A diaryl saturated or unsaturated ketone compound, a preparation method thereof, an ALK4 inhibitor and application thereof

Abstract

The application provides a diaryl unsaturated or saturated ketone compound and a preparation method, ALK4 inhibitor and application thereof, a chemical structural formula of which is shown in the following; the diaryl saturated or unsaturated ketone compound is used for preparing the ALK4 inhibitor. The diaryl saturated or unsaturated ketone compound provided by the application has multiple R1-R2 substituents, and the compound with the novel structure can fill the gap in the development of systematic ALK4 inhibitors. The ALK4 inhibitor of the diaryl saturated or unsaturated ketone compound has excellent inhibition effect, and test results show that the compound after specific modification can specifically target ALK4, and has significant advantages in disease treatment.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a diaryl saturated or unsaturated ketone compound, its preparation method, ALK4 inhibitor, and its applications. Background Technology

[0002] ALK4 (Activin Receptor-Like Kinase 4) is a key receptor kinase in the TGF-β superfamily signaling pathway, primarily involved in Activin / Nodal signal transduction and regulating cell proliferation, differentiation, apoptosis, and embryonic development. ALK4 inhibitors, by selectively blocking the kinase activity of ALK4, have potential therapeutic value in cancer, fibrotic diseases, and metabolic disorders. Current ALK inhibitors mainly face two major challenges: drug resistance (especially "compound mutations") and treatment safety (off-target effects). Their specific iterative progress and problems are as follows:

[0003] Therefore, the core objective of developing next-generation inhibitors is to overcome drug resistance, improve safety, and enhance efficacy on the central nervous system, achieving brain penetration. Designing and synthesizing ALK4 inhibitors to address these shortcomings has significant research value in biomedicine. Summary of the Invention

[0004] The technical problem this invention aims to solve is the lack of research on ALK4 inhibitors in the prior art. Therefore, this invention provides a diaryl saturated or unsaturated ketone compound, its preparation method, an ALK4 inhibitor, and its applications.

[0005] To achieve the above objectives, the present invention provides a diaryl saturated or unsaturated ketone compound comprising the following chemical formula or its isomers:

[0006] Wherein: R1 and R2 are selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)(C1-C3 alkyl), -C (=O)(C1-C3 alkyl), hydroxyl-substituted C1-C3 alkyl, 3-8 membered heterocyclic group, C1-C3 alkyl-substituted 3-8 membered heterocyclic group or halogen-substituted C1-C3 alkyl; The aromatic rings connected to R1 and R2 include one or more of the following: phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, furanyl, pyrrolithyl, hexahydropyridyl, tetrahydropyranyl, tetrahydronaphthyl, furanyl, thiophenyl, pyrrolithyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiophenyl, indolyl, inzolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyrimidinyl, pyridopyrimidinyl, pyridopyridyl, purine, pteridinyl, imidazothiazolyl, imidazopyridazinyl, or pyrazopyrimidinyl. XR3 is O, or when X is N, R3 is OMe or OH.

[0007] Preferably, the chemical structural formula of the compound is any one of formulas A, B, and C: .

[0008] Under the same technical concept, the present invention also provides a method for preparing a diaryl unsaturated or saturated ketone compound, specifically comprising: (1) Add an alkaline salt to raw material I and raw material II, wherein the alkaline salt includes at least one of potassium carbonate, potassium hydroxide or sodium hydride, and then add a solvent, wherein the solvent includes at least one of methanol, ethanol, dimethylformamide or acetonitrile. React until the raw material disappears as monitored by TLC, concentrate and extract, adjust the pH to 5-6, and extract and dry to obtain a solid precursor. (2) The solid precursor was dry-loaded, purified by silica gel column chromatography, and separated by chromatography. The eluent for chromatography was a mixture of dichloromethane and ethanol. After the liquid was evaporated to obtain the solid, dichloromethane was added to dissolve the solid, and then petroleum ether was added to precipitate the solid. The solid was filtered and washed with a mixture of dichloromethane and petroleum ether to obtain a diaryl unsaturated or saturated ketone compound.

[0009] Raw material I and raw material II contain R1 and R2 respectively: R1 and R2 are selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)(C1-C3 alkyl), -C(=O)(C1-C3 alkyl), hydroxyl-substituted C1-C3 alkyl, 3-8 membered heterocyclic group, C1-C3 alkyl-substituted 3-8 membered heterocyclic group or halogen-substituted C1-C3 alkyl; R1 and R2 are linked to an aromatic ring, which includes one or more of the following aromatic rings: phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, furanyl, pyrroleyl, hexahydropyridyl, tetrahydropyranyl, tetrahydronaphthyl, furanyl, thiopheneyl, pyrroleyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiopheneyl, indolyl, inzolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyrimidinyl, pyridopyrimidinyl, pyridopyridinyl, purine, pteridinyl, imidazothiazolyl, imidazopyridazinyl, or pyrazopyrimidinyl.

[0010] Taking a compound with the chemical structural formula as shown in formula C as an example, its synthetic route includes the following formula: .

[0011] Condition A includes: (1) Add K2CO3 and CH3OH, react, rotary evaporate, adjust pH to 5-6, extract and dry to obtain solid precursor; (2) Purification by silica gel column chromatography: CH3OH was added; after the liquid was evaporated to dryness and solid was obtained, DCM was added to dissolve the solid, PE was added, the precipitate was precipitated, filtered, and washed with a DCM:PE = 1:3 mixed solution to obtain diaryl unsaturated or saturated ketone compounds.

[0012] In raw material I and raw material II, R1 and R2 are selected from one or more of H, OH, CH3 or halogens, and are subjected to di-substitution or poly-substitution respectively; Aromatic rings include one or more of benzene rings, naphthalene rings, pyridine, quinoline, furan, or pyrrole.

[0013] Preferably, the preparation method further includes step (3), using the diaryl unsaturated or saturated ketone compound synthesized in step (2) as an intermediate, adding at least one of trimethyl sulfoxide, p-toluenesulfonyl hydrazine or methoxyamine hydrochloride, and reacting at 50-100 °C; after the reaction is complete, the mixture is concentrated, extracted and dried, and purified by silica gel column chromatography to obtain the diaryl unsaturated or saturated ketone compound.

[0014] Preferably, before adding trimethyl sulfoxide, p-toluenesulfonyl hydrazine or methoxyamine hydrochloride, an alkaline salt is added, the alkaline salt including at least one of potassium carbonate, potassium hydroxide or sodium hydride, and the molar ratio of the amount added to the intermediate is 1-6:1; a solvent is added, the solvent including at least one of 1,4-dioxane, DMF or ethanol; The molar ratio of raw material I and raw material II is 1:1. The molar ratio of potassium carbonate, potassium hydroxide, or sodium hydride to raw material I is 5-20:1; The amount of solvent added is from 0.1 molar concentration to 1 molar concentration.

[0015] Under the same technical concept, the present invention also provides an ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound, wherein the diaryl saturated or unsaturated ketone compound is used to prepare the ALK4 inhibitor.

[0016] Preferably, the ALK4 inhibitor further includes the diaryl saturated or unsaturated ketone compound and its pharmacologically acceptable excipients or carriers.

[0017] Preferably, the ALK4 inhibitor is used to prevent or treat ALK4 receptor-mediated diseases including any one of melanoma, lung cancer, or breast cancer.

[0018] Under the same technical concept, the present invention also provides the application of an ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound, wherein the ALK4 inhibitor is applied in diseases in which the ALK4 target is a key pathogenic signaling pathway.

[0019] Preferably, the ALK4 inhibitor can inhibit ALK4 enzyme activity and cell activity, tissue activity and model animal activity based on the enzyme function in the concentration range of 1 mg / kg to 100 mg / kg.

[0020] The above-described solution of the present invention has the following beneficial effects: (1) The diaryl saturated or unsaturated ketone compounds provided by the present invention have multiple R1-R2 substituents. The compounds with this novel structure can fill the gap in the development of systematic ALK4 inhibitors. (2) The ALK4 inhibitors of the diaryl saturated or unsaturated ketone compounds in this invention have excellent inhibitory effects. The test results show that the specially modified compounds can specifically target ALK4 and have significant advantages in the treatment of the disease. (3) The synthesis method of the present invention is simple and convenient, and easy to scale up and process for production. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments or the prior art will be briefly introduced below. Obviously, the following drawings are some embodiments of the present invention. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0022] Figure 1 A schematic diagram of the structure of a diaryl saturated or unsaturated ketone compound provided by the present invention; Figure 2This is an activity inhibition diagram of the TZY29 diaryl saturated or unsaturated ketone compound provided in the embodiments of the present invention for ALK4 inhibition; Figure 3 , 4 The nuclear magnetic resonance spectrum provided by the present invention is exemplified by Example 21. Detailed Implementation

[0023] To make the technical problems, solutions, and advantages of this invention clearer, a detailed description will be provided below with reference to the accompanying drawings and specific embodiments. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0024] In the description of this invention, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the invention. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0025] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a locking connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0026] Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0027] Figure 1 A schematic diagram of the structure of a diaryl saturated or unsaturated ketone compound provided by the present invention; The preparation method of this application embodiment is as follows;

[0028] The method for preparing diaryl saturated or unsaturated ketone compounds provided in this embodiment specifically includes: (1) Take I (0.25 mmol), II (0.25 mmol), and potassium carbonate (250 mg, 1.80 mmol) into a 25 ml round-bottom flask, add methanol (1 ml), and stir at room temperature. The reaction system gradually precipitates, and the reaction is complete as monitored by TLC. The reactants have completely reacted. After removing most of the solvent with a rotary evaporator, add hydrochloric acid to adjust the pH to 5-6, extract three times with dichloromethane, collect the organic layer, add anhydrous sodium sulfate to dry, and then evaporate to dryness to obtain the solid.

[0029] (2) Dry loading, silica gel column chromatography purification, eluent is dichloromethane:methanol=100:1. After the liquid is evaporated to dryness to obtain solid, dichloromethane (2 ml) is added to dissolve the solid, then petroleum ether (6 ml) is added to precipitate the solid. After filtration, the solid is washed 3 times with a dichloromethane:petroleum ether =1:3 mixed solution, and the filter residue is the product.

[0030] Example 1: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 1 is:

[0031] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0032] Yield: 82%. NMR results: 1 H NMR (500 MHz, DMSO- d 6) δ 10.33 (s, 1H), 7.98– 7.92 (m, 2H), 7.88 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.43 (s,1H), 7.33 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ 187.72,160.84, 158.11, 143.47, 134.52, 132.10, 131.13, 129.56, 129.14, 129.07,124.77, 121.92, 121.73, 114.85, 110.24, 55.95, 16.63, 16.37. HRMS (ESI), m / zcalculated for C 18 H 18 O3(M+H) + : 283.1334, found: 283.1337 Example 2: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 2 is:

[0033] ( E )-1-(4-hydroxy-2-methylphenyl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 2-methyl-4-hydroxyacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0034] Yield: 56%. 1 H NMR (500 MHz, Chloroform- d ) δ 7.54 (d, J = 8.0 Hz, 1H), 7.49(d, J = 15.9 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 15.9 Hz, 1H), 7.09 (dd, J = 7.7, 1.6 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.76 – 6.71 (m, 2H), 5.51(s, 1H), 3.87 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 198.92, 164.16, 162.08, 148.97, 144.81, 137.82, 135.47,134.45, 133.78, 133.56, 128.75, 124.86, 121.96, 115.90, 112.77, 58.43, 23.97,18.99.HRMS (ESI), m / z calculated for C 18 H 18 O3(M+H) + : 283.1334, found: 283.1337 Example 3: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 3 is:

[0035] ( E )-1-(3-((diethylamino)methyl)-4-hydroxyphenyl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-(N,N'-diethylamine)methyl-4-hydroxyacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0036] Yield: 63%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.91 (dd, J = 8.5, 2.3 Hz,1H), 7.78 – 7.76 (m, 1H), 7.76 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 15.6 Hz, 1H),7.19 – 7.15 (m, 2H), 7.06 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.87(s, 2H), 2.66 (q, J = 7.2 Hz, 4H), 2.25 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H). 13 C NMR (126 MHz, DMSO-) d6) δ 187.48, 163.85, 158.10, 143.55, 134.49, 131.13, 130.36,130.18, 129.09, 129.04, 123.16, 121.92, 121.58, 116.00, 110.28, 55.95, 55.57,46.18, 16.66, 11.36. HRMS (ESI), m / z calculated for C 22 H 27 NO3(M+H) + 354.2069, found: 354.2072 Example 4: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 4 is:

[0037] ( E )-1-(3-bromo-4-methoxyphenyl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-bromo-4-methoxyacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0038] The yield was 79.4 mg, with a yield of 88%. 1 H NMR (500 MHz, Chloroform- d ) δ 8.20 (t, J = 1.8Hz, 1H), 7.96 (dt, J = 8.6, 1.7 Hz, 1H), 7.73 (d, J = 15.5 Hz, 1H), 7.38 (d, J =15.5 Hz, 1H), 7.15 – 7.10 (m, 2H), 7.02 (s, 1H), 6.95 (d, J = 8.6 Hz, 1H), 3.94(s, 3H), 3.86 (s, 3H), 2.21 (s, 3H). 13 C NMR (126 MHz, Chloroform- d) δ 188.49,159.82, 158.36, 145.85, 134.26, 133.97, 132.44, 131.32, 130.70, 130.06,121.50, 120.57, 112.26, 111.60, 109.73, 56.79, 55.70, 16.66. HRMS (ESI), m / zcalculated for C 18 H 17 BrO3(M+H) + : 361.0439, found: 361.0440 Example 5: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 5 is:

[0039] ( E )-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3,4-ethylenedimethylacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0040] Yield: 65%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.89 (d, J = 15.5 Hz, 1H), 7.74 (dd, J = 8.4, 2.1 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 15.5 Hz, 1H), 7.46(d, J = 1.6 Hz, 1H), 7.33 (dd, J = 7.6, 1.6 Hz, 1H), 7.21 (dd, J = 7.5, 1.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.38 – 4.33 (m, 2H), 4.34 – 4.28 (m, 2H), 3.89 (s, 3H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO- d 6) δ 187.65, 158.10, 148.40,144.32, 143.82, 134.35, 131.70, 131.14, 129.36, 123.11, 122.44, 121.32,118.03, 117.64, 110.08, 65.05, 64.39, 55.98, 16.70. HRMS (ESI), m / zcalculated for C 19 H 18 O4(M+H) + 311.1283, found: 311.1288 Example 6: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 6 is:

[0041] ( E )-1-(benzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3,4-methylenedioxyacetophenone, and the added raw material II is 3-methoxy-4-methylbenzaldehyde.

[0042] 1 H NMR (400 MHz, Chloroform- d ) δ 7.76 (d, J = 15.6 Hz, 1H), 7.65 (dd, J =8.2, 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 15.6 Hz, 1H), 7.16 (d, J =1.0 Hz, 2H), 7.05 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.06 (s, 2H), 3.89 (s, 3H), 2.25 (s, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 188.43, 158.02, 151.62,148.27, 144.76, 133.89, 133.12, 130.99, 130.05, 124.62, 121.04, 120.78,109.21, 108.48, 107.91, 101.86, 55.37, 16.43. HRMS (ESI), m / z calculated forC 18 H 16 O4(M+H) + : 297.1127, found: 297.1135 Example 7: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 7 is:

[0043] ( E )-3-(4-chlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 4-chlorobenzaldehyde.

[0044] Yield: 34%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.90 (d, J = 2.2 Hz, 1H), 7.86(dd, J = 8.5, 2.3 Hz, 1H), 7.78 (d, J = 15.7 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 15.7 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 2.26 (s, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 190.62, 162.37, 143.25, 137.14,135.32, 133.09, 131.02, 130.63, 130.19, 130.04, 126.30, 123.81, 115.41,16.19. HRMS (ESI), m / z calculated for C 16 H 13 ClO2(M+H) + : 273.0682, found:273.0684 Example 8: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 8 is:

[0045] ( E )-3-(4-aminophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 4-aminobenzaldehyde.

[0046] Yield: 32%. 1 H NMR (400 MHz, Methanol- d 4) δ 7.85 (dd, J = 2.2, 0.9 Hz, 1H), 7.81 (dd, J = 8.4, 2.3 Hz, 1H), 7.67 (d, J = 15.4 Hz, 1H), 7.53 – 7.44 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 6.74 – 6.66 (m, 2H), 2.25 (s, 3H). 13 C NMR (101 MHz, Methanol-) d 4) δ 191.46, 161.91, 152.79, 146.65, 132.77, 131.73, 131.26,129.64, 126.04, 125.12, 117.29, 115.62, 115.33, 16.23. HRMS (ESI), m / zcalculated for C 16 H 15 NO2(M+H)+ : 254.1181, found: 254.1185 Example 9: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 9 is:

[0047] ( E )-3-(3-(difluoromethoxy)phenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 3-difluoromethoxybenzaldehyde.

[0048] Yield: 54%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.98 (d, J = 2.2 Hz, 1H), 7.98 (d, J =15.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.72 (dt, J = 7.7, 1.1 Hz, 1H), 7.66 (d, J = 15.6 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.49 –7.12 (m, 1H), 7.24 (dd, J = 8.2, 2.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 2.21 (s,3H).HRMS (ESI), m / z calculated for C 17 H 14 F2O3(M+H) + : 305.0989, found: 305.0993 Example 10: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 10 is:

[0049] ( E)-1-(4-hydroxy-3-methylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 4-methoxybenzaldehyde.

[0050] Yield: 67%. 1 H NMR (400 MHz, Methanol- d 4) δ 7.89 (dd, J = 2.3, 0.9 Hz, 1H), 7.84 (dd, J = 8.4, 2.3 Hz, 1H), 7.72 (d, J = 15.5 Hz, 1H), 7.74 – 7.66 (m, 2H), 7.63 (d, J = 15.5 Hz, 1H), 7.03 – 6.95 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.85(s, 3H), 2.26 (s, 3H). 13 C NMR (101 MHz, Methanol- d 4) δ 181.44, 153.58, 152.46,135.34, 123.26, 121.74, 121.24, 120.16, 119.44, 116.49, 110.86, 105.78,105.68, 46.20, 6.52. HRMS (ESI), m / z calculated for C 17 H 16 O3(M+H) + : 269.1177, found: 269.1184 Example 11: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 11 is:

[0051] ( E )-3-(3-bromo-4-methoxyphenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 3-bromo-4-methoxybenzaldehyde.

[0052] Yield: 43%. 1 H NMR (400 MHz, Methanol- d 4) δ 8.00 (d, J = 15.3, 2.2 Hz, 1H), 7.91 (dd, J = 2.3, 0.9 Hz, 1H), 7.86 (dd, J = 8.4, 2.3 Hz, 1H), 7.70 (dd, J = 8.6, 2.2 Hz, 1H), 7.68 (d, J = 15.5 Hz, 1H), 7.63 (d, J = 15.2 Hz, 1H), 7.10 (d, J = 8.6Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.26 (s, 3H). HRMS (ESI), m / zcalculated for C 17 H 15 BrO3(M+H) + 347.0283, found: 347.0293 Example 12: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 12 is:

[0053] ( E )-3-(3,4-dimethoxyphenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 3,4-dimethoxybenzaldehyde.

[0054] Yield 54%. 1H NMR (500 MHz, Methanol-d4) δ 7.90 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.5, 2.3 Hz, 1H), 7.69 (d, J = 15.5 Hz, 1H), 7.63 (d, J = 15.5Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 (d, J= 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.26 (s,3H). 13 C NMR (126 MHz, Methanol- d 4) δ 191.18, 162.03, 152.91, 150.78, 145.35,132.99, 130.96, 129.88, 129.59, 126.13, 124.60, 120.87, 115.36, 112.66,111.89, 56.60, 56.44, 16.19. HRMS (ESI), m / z calculated for C 18 H 18 O4(M+H) + :299.1283, found: 299.1286 Example 13: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 13 is:

[0055] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(5-methylfuran-2-yl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 4-methylfuranaldehyde.

[0056] Yield: 60%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.32 (s, 1H), 7.87 – 7.82 (m, 1H), 7.79 (dd, J= 8.4, 2.3 Hz, 1H), 7.44 (d, J = 15.3 Hz, 1H), 7.39 (d, J = 15.4Hz, 1H), 6.94 (d, J = 3.3 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.31 (dd, J = 3.4, 1.2Hz, 1H), 2.38 (s, 3H), 2.19 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 187.07,160.74, 155.96, 150.49, 131.79, 129.73, 129.50, 128.76, 124.80, 118.58,117.64, 114.95, 110.09, 16.33, 14.19. HRMS (ESI), m / z calculated for C 15 H 14 O3(M+H) + : 243.1021, found: 243.1026 Example 14: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 14 is:

[0057] ( E )-3-(6-aminopyridin-3-yl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-aminopyridine-3-carboxaldehyde.

[0058] Yield: 72%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.27 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 8.8, 2.4 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.86 (dd,J = 8.4, 2.3 Hz, 1H), 7.65 (d, J = 15.4 Hz, 1H), 7.56 (d, J = 15.4 Hz, 1H), 6.88 (d, J = 8.4Hz, 1H), 6.62 (s, 2H), 6.50 (d, J = 8.7 Hz, 1H), 2.19 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 187.31, 161.51, 160.47, 151.94, 141.34, 136.08, 131.97, 129.84,128.76, 124.55, 119.73, 117.33, 114.79, 108.67, 16.39. HRMS (ESI), m / zcalculated for C 15 H 14 N2O2(M+H) + : 255.1133, found: 255.1138 Example 15: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 15 is:

[0059] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(6-methylpyridin-3-yl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-methylpyridine-3-carboxaldehyde.

[0060] Yield: 47%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.38 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 8.1, 2.3 Hz, 1H), 8.02 – 7.97 (m, 2H), 7.92 (dd, J = 8.4, 2.3Hz, 1H), 7.67 (d, J= 15.6 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.4 Hz,1H), 2.52 (s, 3H), 2.21 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 187.36, 161.01,160.21, 150.29, 139.71, 135.52, 132.30, 129.26, 129.21, 128.45, 124.80,123.73, 123.35, 114.92, 24.57, 16.37. HRMS (ESI), m / z calculated for C 16 H 15 NO2(M+H) + : 254.1181, found: 254.1189 Example 16: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 16 is:

[0061] ( E )-3-(benzo[b]thiophen-2-yl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-benzothiaphenol-formaldehyde.

[0062] Yield: 68%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.42 (s, 1H), 8.01 – 7.91 (m,4H), 7.91 – 7.84 (m, 2H), 7.58 (d, J = 15.2 Hz, 1H), 7.48 – 7.37 (m, 2H), 6.93(d, J = 8.4 Hz, 1H), 2.21 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 186.95, 161.13,140.57, 140.07, 139.95, 136.22, 132.11, 130.29, 129.15, 129.11, 126.89,125.55, 125.03, 124.96, 123.63, 123.17, 115.01, 16.36. HRMS (ESI), m / zcalculated for C 18 H 14 O2S(M+H) + : 295.0793, found: 295.0798 Example 17: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 17 is:

[0063] ( E )-3-(benzofuran-2-yl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-benzofuran-formaldehyde.

[0064] Yield: 43%. 1 H NMR (500 MHz, DMSO- d 6) δ 10.43 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 8.4, 2.3 Hz, 1H), 7.77 (d, J = 15.3 Hz, 1H), 7.72 (d, J = 7.7Hz, 1H), 7.69 – 7.61 (m, 2H), 7.46 (s, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 2.21 (s, 3H). 13 C NMR (126 MHz, DMSO- d6)δ 186.93, 161.17, 155.37, 153.53, 132.09, 129.85, 129.15, 129.13, 128.75,127.21, 125.00, 124.03, 122.56, 122.47, 115.08, 112.77, 111.80, 16.34. HRMS(ESI), m / z calculated for C 18 H 14 O3(M+H) + : 279.1021, found: 279.1024 Example 18: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 18 is:

[0065] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(quinolin-2-yl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-quinoline carboxaldehyde.

[0066] Yield: 73%. 1 H NMR (500 MHz, DMSO- d 6) δ 10.47 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 15.6 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H),8.04 – 7.98 (m, 2H), 7.95 (dd, J = 8.4, 2.3 Hz, 1H), 7.83 – 7.80 (m, 1H),7.78(d, J = 15.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 187.27, 160.85, 153.95, 147.66, 142.16,136.91, 131.89, 130.17, 129.24, 128.94, 128.67, 127.90, 127.79, 127.38,127.23, 124.56, 120.84, 114.62, 15.93.HRMS (ESI), m / z calculated for C 19 H 15 NO2(M+H) + : 290.1181, found: 290.1190 Example 19: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 19 is:

[0067] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2-naphthoaldehyde.

[0068] Yield: 61%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.12 (dd, J = 8.7, 1.7 Hz, 1H), 8.06 (d, J = 15.8 Hz, 1H), 8.04 – 7.91 (m,5H), 7.85 (d, J = 15.5 Hz, 1H), 7.60 – 7.51 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 187.62, 160.97, 143.01, 134.25,133.47, 133.08, 132.28, 130.75, 129.49, 129.19, 128.93, 128.87, 128.17,127.73, 127.20, 124.90, 124.82, 122.96, 114.96, 16.40. HRMS (ESI), m / zcalculated for C 20 H 16 O2(M+H) + : 289.1228, found: 289.1230 Example 20: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 20 is:

[0069] ( E )-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 3,4-ethylenediethylenebenzaldehyde.

[0070] Yield: 41%. 1 H NMR (500 MHz, DMSO- d 6) δ 10.31 (s, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 8.5, 2.3 Hz, 1H), 7.76 (d, J = 15.5 Hz, 1H), 7.57 (d, J = 15.5Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 6.90 (t, J = 8.6Hz, 2H), 4.31 – 4.26 (m, 4H), 2.20 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ187.54, 160.74, 145.99, 144.06, 142.83, 132.15, 129.60, 129.00, 128.92,124.66, 123.22, 120.72, 117.84, 117.45, 114.86, 64.84, 64.43, 16.35. HRMS(ESI), m / z calculated for C 18 H 16 O4(M+H) + : 297.1127, found: 297.1136 Example 21: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 21 is:

[0071] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(4-methoxynaphthalen-1-yl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 4-methoxynaphthaldehyde. Figure 3 , 4 The nuclear magnetic resonance spectrum provided by the present invention is exemplified by Example 21.

[0072] Yield: 41%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.33 (s, 1H), 8.44 (d, J = 15.2 Hz,1H), 8.27 – 8.23 ​​(m, 3H), 7.99 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, 1H), 7.90 (d, J = 15.2 Hz, 1H), 7.68 (ddd, J = 8.4, 6.7, 1.4 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 4.06(s, 3H), 2.22 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 187.08, 160.34,156.85, 138.42, 132.22, 131.69, 129.17, 128.59, 127.70, 126.77, 125.64,124.82, 124.29, 123.72, 122.84, 122.24, 122.05, 114.46, 104.62, 55.94,15.93.HRMS (ESI), m / z calculated for C 21 H 18 O3(M+H) + 319.1334, found: 319.1335 Example 22: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 22 is:

[0073] ( E )-3-(benzo[d][1,3]dioxol-4-yl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one Using the aforementioned method for preparing diaryl saturated or unsaturated ketone compounds, the added raw material I is 3-methyl-4-hydroxyacetophenone, and the added raw material II is 2,3-methylenedioxybenzaldehyde.

[0074] Yield: 96%. 1 H NMR (400 MHz, Methanol- d 4) δ 7.83 (d, J = 15.7 Hz, 1H), 7.83(d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.66 (d, J = 15.7 Hz, 1H), 7.09 (dd, J = 6.3, 2.9 Hz, 1H), 6.91 – 6.86 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 2.25 (s, 3H).13 C NMR (101 MHz, Methanol- d 4) δ 190.90, 162.33,149.51, 148.13, 139.02, 132.93, 130.67, 129.93, 126.29, 125.27, 123.77,123.07, 119.21, 115.38, 110.86, 103.01, 16.23. HRMS (ESI), m / z calculated forC 17 H 14 O4(M+H) + : 283.0970, found: 283.0978 Example 23: The structural formula of the diaryl saturated or unsaturated ketone compound provided in this embodiment is shown in Example 23 below;

[0075] ( E )-3-(4-fluoro-3-methoxyphenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one The synthesis method of Example 23 is as follows:

[0076] Take 37.5 mg of 4-hydroxy-2-methylacetophenone (38.5 mg, 0.25 mmol) and 3-methoxy-4-fluorobenzaldehyde (38.5 mg, 0.25 mmol) and KOH (250 mg, 4.45 mmol) in a 25 ml round-bottom flask, add 1 ml of H2O and stir at 50 °C.

[0077] TLC monitoring showed the reaction was complete, indicating the reactants had completely reacted. EA was extracted three times with H₂O, the pH was adjusted to 5-6, the collected organic layer was retained, dried with anhydrous sodium sulfate, filtered, and the solution was removed by rotary evaporation to obtain the solid precursor. The solid precursor was dry-loaded and purified by silica gel column chromatography, followed by separation by methanol-dichloromethane column chromatography. The liquid was evaporated to dryness to obtain the solid, which was then dissolved in dichloromethane. Petroleum ether was added to precipitate the solid, which was then filtered, washed, and the washing eluent was PE:EA:DCM = 10:1:1. 30.2 mg of product was obtained, with a yield of 42%.

[0078] The NMR spectrum results for Example 23 are as follows: 1H NMR (500 MHz, DMSO- d 6) δ 10.33 (s, 1H), 7.96 – 7.91 (m, 2H), 7.88(d, J = 15.5 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.64 (d, J = 15.6 Hz, 1H), 7.43 (ddd, J = 8.4, 4.5, 2.0 Hz, 1H), 7.27 (dd, J = 11.3, 8.4 Hz, 1H), 6.92 (d, J =8.3 Hz, 1H), 3.94 (s, 3H), 2.21 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 187.64,160.92, 154.19, 152.22, 147.99, 147.91, 142.26, 132.56, 132.53, 132.15,129.44, 129.20, 124.81, 122.80, 122.74, 122.68, 122.66, 116.72, 116.57,114.87, 113.92, 113.90, 56.73, 16.36. 19 F NMR (471 MHz, DMSO- d 6) δ -131.86. HRMS (ESI), m / z calculated forC 17 H 15 FO3(M+H) + : 287.1083, found: 287.1085 Example 24: The structural formula of the diaryl saturated or unsaturated ketone compound provided in this embodiment is as follows:

[0079] ( E )-1-(4-hydroxy-3-methylphenyl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one The synthesis method of Example 24 is as follows:

[0080] 4-Hydroxy-2-methylacetophenone (37.5 mg, 0.25 mmol) and 5-methyl-2-thiophenecarboxaldehyde (31.5 mg, 0.25 mmol) and KOH (250 mg, 4.45 mmol) were placed in a 25 mL round-bottom flask, and CH3OH (1 mL) was added. The mixture was then stirred at 50 °C. The reaction was monitored by TLC until complete, indicating that the starting material had completely reacted. After removing most of the solvent using a rotary evaporator, DCM was added to dissolve the solvent completely. The mixture was then concentrated and extracted. The pH was adjusted to 5-6, and the extract was dried to obtain the solid precursor.

[0081] Dry loading was performed, followed by silica gel column chromatography purification, and separation by methanol-dichloromethane column chromatography. The liquid was evaporated to dryness to obtain a solid, which was then dissolved in dichloromethane. Petroleum ether was added to precipitate the solid, which was then filtered, washed, and the eluent was PE:EA = 10:1. 52.2 mg of the product from Example 24 was obtained, with a yield of 81%.

[0082] The NMR spectrum results for Example 24 are as follows: 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.4, 2.3 Hz, 1H), 7.76 (d, J = 15.2 Hz, 1H), 7.44 (d, J = 3.6Hz, 1H), 7.39 (d, J = 15.3 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.88 (d, J =4.0 Hz, 1H), 2.50 (s, 3H), 2.20 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 186.60,160.34, HRMS (ESI), m / z calculated for C 15 H 14 O2S(M+H) + : 259.0793, found: 259.0794 Example 25: The chemical formula of the diaryl unsaturated or saturated ketone compound in Example 25 is:

[0083] ( E )-3-(3-methoxy-4-methylphenyl)-1-(5-methylthiophen-2-yl)prop-2-en-1-one The preparation method of diaryl saturated or unsaturated ketone compounds as in Example 1 was adopted, wherein the added raw material I was 4-methylthiophene-1-ethyl ketone and the added raw material II was 3-methoxy-4-methylbenzaldehyde.

[0084] Yield: 22%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.34 (d, J = 15.5 Hz, 1H), 7.27 (q, J = 1.1 Hz, 1H), 7.18(d, J = 1.3 Hz, 2H), 7.05 (s, 1H), 3.90 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 2.25 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 182.09, 158.01, 145.14, 144.32,139.02, 133.71, 133.66, 131.00, 130.18, 129.67, 121.01, 120.65, 109.40,55.38, 16.47, 15.71. HRMS (ESI), m / z calculated for C 16 H 16 O2S (M+H) + : 273.0949,found: 273.0949 Example 26: The structural formula of the diaryl saturated or unsaturated ketone compound provided in this embodiment is shown in Example 26 below; The synthesis method of Example 26 is as follows:

[0085] After sealing 10 ml of the tube in an anhydrous and oxygen-free environment, add the diaryl unsaturated or saturated ketone compound (100 mg, 0.35 mmol) from Example 1, p-toluenesulfonyl hydrazine (72 mg, 0.39 mmol), K2CO3 (72 mg, 1.5 mmol), and replace with nitrogen three times. Then add 1,4-dioxane (0.7 ml) under nitrogen purging and react at 100 °C.

[0086] The reaction was allowed to proceed overnight, and TLC was used to confirm complete reaction. The product was extracted three times with EA and H₂O, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and then removed by rotary evaporation. Purification was performed by silica gel column chromatography with a PE:EA ratio of 15:1 as the eluent. 51.7 mg of product was obtained, representing a yield of 52%.

[0087] 1-(4-hydroxy-3-methylphenyl)-3-(3-methoxy-4-methylphenyl)propan-1-one 1 H NMR (400 MHz, Chloroform- d ) δ 8.22 (d, J = 2.2 Hz, 1H), 8.17 (dd, J =8.3, 2.3 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (dd, J =7.5, 1.6 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.63 (s, 1H), 4.24 (s, 3H), 3.67(dd, J = 8.7, 6.8 Hz, 2H), 3.45 (dd, J = 8.7, 6.8 Hz, 2H), 2.71 (s, 3H), 2.61 (s, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 198.98, 158.74, 157.72, 140.24, 131.72,130.61, 129.75, 128.28, 124.32, 124.21, 119.98, 114.79, 110.39, 55.29, 40.42,30.57, 15.88, 15.83. HRMS (ESI), m / z calculated for C 18 H 20 O3(M+H) + : 285.1490, found: 285.1491 Example 27: The structural formula of the diaryl saturated or unsaturated ketone compound provided in this embodiment is shown in Example 27 below; (4-hydroxy-3-methylphenyl)(2-(3-methoxy-4-methylphenyl)cyclopropyl)methanone 1 H NMR (400 MHz, Chloroform- d ) δ 7.83 (dd, J = 2.3, 0.9 Hz, 1H), 7.79(dd, J = 8.3, 2.3 Hz, 1H), 7.06 (dd, J = 7.5, 0.9 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H), 6.65 (dd, J = 7.5, 1.7 Hz, 1H), 5.42 (s, 1H), 3.83(s, 3H), 2.81 (ddd, J = 8.1, 5.3, 4.0 Hz, 1H), 2.65 (ddd, J = 9.0, 6.6, 4.0 Hz,1H), 2.29 (s, 3H), 2.19 (s, 3H), 1.85 (ddd, J = 9.2, 5.3, 4.1 Hz, 1H), 1.51(ddd, J = 8.1, 6.6, 4.1 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d ) δ 197.32,158.21, 157.75, 139.55, 131.61, 130.88, 130.61, 128.28, 124.95, 123.96,117.32, 114.72, 108.84, 55.31, 29.76, 28.95, 18.76, 15.88, 15.73. HRMS (ESI),m / z calculated for C 19 H 20 O3(M+H) + : 297.1490, found: 297.1497 The synthesis method of Example 27 is as follows:

[0088] Take 10 ml of the sealed tube, and after anhydrous and oxygen-free conditions, add the diaryl unsaturated or saturated ketone compound from Example 1 (28.2 mg, 0.1 mmol), 60% NaH (22 mg, 0.55 mmol), and trimethyl sulfoxide (24.2 mg, 0.11 mmol). After purging with nitrogen three times, add DMF (0.2 ml) under nitrogen purging and react at 50 °C.

[0089] The reaction was confirmed to be complete by TLC. EA was extracted three times with H₂O, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solution was removed by rotary evaporation. Purification was performed by silica gel column chromatography with an eluent of PE:EA = 10:1. 20.2 mg of product was obtained, with a yield of 68%.

[0090] Example 28 The structural formula of the diaryl saturated or unsaturated ketone compound provided in this embodiment is as follows:

[0091] (1 E ,2 E )-1-(4-hydroxy-3-methylphenyl)-3-(3-methoxy-4-methylphenyl)prop-2-en-1-one O-methyl oxime 1 H NMR (400 MHz, DMSO- d 6) δ 10.00 (s, 1H), 7.76 (d, J = 16.5 Hz, 1H), 7.53 (d, J= 2.2 Hz, 1H), 7.51 – 7.43 (m, 3H), 7.39 (dd, J = 7.6, 1.6 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 16.5 Hz, 1H), 4.26 (s, 3H), 4.16 (s, 3H), 2.50 (s, 3H), 2.49 (s, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 158.04, 156.94,156.55, 139.21, 135.39, 131.57, 131.11, 128.04, 127.59, 125.44, 124.33,119.95, 117.49, 114.81, 109.44, 62.08, 55.77, 16.49, 16.41. HRMS (ESI), m / zcalculated for C 19 H 21 N₂O₃(M+H) + 312.1599, found: 312.1604 The synthesis method of Example 28 is as follows:

[0092] Example 1 (56.4 mg, 0.2 mmol) was dissolved in EtOH (0.4 ml), and then methoxyamine hydrochloride (25 mg, 0.3 mmol) was added and reacted in an oil bath at 70 °C.

[0093] TLC monitoring showed that most of the reactants had reacted completely. A rotary evaporator was used to remove most of the solvent, and DCM was added to ensure complete dissolution. The mixture was then dry-loaded and purified by silica gel column chromatography with a PE:EA ratio of 10:1 as the eluent. Example 28 yielded 18.6 mg of the product, a yield of 30%.

[0094] Bioactivity tests were conducted on the diaryl unsaturated or saturated ketone compounds obtained in the examples and the control substance LY364947 (CAS: 396129-53-6). Operating steps: Prepare 2x ATP / substrate solution and 2x kinase solution, and add kinase reaction buffer. Use an Echo 655 to transfer 100 nL of diaryl saturated or unsaturated ketone compound dilution to a 384 test plate; Centrifuge the sample and add 5 μL of 2x kinase solution to the 384 test plate. Centrifuge at 1000 rpm for 1 minute and then incubate at 25°C for 10 minutes.

[0095] Add 5 μL of substrate and ATP solution to a 384-well plate and centrifuge at 1000 rpm for 10 minutes.

[0096] Rotate at 1 minute and then incubate at 25°C for 120 minutes.

[0097] Transfer 5 μL of ADP-Glo ​​to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 40 minutes.

[0098] Transfer 10 μL of the test solution to a 384 plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 40 minutes.

[0099] The luminescent signal was read using a multifunctional enzyme labeler.

[0100] The reagents and brand codes used in the examples are shown in Table 1 below: Table 1. Reagents and Brand Codes Used in the Examples

[0101] The reference standards are shown in Table 2 below: Table 2. ALK4 enzyme, substrate, and ATP control concentrations.

[0102] The inhibition rates of the embodiments in this application and the control substance are as follows: Figure 2 As shown, the results are presented in Table 3 below: Table 3. ALK4 inhibition rate of the examples and comparative experiments

[0103] The inhibitory effects of diaryl unsaturated or saturated ketone compounds obtained in the examples on the proliferation of melanoma cells were determined by the CCK-8 assay. A375, SK28, and SK5 cells frozen in liquid nitrogen were quickly placed in a 37°C water bath and agitated continuously to thaw rapidly. The thawed cell suspension was transferred to a centrifuge tube containing cell culture medium and centrifuged at 1000 r / min for 5 min, then the supernatant was discarded. 1 mL of complete culture medium was then added to the tube to resuspend the cells.

[0104] A375, SK28, and SK5 cells were passaged in DMEM medium containing 10% fetal bovine serum, 1% streptomycin, and 1% penicillin at 35 °C. A375, SK28, and SK5 cells in the logarithmic growth phase were collected for later use. Cells were digested with trypsin, and culture medium was added and mixed thoroughly by pipetting. 10 μl of the cell suspension was transferred to a cell counting plate, allowed to stand for a few minutes, and then the cells were counted under a microscope. Cell counting method: Number of cells required for seeding / Number of cells required per milliliter of culture medium = Required volume of stock medium.

[0105] Melanoma cells were seeded at a density of 3000 cells per well in 96-well plates. To reduce error, a ring of PBS or culture medium was added to the outermost layer of the 96-well plate. After cell attachment, the supernatant was replaced with 200 μL of Dulbecco modified Eagle (DMEM) medium supplemented with 10% fetal bovine serum, containing different concentrations of diaryl unsaturated or saturated ketone compounds (1 μM, 10 μM). Each drug concentration was used in triplicate, and the cells were cultured for another 48 hours. The supernatant was discarded, and 110 μL of CCK-8 working solution (culture medium and CCK-8 reagent were prepared at a ratio of 10:1) was added to each well. The cells were incubated at 37°C in a 5% CO2 incubator for 1.5-2 hours. The absorbance at 450 nm was read using a microplate reader, and cell viability was calculated. The results are shown in Table 4 below: (Formula: Cell viability = Absorbance of drug-treated well / Absorbance of control group × 100%).

[0106] Table 4. Inhibitory effect of diaryl unsaturated or saturated ketone compounds on melanoma cell proliferation and survival rate as determined by the CCK-8 assay.

[0107] The present invention and its embodiments have been described above. This description is not restrictive, and the actual structure is not limited thereto. In conclusion, if those skilled in the art, inspired by this description, design similar structures and embodiments without departing from the spirit of the invention, such designs should fall within the scope of protection of this invention.

Claims

1. A diaryl unsaturated or saturated ketone compound, characterized in that, It contains the following chemical formula or its isomers: Wherein: R1 and R2 are the same or different selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)(C1-C3 alkyl), -C (=O)(C1-C3 alkyl), hydroxyl-substituted C1-C3 alkyl, 3-8 membered heterocyclic group, C1-C3 alkyl-substituted 3-8 membered heterocyclic or halogen-substituted C1-C3 alkyl; The aromatic rings connected to R1 and R2 include one or more of the following: phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, furanyl, pyrrolithyl, hexahydropyridyl, tetrahydropyranyl, tetrahydronaphthyl, furanyl, thiophenyl, pyrrolithyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiophenyl, indolyl, inzolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyrimidinyl, pyridopyrimidinyl, pyridopyridyl, purine, pteridinyl, imidazothiazolyl, imidazopyridazinyl, or pyrazopyrimidinyl. XR3 is O, or when X is N, R3 is OMe or OH.

2. The compound according to claim 1, characterized in that, The chemical structural formula of the compound is any one of formulas A, B, and C: 。 3. An ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound, characterized in that, The diaryl saturated or unsaturated ketone compounds are used to prepare ALK4 inhibitors.

4. The ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound as described in claim 3, characterized in that, The ALK4 inhibitor also includes the diaryl saturated or unsaturated ketone compound and its pharmacologically acceptable excipients or carriers.

5. The ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound as described in claim 4, characterized in that, The ALK4 inhibitors are used to prevent or treat any of the following ALK4 receptor-mediated diseases: melanoma, lung cancer, or breast cancer.

6. A method for preparing a diaryl saturated or unsaturated ketone compound, characterized in that, Includes the following steps: (1) Add an alkaline salt to raw material I and raw material II, wherein the alkaline salt includes at least one of potassium carbonate, potassium hydroxide or sodium hydride, and then add a solvent, wherein the solvent includes at least one of methanol, ethanol, dimethylformamide or acetonitrile. React until the raw material disappears as monitored by TLC, concentrate and extract, adjust the pH to 5-6, and extract and dry to obtain a solid precursor. (2) The solid precursor was dry-loaded, purified by silica gel column chromatography, and separated by chromatography. The eluent for chromatography was a mixture of dichloromethane and ethanol. After the liquid was evaporated to obtain the solid, dichloromethane was added to dissolve the solid, and then petroleum ether was added to precipitate the solid. The solid was filtered and washed with a mixture of dichloromethane and petroleum ether to obtain a diaryl unsaturated or saturated ketone compound. Raw material I and raw material II contain R1 and R2 respectively: R1 and R2 are selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)(C1-C3 alkyl), -C(=O)(C1-C3 alkyl), hydroxyl-substituted C1-C3 alkyl, 3-8 membered heterocyclic group, C1-C3 alkyl-substituted 3-8 membered heterocyclic group or halogen-substituted C1-C3 alkyl; R1 and R2 are linked to an aromatic ring, which includes one or more of the following aromatic rings: phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, furanyl, pyrroleyl, hexahydropyridyl, tetrahydropyranyl, tetrahydronaphthyl, furanyl, thiopheneyl, pyrroleyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiopheneyl, indolyl, inzolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyrimidinyl, pyridopyrimidinyl, pyridopyridinyl, purine, pteridinyl, imidazothiazolyl, imidazopyridazinyl, or pyrazopyrimidinyl.

7. The preparation method according to claim 8, characterized in that, The preparation method further includes step (3), using the diaryl unsaturated or saturated ketone compound synthesized in step (2) as an intermediate, adding at least one of trimethyl sulfoxide, p-toluenesulfonyl hydrazine or methoxyamine hydrochloride, and reacting at 50-100 °C; after the reaction is complete, the mixture is concentrated, extracted and dried, and purified by silica gel column chromatography to obtain the diaryl unsaturated or saturated ketone compound.

8. The application of an ALK4 inhibitor of a diaryl saturated or unsaturated ketone compound as described in any one of claims 3-5, characterized in that, The ALK4 inhibitors are used in diseases in which ALK4 is a key pathogenic signaling pathway.

9. The application as described in claim 8, characterized in that, The ALK4 inhibitor can inhibit ALK4 enzyme activity and cell activity, tissue activity and model animal activity based on the function of this enzyme in the concentration range of 1 mg / kg to 100 mg / kg.

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