 mmol, 530.4 mg) was dissolved in DMF. (2 ml) was added to the reaction, and the reaction was continued at 120 ° C for 18 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, water and ethyl acetate were added, the aqueous layer was extracted with ethyl acetate (10ml×3), and the organic phase was combined, dried over anhydrous Na ₂ SO ₄ , Body 49b. The title compound 49 was synthesized according to the method for the synthesis of compound 34 of Example 34 using 49b, with a three-step total yield of 48%. ^{1 H NMR (400MHz, DMSO)} : δ10.40 (s, 1H), 7.64 (d, J = 8.4Hz, 2H), 7.39 (d, J = 8.4Hz, 2H), 7.33 (t, J = 7.6Hz , 2H), 7.26-7.20 (m, 3H), 6.98 (s, 1H), 4.06 (s, 2H), 2.33 (s, 6H) ppm.

Example 50 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-(phenylsulfinyl)phenyl)acetamide (Compound 50)

The compound 50b was oxidized by m-CPBA using the compound 49b according to the method of the synthesis of the objective compound 35 of Example 35. Then, the title compound 50 was synthesized by the method of synthesizing the compound 34 of Example 34 using Compound 50a, with a three-step total yield of 41%. ^{1 H NMR (400MHz, DMSO)} : δ10.46 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 7.52 (t, J = 7.6Hz , 2H), 7.27-7.22 (m, 3H), 6.97 (s, 1H), 4.09 (s, 2H), 2.34 (s, 6H) ppm.

Example 51 Synthesis of 2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(4-(phenylsulfonyl)phenyl)acetamide (Compound 51)

Compound 49b was oxidized by m-CPBA according to the synthesis of the title compound 36 of Example 36 to give Compound 51a. The title compound 51 was synthesized by the method for the synthesis of the compound 34 of the compound of Example 34, using compound 51a. ^{1 H NMR (400MHz, DMSO)} : δ10.46 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.57 (t, J = 7.6Hz , 2H), 7.27-7.20 (m, 3H), 6.97 (s, 1H), 4.08 (s, 2H), 2.33 (s, 6H) ppm.

Example 52, 2-((4-Methyl-6-hydroxy-1,6-dihydropyrimidin-2-yl)thio)-N-(4-(anilino)phenyl)acetamide (Compound 52 )Synthesis

Using the intermediate 33b and methylthiouracil as starting materials, the title compound 52 was synthesized according to the method of the synthesis of the compound 33 of Example 33 in a yield of 65%. ^{1 H NMR (400MHz, DMSO)} : δ12.56 (br s, 1H), 10.16 (s, 1H), 8.20 (s, 1H), 7.46 (s, 1H), 7.24 (t, J = 8.0Hz, 2H ), 7.15 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.75 (dd, J = 1.6 Hz, J = 7.6 Hz, 2H), 6.01 (br s, 1H), 4.06 (s, 2H), 2.15 (s, 3H) ppm.

Example 53, Inhibitory Activity of the Compound of the Present Invention on SIRT2 Protein in Vitro

The test method is as follows:

(1) Experimental materials:

Purchased SIRT2 enzyme from BPS Bioscience, USA (product number: 50013); Perkin Elmer, USA 384-well plate (product number: 6007279); Sigma's positive control product Suramin (product number: S2671).

(2) Experimental method:

First, a tris-hydroxymethane buffer was prepared; then, all test compounds and the positive control compound Suramin were dissolved in 100% DMSO to prepare test solutions of different concentrations and transferred to the test wells; then SIRT2 was dissolved. Preparing the enzyme solution in the buffer solution; simultaneously dissolving the nicotinamide adenine nucleotide (NAD ⁺ ) and the acetylated substrate peptide in a buffer solution to prepare a substrate buffer solution; then adding 10 μL of the enzyme to the test well plate respectively After the solution or the blank control buffer solution, the test plate was incubated at room temperature for 15 minutes; 10 μL of the substrate buffer was added to each well for 4 hours; after the reaction was completed, the trypsin solution was added to each well for 1.5 hours; The Synergy MX plate reader measures the luminescence intensity of the above reaction solution at excitation light wavelengths of 360 nM and 460 nM to determine the inhibitory activity of the compound on SIRT2.

(3) Experimental results:

The inhibitory activity of the compound of the present invention against SIRT2 was tested by the above experimental methods. The inhibitory activity of the specific compound at a concentration of 5 μM and 50 μM and the effective inhibitory concentration (IC ₅₀ ) of some compounds against SIRT2 are shown in Table 1, wherein "-" Indicates not tested.

Table 1. Inhibitory activity of the compound of the present invention on SIRT2 (Inh%)

The above results indicate that the compound of the present invention has a good inhibitory activity against SIRT2 and can be used for the preparation of an inhibitor of a sirtuin-2-related protein.

Example 54. Inhibitory effect of the compound of the present invention on proliferation of various tumor cell lines

(1) Experimental materials:

Main reagents: RPMI-1640, fetal calf serum, trypsin, etc. were purchased from Gibco BRL (Invitrogen Corporation, USA), and IMDM medium was purchased from ATCC (American Type Culture Collection). Tetramethylazozolium salt (MTT) and dimethyl sulfoxide (DMSO) are products of Sigma (USA). Human liver cancer cell line (HUH7), human hepatoma cell line (SMMC7721), hepatoblastoma cell line (HepG2), human breast cancer cell line (MCF-7), human lung cancer cell line (NCI-H460), human lung cancer cell Line (A549), human pancreatic cancer cell line (MIAPACA), human promyelocytic leukemia cell line (HL60), human chronic myeloid leukemia cell line (K562), human prostate cancer cell line (DU-145), etc. were purchased from the United States. ATCC (American type culture collection), kept by our laboratory.

(2) Experimental method:

A cell suspension having a cell concentration of 1 to 2 × 10 4 /mL was adjusted with a complete cell culture solution, and seeded in a 96-well plate, and 200 μl of a cell suspension per well was cultured overnight. On the next day, the supernatant was aspirated (the supernatant was aspirated after centrifugation), and then the cells were treated with a gradient concentration of the test compound. At the same time, a drug-free negative control group and an equal volume of solvent control group were used, and the DMSO concentration was 0.1%. Three doses of each well were set in each dose group, and cultured at 37 ° C, 5% CO ₂ . After 72 hours, add 20 μl of MTT reagent at a concentration of 5 mg/mL to each well. After 2-4 hours of incubation, discard the supernatant, add 150 μL of DMSO to each well, mix by shaking for 15 min, and measure the absorbance with a microplate reader (λ = 570 nm). (A) value (A value is proportional to the number of viable cells), and the average value is taken. The relative cell proliferation inhibition rate = (negative control group A ₅₇₀ - experimental group A ₅₇₀ ) / negative control group A ₅₇₀ × 100%. The experiment was repeated at least 3 times. The experimental data were expressed as mean, and the data were analyzed by t test. P<0.05 was considered statistically significant. The inhibition of cell proliferation by each of the following compounds was expressed by IC ₅₀ or inhibition rate.

(3) Experimental results:

Using the above method, the compounds 1, 13, 19, 20, 21, 49 of the present invention were tested against human hepatoma cell line (HUH7), human hepatoma cell line (SMMC7721), hepatoblastoma cell line (HepG2), human breast cancer. Cell line (MCF-7), human lung cancer cell line (NCI-H460), human lung cancer cell line (A549), human pancreatic cancer cell line (MIAPACA), human promyelocytic leukemia cell line (HL60), human chronic myeloid lineage The leukemia cell line (K562), human prostate cancer cell (DU-145), and the like were tested for proliferation inhibitory activity, specifically, the inhibitory activity of the compound at a concentration of 50 μM and 100 μM, as shown in Table 2.

Table 2. Proliferation inhibitory activity of the compounds of the present invention on different tumor cell lines (Inh%)

The above results indicate that the compound of the present invention has a good inhibitory effect on cell proliferation of liver cancer, hepatoblastoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer and leukemia, and can be used for preparing a medicament for treating and/or preventing tumors. .

In summary, the novel compound of the formula I of the present invention not only has good inhibitory activity against SIRT2, but also has a good inhibitory effect on tumors, has good medicinal potential, and provides a new drug for clinical use. At the same time, the novel compound of the invention has simple preparation method, mild reaction condition, convenient operation and control, low energy consumption, high yield and low cost, and is suitable for industrial production.

Claims (9)

1. a compound of formula I or a pharmaceutically acceptable salt, crystalline form or solvate thereof:

   

   among them,

   Z is selected from

   

   R _{1 is} selected from H or

   

   X is selected from

   

   

   R _{4 is} selected from aryl, heteroaryl, substituted aryl, substituted heteroaryl or

   

   The substituents of the substituted aryl group and the substituted heteroaryl group are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group,

   

   

   Halogen, hydroxy, thiol, ether, ester, amino or nitro;

   R _4a and R _4b are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, aryl, heteroaryl or C ₃ -C ₆ cycloalkyl ;

   R _{2 is} selected from

   

   or

   

   R _2a to R _2f are each independently selected from H, a hydroxyl group, a halogen, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group or a phenyl group;

   R _{3 is} selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or

   

   Y is selected from

   

   

   R _{5 is} selected from aryl, heteroaryl, substituted aryl or substituted heteroaryl, and the substituents of the substituted aryl and substituted heteroaryl are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, halogen, hydroxy, decyl, ether, ester, amino, nitro, amido or aminoacyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt, crystalline form or solvate thereof, wherein the compound is

   
3. The compound according to claim 2, or a pharmaceutically acceptable salt, crystalline form or solvate thereof, which is characterized in that:

   In R ₄ , the aryl group is a phenyl group or a naphthyl group, and the heteroaryl group is a pyridyl group, a furyl group, a thienyl group, a quinolyl group, a carbazolyl group or a quinolyl group, the substituted aryl group and the substituent. The substituents of the heteroaryl group are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group,

   

   R _4a and R _4b are each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl, phenyl or thienyl;

   In R ₂ , R _2a , R _2c and R _2f are each independently selected from H, a hydroxyl group, a halogen, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkyl group or a phenyl group. , R _2b , R _2d , and R _2e are each H.
4. The compound according to claim 2, or a pharmaceutically acceptable salt, crystalline form or solvate thereof, which is characterized in that:

   R _{5 is} selected from the group consisting of phenyl, pyridyl, furyl, thienyl, substituted phenyl, substituted pyridyl, substituted furyl or substituted thienyl; substituted phenyl, substituted pyridyl, substituted furanyl and substituted thienyl The substituents are each independently selected from a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group or a C ₁ -C ₄ haloalkyl group.
5. The compound according to claim 2, or a pharmaceutically acceptable salt, crystalline form or solvate thereof, wherein the compound is

   

   

   
6. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, crystal form or solvate thereof, for the preparation of an inhibitor of a sirtuin-2 related protein.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, crystalline form or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of a tumor.
8. The use according to claim 7, characterized in that the tumor is liver cancer, hepatoblastoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer or leukemia.
9. A pharmaceutical composition for treating and/or preventing a tumor, which comprises the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, a crystalline form or a solvate thereof as an active ingredient. And a preparation prepared by using a pharmaceutically acceptable excipient.

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