3-Hydroxypyridine-4(H)-ketone derivatives, their preparation methods and applications

Abstract

This invention discloses a 3-hydroxypyridine-4(H)-one derivative, its preparation method, and its applications. The invention selects the 3-hydroxypyridine-4(H)-one fragment as the iron-chelating active moiety; its connection with a non-natural amino alcohol improves its lipophilicity and slows down metabolism. The compounds of this invention inhibit ferroptosis by chelating excess iron and providing antioxidant effects, thereby treating related diseases. This invention innovatively improves the anti-ferroptosis activity of iron chelators, effectively inhibiting ferroptosis to treat related diseases.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and medicinal chemistry, specifically to compounds based on the 3-hydroxypyridine-4(H)-one structure, their preparation methods, and their application in inhibiting ferroptosis. Background Technology

[0002] Iron is essential for basic metabolic processes in cells and organisms. Iron in the human body cannot be excreted in a regular manner, so iron absorption needs to be strictly controlled. When the body's iron levels are overloaded, ferroptosis occurs through the iron-regulating pathway. Ferroptosis is a regulatory cell death process induced by iron ions and reactive oxygen species-induced lipid peroxidation, distinct from apoptosis, necrosis, and autophagy at the morphological, biological, and genetic levels. It primarily involves two pathways: the iron-regulating pathway and alterations in phospholipid oxidation. In the iron-regulating pathway, transferrin receptor 1 (TfR1) binds to transferrin to form Fe... 3+ The uptake complex is reduced to Fe by the reductase. 2+ Then, divalent metallotransferase 1 (DMT1) transports Fe... 2+ Translated from within the body into an unstable iron reservoir. Fe 2+ The output is mediated by ferritin, Fe 2+ On the one hand, it generates lipid ROS through the Fenton reaction; on the other hand, it binds to LOXs to catalyze lipid peroxidation. The biosynthesis of glutathione (GSH) requires X... c - Anti-transporter protein. Glutathione peroxidase 4 (GPX4) safely reduces phospholipid hydroperoxides to their corresponding lipid alcohols using two GSH molecules. Therefore, elevated intracellular iron levels and GPX4 consumption promote the accumulation of phospholipid hydroperoxides, thereby disrupting membrane integrity via the ferroptosis pathway and leading to a range of diseases, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.), cancer, ischemia / oxygen reperfusion injury, and acute kidney injury. Based on the above ferroptosis pathway, reducing unstable iron stores—i.e., chelating ferric ions with iron chelators and antioxidant activity—are promising targets for inhibiting ferroptosis.

[0003] Currently, clinically used iron chelators include deferoxamine, deferoxone, and deferoxazole, but each has certain drawbacks. Deferoxone is currently a relatively good drug for delaying symptoms in PD patients, with a good iron-clearing effect; however, it is easily metabolized by glucose. Later, a hydroxyl group was introduced to replace the sacrificial site and interact with glucose, allowing 3-hydroxypyridin-4(H)-one to better exert its iron-chelating ability. It has been shown that the introduction of a hydroxyl group significantly reduces the rate of metabolism and achieves a pFe concentration comparable to deferoxone. 3+The value significantly improved the oral activity. Trolox, an antioxidant, has been reported to inhibit ferroptosis; this study used Trolox as a positive control to investigate the antioxidant capacity of the target compound.

[0004] In summary, selecting the 3-hydroxypyridine-4(H)-one fragment as the iron-chelating active moiety and linking it to a non-natural amino alcohol can improve its lipophilicity and slow down its metabolic rate. The compounds of this invention achieve therapeutic effects by inhibiting ferroptosis through the excess iron in the chelate and its antioxidant properties. Summary of the Invention

[0005] This invention designs and synthesizes novel 3-hydroxypyridine-4(H)-one derivatives based on computer-aided drug design, drug-likeness rules, and prediction of blood-brain barrier permeability. Based on the antioxidant capacity of the metal complex group, it inhibits ferroptosis by chelating excess iron in the body and resisting oxidation.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a 3-hydroxypyridine-4(H)-one derivative of formula (I) and a pharmaceutically acceptable salt thereof:

[0008]

[0009] In equation (Ⅰ), R 1 C1-C6 straight-chain alkyl

[0010] R 2 for Y1 and Z1 are each independently H, a C1-C6 straight-chain or branched alkyl group, a C1-C6 straight-chain or branched alkoxy group, a C1-C6 straight-chain or branched haloalkyl group, or a halogen.

[0011] Furthermore, the 3-hydroxypyridine-4(H)-ketone derivative has the following structure:

[0012] With the same substituents, the S configuration generally exhibits better ferroptosis activity than the R configuration derivative.

[0013] Preferred, R 1 -CH3; R 2 For -Ph,

[0014] Specifically, the 3-hydroxypyridine-4-one derivative shown in formula (Ⅰ) is one of the following compounds:

[0015]

[0016]

[0017]

[0018] The present invention particularly prefers the 3-hydroxypyridine-4(H)-one derivatives to be compounds 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27 or 28, with compound 24 being the most preferred.

[0019] Specifically, the pharmaceutically acceptable salt is the hydrochloride salt of a 3-hydroxypyridine-4(H)-one derivative of formula (I).

[0020] Secondly, the present invention also provides the use of the 3-hydroxypyridine-4(H)-one derivative of formula (I) above and its pharmaceutically acceptable salt in the preparation of a medicament for treating related diseases by inhibiting ferroptosis. Preferably, the disease is a neurodegenerative disease or acute renal failure.

[0021] Furthermore, the 3-hydroxypyridine-4(H)-ketone derivative has the following structure:

[0022]

[0023] Further preferred is that the 3-hydroxypyridine-4(H)-one derivative is one of compounds 1-32.

[0024] The present invention particularly prefers the 3-hydroxypyridine-4(H)-one derivatives to be compounds 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27 or 28, with compound 24 being the most preferred.

[0025] Thirdly, the present invention also provides a method for preparing the 3-hydroxypyridine-4(H)-one derivative shown in formula (I). The synthetic idea is as follows: For the preparation method of the hydroxyl-protected pyridinone shown in formula a, please refer to patent CN 112552232A; using 2-bromoethyl ketone with different substituents shown in formula b as raw material, the N-position side chain substituted 3-hydroxy-protected pyridinone shown in formula c is synthesized. Then, by adding a metal catalyst, the carbonyl group on the side chain is selectively reduced to hydroxyl (R and S configuration) to obtain the compound shown in formula d. Finally, the protection is removed to obtain the target compound shown in formula (I).

[0026] Specifically, the 3-hydroxypyridine-4(H)-ketone derivative shown in (Ⅰ) of the present invention is prepared according to the following method:

[0027] (1) The hydroxyl-protected pyridinone shown in formula a, the 2-bromoethylone compound shown in formula b, and potassium carbonate are dissolved in N,N-dimethylformamide (DMF) and stirred at room temperature for 4 hours. The resulting reaction solution A is post-treated to obtain compound c. The molar ratio of the hydroxyl-protected pyridinone shown in formula a, the 2-bromoethylone compound shown in formula b, and potassium carbonate is 1:1.1:1.1.

[0028] (2) Dissolve the compound of formula c described in step (1) in methanol, add a ruthenium catalyst, stir at room temperature for 1 h under nitrogen protection and room temperature conditions, then add a mixed solution of triethylamine and formic acid dropwise. After the addition is complete, continue stirring at room temperature for 3 h to obtain reaction solution B; the molar ratio of the metal catalyst to the compound of formula c is 1:0.05-0.15; the molar ratio of the triethylamine to the formic acid to the compound of formula c is 1:0.004:0.0024; the ruthenium catalyst is (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride or (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride;

[0029] (3) Dissolve the compound of formula d described in step (2) in dichloromethane, and slowly add a 1.0 mol / L dichloromethane solution of boron trichloride at -10°C under nitrogen protection. After the addition is complete, continue the reaction at -10°C for 30 min, transfer to room temperature and continue stirring for 8-12 h. The resulting reaction solution C is post-treated to obtain the 3-hydroxypyridine-4(H)-ketone derivative shown in formula (Ⅰ); the molar ratio of the compound of formula d described in step (3) to the boron trichloride in the dichloromethane solution of boron trichloride is 1:3 to 6.

[0030]

[0031] Furthermore, the volume of N,N-dimethylformamide in step (1) is 4-5 mL / mmol, calculated as the amount of the 2-bromoethylone compound represented by formula a.

[0032] Further, the post-treatment A in step (1) is as follows: the reaction solution A is poured into a separatory funnel, washed with water, extracted with ethyl acetate, dried, and purified by column silica gel chromatography with a mixed solution of dichloromethane and methanol in volume ratios of 100:1, 80:1, and 50:1. The eluent of the target product is collected, concentrated under reduced pressure, and dried to obtain the compound shown in formula c.

[0033] Further, in step (2), the molar ratio of methanol to compound c is 5-10 mL / mmol; the post-treatment B in step (2) is as follows: the reaction solution B is concentrated under reduced pressure to remove the solvent, extracted with dichloromethane, washed with water, dried, purified by column chromatography with a mixed solvent of petroleum ether and ethyl acetate in a ratio of 2:1 and 1:1, the eluent of the target product is collected, concentrated under reduced pressure and dried to obtain compound d.

[0034] Furthermore, the volume of dichloromethane in step (3) is 10-20 mL / mmol in terms of the amount of substance of compound d.

[0035] In one embodiment of the present invention, the post-treatment C in step (3) is as follows: the reaction solution C is quenched by adding methanol A dropwise, distilled under reduced pressure (to remove the solvent), and methanol B is added dropwise at 65°C to dissolve the solid. After complete dissolution, the solution is naturally cooled to room temperature (so that the product slowly precipitates). Diethyl ether is added (slowly), and the solution is cooled at -20°C for 2 hours (so that the product no longer precipitates). The solution is filtered, and the resulting filter cake is dried under vacuum to obtain the 3-hydroxypyridine-4(H)-ketone derivative shown in formula (Ⅰ). The volume ratio of methanol B to diethyl ether is 1:5.

[0036] Furthermore, the volume of methanol A, expressed as the molar amount of compound d, is 15-30 mL / mmol.

[0037] The letters A, B, C, etc. in the above steps are only used to distinguish substances at different stages and have no other special meaning.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: the existing iron chelating agents have poor anti-ferroptosis activity. The present invention synthesizes some novel 3-hydroxypyridine-4(H)-one iron chelating agents, which innovatively improves the anti-ferroptosis activity of iron chelating agents and can effectively inhibit ferroptosis to treat related diseases. Attached Figure Description

[0039] Figure 1 Fluorescence decay curves (A) and net AUC versus concentration standard curve (B) of Trolox series concentration solutions.

[0040] Figure 2 Compound cytotoxicity to HT22 cells Detailed Implementation

[0041] The present invention will be further illustrated below with specific examples, but the present invention is not limited to these embodiments.

[0042] Example 1

[0043] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (1):

[0044] (1) 2-Bromoacetophenone (4.38 g, 22 mmol), 3-hydroxy-2-methylpyridin-4(1H)-one (4.31 g, 20 mmol), potassium carbonate (3.04 g, 22 mmol), and DMF (80 mL) were added to a single-necked flask. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was extracted with ethyl acetate (30 mL), washed with water (100 mL × 6), and the organic layer was dried over anhydrous sodium sulfate for 1 h. After drying, the mixture was filtered, concentrated under pressure, and purified by column chromatography with dichloromethane and methanol at volume ratios of 100:1, 80:1, and 50:1. The eluent containing the target compound was collected and concentrated under reduced pressure to obtain a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one (3.28 g), with a yield of 56%.

[0045] (2) Add the above-mentioned yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one (1.01 g, 3 mmol), catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), and methanol (15 mL) to a single-necked flask. After stirring for 1 h under N2 protection at room temperature, add triethylamine:formic acid dropwise to the system at a ratio of 5:3. After the addition is complete, continue... The reaction was carried out for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with dichloromethane (20 mL). The solution was washed with water (10 mL × 3). After the organic layer was removed, the solution was dried with anhydrous sodium sulfate for 1 hour. The solution was filtered and concentrated under reduced pressure. The solution was purified by column chromatography with a mixture of petroleum ether and ethyl acetate in a ratio of 2:1 and 1:1. The eluent containing the target compound was collected and distilled under reduced pressure to obtain a gray solid (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (619.00 mg), with a yield of 62%.

[0046] (3) Add the above-mentioned gray solid (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (335.40 mg, 1 mmol) and dichloromethane (10 mL) to a single-necked flask. Under nitrogen protection, stir for 15 min at -10 °C. Slowly add 1.0 mol / L boron trichloride (3 mL, dichloromethane as solvent) dropwise to the reaction system. After the addition is complete, continue stirring at -10 °C for 30 min, then transfer to room temperature and react for 12 h. After the reaction is complete, add dropwise... The reaction was quenched with methanol (15 mL). After the reaction was completed, the reaction solution was concentrated under reduced pressure (to remove the solvent). The reaction flask was placed in a water bath at 65 °C, and methanol was slowly added dropwise to dissolve the product. After complete dissolution, the mixture was allowed to cool naturally to room temperature to allow the product to precipitate slowly. At this point, 5 times the volume of diethyl ether was slowly added, and the mixture was placed in a refrigerator to cool for 2 hours until the product no longer precipitated. The mixture was then filtered and dried under vacuum to obtain a white solid (R)-3-hydroxy-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (191.20 mg), with a yield of 68%.

[0047] mp251~252℃; 1 H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.26 (d, J = 6.9

[0048] Hz,1H),7.46(d,J=7.6Hz,2H),7.38(d,J=7.1Hz,3H),7.33(d,J=7.2Hz,1H),6.05(s,1H),4.97( dd,J=9.3,3.4Hz,1H),4.56(dd,J=14.1,3.5Hz,1H),4.41(dd,J=14.0,9.1Hz,1H),2.56(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.81,142.57,142.12,141.30,139.32,128.36,127.93,126.18,110.11,70.89,61.70,12.87.

[0049] Example 2

[0050] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (2):

[0051] (1) The operation steps are the same as those in Example 1, except that a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one (3.76 g) is obtained, with a yield of 56%.

[0052] (2) The operation steps are the same as step (2) in Example 1, except that the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol) to obtain a gray solid (S)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (653.14 mg), with a yield of 65%.

[0053] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (335.40 mg, 1 mmol), and a white solid (S)-3-hydroxy-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one (201.4 g) is obtained, with a yield of 72%.

[0054] mp251~252℃; 1 H NMR (600MHz, DMSO-d6) δ10.64 (s, 1H), 8.20 (d, J = 6.7

[0055] Hz,1H),7.50(d,J=7.0Hz,3H),7.37(dd,J=8.4,6.9Hz,2H),7.32–7.28(m,1H),5.99(s,1H),5.09 (dd,J=8.7,3.2Hz,1H),4.45(dd,J=10.1,3.2Hz,1H),4.21(dd,J=10.0,8.7Hz,1H),2.54(s,3H). 13 C NMR (150MHz, DMSO-d6) δ158.24,142.78,140.30,139.71,133.61,128.16,127.60,126.47,108.45,75.21,70.19,13.83.

[0056] Example 3

[0057] Preparation method of (R)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)one (3)

[0058] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-4'-fluoroacetophenone (4.77 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.78 g), with a yield of 54%.

[0059] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.05 g, 3 mmol), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (829.06 mg), with a yield of 78%.

[0060] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 mg, 1 mmol), and a white solid (R)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (177.74 mg) is obtained, with a yield of 59%.

[0061] mp230~231℃; 1 H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.21 (d, J = 6.7

[0062] Hz,1H),7.58-7.48(m,3H),7.24-7.16(m,2H),6.01(s,1H),5.09(dd,J=8.5,3.3 Hz, 1H), 4.44 (dd, J=10.1, 3.4Hz, 1H), 4.21 (dd, J=10.1, 8.5Hz, 1H), 2.53 (s, 3H). 13 CNMR(100MHz,DMSO-d6)δ161.59(d, 1 J C-F =243Hz),158.20,142.78,139.70,136.52(d, 4 J C-F =3Hz), 133.52, 128.48 (d, 3 JC-F =8Hz), 114.84(d, 2 J C-F =21Hz),108.41,75.06,69.49,13.76.

[0063] Example 4

[0064] Preparation method of (S)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)one (4)

[0065] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-fluoroacetophenone (4.77 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.87 g), with a yield of 55%.

[0066] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.05 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol) to obtain a gray solid (S)-3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (735.77 mg), with a yield of 69%.

[0067] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 mg, 1 mmol), to obtain a white solid (S)-1-(2-(4-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (148.36 mg), with a yield of 50%.

[0068] mp229~230℃; 1 H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.21 (dd, J=

[0069] 7.0,3.6Hz,1H),7.59-7.46(m,3H),7.25-7.15(m,2H),6.00(s,1H),5.09(dd,J=8.5,3.3Hz, 1H), 4.44 (dd, J=10.1, 3.4Hz, 1H), 4.21 (ddd, J=12.4, 8.9, 3.6Hz, 1H), 2.53 (d, J=1.2Hz, 3H). 13 C NMR(100MHz,DMSO-d6)δ162.80(d, 1 J C-F =243Hz),158.21,142.76,139.72,136.53(d, 4 J C-F =3Hz), 133.54, 128.47 (d, 3 J C-F =8Hz), 114.84(d, 2 J C-F =21Hz),108.41,75.03,69.50,13.76.

[0070] Example 5

[0071] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(p-tolyl)ethyl)-2-methylpyridin-4(1H)-one (5)

[0072] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-methylacetophenone (4.69 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(p-tolyl)ethyl)pyridin-4(1H)-one (3.50 g), with a yield of 50%.

[0073] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(p-tolyl)ethyl)pyridin-4(1H)-one (1.04 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(4-methylphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (718.08 mg), with a yield of 69%.

[0074] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(4-methylphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (349.43 mg, 1 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(p-tolyl)ethyl)-2-methylpyridin-4(1H)-one (176.57 mg) is obtained, with a yield of 60%.

[0075] mp226~227℃; 1 H NMR (400MHz, DMSO-d6) δ15.57(s,1H),10.69(s,1H),8.29-8.22(m,1H),7.61(d,J=6.7Hz,1H),7.53-7.47(m,2H),7.25-7.20(m,2 H),5.52(ddd,J=7.7,4.7,2.1Hz,1H),4.87(dd,J=11.2,8.2Hz,1H),4.76(dd,J=11.2,4.8Hz,1H),2.57-2.53(m,3H),2.31(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.13,142.74,140.68,138.52,134.33,133.55,129.16,127.74,108.88,73.07,59.79,20.70,13.99.

[0076] Example 6

[0077] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(p-tolyl)ethyl)-2-methylpyridin-4(1H)-one (6)

[0078] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-4'-methylacetophenone (4.69 g, 22 mmol), and a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(p-tolyl)ethyl)pyridin-4(1H)-one (3.37 g) is obtained, with a yield of 49%.

[0079] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(p-tolyl)ethyl)pyridin-4(1H)-one (1.04 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol) and methanol (18 mL), to obtain a gray solid (S)-3-(benzyloxy)-1-(2-(4-methylphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (738.00 mg), with a yield of 70%.

[0080] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(4-methylphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (349.43 mg, 1 mmol), to obtain a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(p-tolyl)ethyl)-2-methylpyridin-4(1H)-one (207.91 mg), with a yield of 70%.

[0081] mp226~227℃; 1 H NMR (400MHz, DMSO-d6) δ15.57(s,1H),10.69(s,1H),8.28-8.23(m,1H),7.61(d,J=6.7Hz,1H),7.52-7.45(m,2H),7.23(d,J =7.8Hz,2H),5.55-5.49(m,1H),4.87(dd,J=11.2,8.2Hz,1H),4.76(dd,J=11.2,4.8Hz,1H),2.58-2.53(m,3H),2.31(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.15,142.77,140.69,138.61,134.40,133.64,129.25,127.83,108.93,73.10,59.89,20.79,14.08.

[0082] Example 7

[0083] Preparation method of (R)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)one (7)

[0084] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-4'-chloroacetophenone (5.14 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.64 g), with a yield of 50%.

[0085] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.10 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (763.37 mg), with a yield of 69%.

[0086] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), and a white solid (R)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (187.49 mg) is obtained, with a yield of 59%.

[0087] mp227~228℃; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.27-8.19(m,1H),7.51(dd,J=13.3,7.7Hz,3H),7.44(d,J=8.1Hz,2H) ,6.05(s,1H),5.10(dd,J=8.4,3.2Hz,1H),4.45(dd,J=10.2,3.4Hz,1H),4.20(t,J=9.3Hz,1H),2.53(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.18,142.79,139.77,139.40,133.62,132.14,128.43,128.14,108.46,74.93,69.52,13.85.

[0088] Example 8

[0089] Preparation method of (S)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)one (8)

[0090] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-chloroacetophenone (5.14 g, 22 mmol) and DMF (90 mL), to obtain a yellow solid 3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.31 g), with a yield of 45%.

[0091] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.10 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (757.82 mg), with a yield of 68%.

[0092] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), to obtain a white solid (S)-1-(2-(4-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (192.24 mg), with a yield of 61%.

[0093] mp224~225℃; 1 H NMR (400MHz, DMSO-d6) δ15.50(s,1H),10.70(s,1H),8.27(td,J=5.8,4.9,2.0Hz,1H),7.70-7.58(m,3H),7.57-7.45(m,2 H),5.59(qd,J=4.7,2.0Hz,1H),4.88(dd,J=11.2,7.8Hz,1H),4.79(dd,J=11.2,5.1Hz,1H),2.54(dd,J=5.8,2.0Hz,3H). 13C NMR (100MHz, DMSO-d6) δ158.10,142.76,140.79,136.41,133.69,129.95,128.87,128.73,108.95,72.76,58.80,14.10.

[0094] Example 9

[0095] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (9)

[0096] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-methoxyacetophenone (5.04 g, 22 mmol) and DMF (90 mL), to obtain a yellow solid 3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.74 g), with a yield of 51%.

[0097] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.09 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (748.77 mg), with a yield of 68%.

[0098] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (365.43 mg, 3 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (191.11 mg) is obtained, with a yield of 61%.

[0099] mp227~228℃; 1 H NMR (400MHz, DMSO-d6) δ10.64 (s, 1H), 8.23 ​​(dd, J=

[0100] 6.6,3.1Hz,1H),7.59-7.46(m,2H),7.30(t,J=8.0Hz,1H),7.01(ddd,J=10.3,7.5,2.7Hz,2H),5.89(s,1H) ,5.34(d,J=8.6Hz,1H),4.40(d,J=10.4Hz,1H),4.09(t,J=9.5Hz,1H),3.83(d,J=2.6Hz,3H),2.54(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.71,158.00,142.72,139.29,133.74,132.10,127.66,113.53,108.37,74.96,69.65,55.10,13.82.

[0101] Example 10

[0102] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (10)

[0103] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-methoxyacetophenone (5.04 g, 22 mmol) and DMF (90 mL) to obtain a yellow solid 3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.04 g), with a yield of 42%.

[0104] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.09 g, 3 mmol), the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), and methanol (18 mL), to obtain a gray solid (S)-3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (743.29 mg), with a yield of 68%.

[0105] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (365.43 mg, 3 mmol), to obtain a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (185.81 mg), with a yield of 60%.

[0106] mp226~227℃; 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.17(s,1H),7.56(s,1H),7.44(s,1H),7.39(d,J=7.0Hz,2H),6.91(d,J =6.9Hz,1H),5.99(s,1H),5.01(d,J=7.3Hz,1H),4.37(d,J=8.6Hz,1H),4.14(s,1H),3.73(s,3H),2.52(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.71,158.14,142.72,139.53,133.74,132.15,127.66,113.53,108.37,75.24,69.65,55.10,13.82.

[0107] Example 11

[0108] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-2-methylpyridin-4(1H)-one (11)

[0109] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-trifluoromethylacetophenone (5.87 g, 22 mmol) and DMF (90 mL), to obtain a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)pyridine-4(1H)-one (4.11 g), with a yield of 51%.

[0110] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)pyridin-4(1H)-one (1.20 g, 3 mmol), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(4-(trifluoromethyl)phenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (1.21 g), with a yield of 69%.

[0111] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(4-(trifluoromethyl)phenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (403.40 mg, 1 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-2-methylpyridin-4(1H)-one (208.79 mg) is obtained, with a yield of 60%.

[0112] mp231~232℃; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.26-8.19(m,1H),7.75(d,J=2.1Hz,4H),7.50(d,J=6.7Hz,1H),6. 20(s,1H),5.20(dd,J=8.6,3.4Hz,1H),4.51(dd,J=10.1,3.4Hz,1H),4.23(t,J=8.6Hz,1H),2.53(s,3H). 13 CNMR(100MHz,DMSO-d6)δ158.17,145.17,142.80,139.82,133.63,128.21(q, 2 J C-F =32Hz), 127.34, 125.01(q, 4 J C-F =4Hz), 122.96(q, 1 J C-F =270Hz),108.47,74.83,69.67,13.83.

[0113] Example 12

[0114] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-2-methylpyridin-4(1H)-one (12)

[0115] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-4'-trifluoromethylacetophenone (5.87 g, 22 mmol) and DMF (90 mL), to obtain a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)pyridin-4(1H)-one (4.15 g), with a yield of 52%.

[0116] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)pyridine-4(1H)-one (1.20 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(4-(trifluoromethyl)phenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (843.51 mg), with a yield of 70%.

[0117] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(4-(trifluoromethyl)phenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (403.40 mg, 1 mmol), to obtain a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-2-methylpyridin-4(1H)-one (212.64 mg), with a yield of 61%.

[0118] mp231~232℃; 1 H NMR (400MHz, DMSO-d6) δ10.64 (s, 1H), 8.22 (dd, J=

[0119] 6.6,2.5Hz,1H),7.75(d,J=2.1Hz,4H),7.56-7.47(m,1H),6.22(s,1H),5.21(dd,J =8.5, 3.5Hz, 1H), 4.51 (dd, J = 10.1, 3.4Hz, 1H), 4.23 (t, J = 8.9Hz, 1H), 2.54 (s, 3H). 13 CNMR(100MHz,DMSO-d6)δ158.18,145.17,142.80,139.82,133.62,128.21(q, 2 J C-F =32Hz), 127.34, 125.01(q, 3 J C-F =4Hz), 122.96(q, 1 J C-F =270Hz),108.47,74.84,69.67,13.82.

[0120] Example 13

[0121] Preparation method of (R)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (13)

[0122] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-2'-chloroacetophenone (5.14 g, 22 mmol) and DMF (90 mL), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.64 g), with a yield of 50%.

[0123] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.10 g, 3 mmol) and methanol (18 mL), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (763.37 mg), with a yield of 69%.

[0124] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), and a white solid (R)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (187.49 mg) is obtained, with a yield of 59%.

[0125] mp220~221℃; 1 H NMR (400MHz, DMSO-d6) δ10.79-10.52(m,1H),8.27-8.19(m,1H),7.73(d,J=7.6Hz,1H),7.54(d,J=6.6Hz,1H),7.47(d,J=7.9Hz,1H),7.42(d,J=7.5 Hz,1H),7.37(td,J=7.5,1.9Hz,1H),6.22(s,1H),5.39(d,J=8.4Hz,1H),4 .44(dt,J=10.7,2.3Hz,1H),4.21(t,J=9.6Hz,1H),2.54(d,J=1.9Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ158.28,142.84,139.94,137.48,133.67,131.17,129.55,129.15,128.66,127.49,108.50,73.63,67.50,13.91.

[0126] Example 14

[0127] Preparation method of (S)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (14)

[0128] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-2'-chloroacetophenone (5.14 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.31 g), with a yield of 45%.

[0129] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.10 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (757.82 mg), with a yield of 68%.

[0130] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), to obtain a white solid (S)-1-(2-(2-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (192.24 mg), with a yield of 61%.

[0131] mp220~221℃; 1 H NMR (400MHz, DMSO-d6) δ10.75-10.56(m,1H),8.26-8.17(m,1H),7.73(d,J=7.6Hz,1H),7.54(d,J=6.6Hz,1H),7.47(d,J=7.9Hz,1H),7.42(d,J=7.5 Hz,1H),7.37(td,J=7.5,1.9Hz,1H),6.22(s,1H),5.39(d,J=8.4Hz,1H),4 .44(dt,J=10.7,2.3Hz,1H),4.21(t,J=9.6Hz,1H),2.54(d,J=1.9Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ158.28,142.84,139.94,137.48,133.67,131.17,129.55,129.15,128.66,127.49,108.50,73.63,67.50,13.91.

[0132] Example 15

[0133] Preparation method of (R)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (15)

[0134] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-2'-fluoroacetophenone (4.77 g, 22 mmol) and DMF (90 mL), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.78 g), with a yield of 54%.

[0135] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.05 g, 3 mmol) and methanol (18 mL), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (829.06 mg), with a yield of 78%.

[0136] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 g, 1 mmol), and a white solid (R)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (177.74 mg) is obtained, with a yield of 59%.

[0137] mp219~220℃; 1 H NMR (400MHz, DMSO-d6) δ10.65 (s, 1H), 8.21 (d, J = 6.6

[0138] Hz,1H),7.65(td,J=7.7,1.9Hz,1H),7.51(d,J=6.7Hz,1H),7.37(q,J=6.9Hz,1H),7.22(dt,J=15.5,5.1Hz,2H ), 6.13(s,1H),5.33(dd,J=8.5,2.8Hz,1H),4.43(dd,J=10.1,3.2Hz,1H),4.28(t,J=9.6Hz,1H),2.53(s,3H). 13C NMR(100MHz,DMSO-d6)δ159.22(d, 1 J C-F =243Hz),158.24,142.83,139.80(d, 4 J C-F =3Hz), 133.57, 129.71(d, 3 J C-F =6Hz), 128.51(d, 3 J C-F =4Hz), 127.06(d, 2 J C-F =13Hz), 124.57, 115.12(d, 2 J C-F =22Hz),108.47,73.91,64.60,13.83.

[0139] Example 16

[0140] Preparation method of (S)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (16)

[0141] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-2'-fluoroacetophenone (4.77 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.87 g), with a yield of 55%.

[0142] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.05 g, 3 mmol), the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), and methanol (18 mL), to obtain a gray solid (S)-3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (735.77 mg), with a yield of 69%.

[0143] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 g, 1 mmol), and a white solid (S)-1-(2-(2-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (148.36 mg) is obtained, with a yield of 50%.

[0144] mp209~210℃; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.26-8.21(m,1H),7.65(t,J=7.6Hz,1H),7.53(dd,J=6.9,2.7Hz,1H),7.38(t,J=7.1 Hz,1H),7.33-7.17(m,2H),6.12(s,1H),5.33(d,J=8.2Hz,1H),4.44(d,J=10.5Hz,1H),4.30(t,J=9.7Hz,1H),2.53(s,3H). 13 C NMR(100MHz,DMSO-d6)δ159.23(d, 1 J C-F =242Hz),158.29,158.02,142.81,139.92,133.75,129.74(d, 3 J C-F =8Hz), 128.50(d, 3 J C-F =5Hz), 127.12(d, 2 J C-F =14Hz), 124.58(d, 4 J C-F =3Hz), 115.16(d, 2 J C-F =21Hz),108.49,73.87,64.65,13.93.

[0145] Example 17

[0146] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(2-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (17)

[0147] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-2'-methoxyacetophenone (5.04 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.74 g), with a yield of 51%.

[0148] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.09 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (748.77 mg), with a yield of 68%.

[0149] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (365.43 mg, 3 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(2-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (191.11 mg) is obtained, with a yield of 61%.

[0150] mp218~219℃; 1 H NMR (400MHz, DMSO-d6) δ10.65 (s, 1H), 8.24 (dd, J=

[0151] 6.8,2.6Hz,1H),7.59-7.44(m,2H),7.30(t,J=7.9Hz,1H),7.07–6.95(m,2H),5.87(s,1H),5.34(d, J=8.6Hz,1H),4.40(dd,J=10.4,2.9Hz,1H),4.16-4.05(m,1H),3.83(d,J=2.0Hz,3H),2.54(s,3H). 13C NMR (100MHz, DMSO-d6) δ158.39,155.63,142.85,139.71,133.60,128.76,127.84,126.94,120.43,110.56,108.30,74.22,64.92,55.45,13.82.

[0152] Example 18

[0153] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(2-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (18)

[0154] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-2'-methoxyacetophenone (5.04 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.04 g), with a yield of 42%.

[0155] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.09 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (743.29 mg), with a yield of 68%.

[0156] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(2-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (365.43 mg, 3 mmol), and a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(2-methoxyphenyl)ethyl)-2-methylpyridin-4(1H)-one (185.81 mg) is obtained, with a yield of 60%.

[0157] mp216~217℃; 1 H NMR (400MHz, DMSO-d6) δ10.64 (s, 1H), 8.23 ​​(dd, J=

[0158] 6.6,3.1Hz,1H),7.59-7.46(m,2H),7.30(t,J=8.1Hz,1H),7.01(td,J=7.8,4.0Hz,2H),5.89(s,1H),5. 34(d,J=8.6Hz,1H),4.40(d,J=10.4Hz,1H),4.09(t,J=9.5Hz,1H),3.83(d,J=2.5Hz,3H),2.54(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.37,155.63,142.85,139.71,133.59,128.75,127.84,126.95,120.43,110.55,108.29,74.23,64.91,55.45,13.81.

[0159] Example 19

[0160] Preparation method of (R)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (19)

[0161] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3'-chloroacetophenone (5.14 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.64 g), with a yield of 50%.

[0162] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.10 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (763.37 mg), with a yield of 69%.

[0163] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), and a white solid (R)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (187.49 mg) is obtained, with a yield of 59%.

[0164] mp217~218℃; 1 H NMR (400MHz, DMSO-d6) δ10.74-10.54(m,1H),8.23(t,J=7.4Hz,1H),7.58(s,1H),7.56-7.33(m,4H),6.09(d,J=4 6.7Hz, 1H), 5.11 (dd, J=8.4, 3.4Hz, 1H), 4.49 (dd, J=10.2, 3.5Hz, 1H), 4.24 (q, J=10.4, 9.9Hz, 1H), 2.54 (s, 3H). 13 CNMR(100MHz,DMSO-d6)δ158.23,143.03,142.76,139.87,133.64,132.96,130.11,127.56,126.42,125.22,108.51,74.79,69.58,13.87.

[0165] Example 20

[0166] Preparation method of (S)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (20)

[0167] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-3'-chloroacetophenone (5.14 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.31 g), with a yield of 45%.

[0168] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.10 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (757.82 mg), with a yield of 68%.

[0169] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (369.85 mg, 1 mmol), to obtain a white solid (S)-1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (192.24 mg), with a yield of 61%.

[0170] mp215~216℃; 1 H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.21 (t, J = 4.7

[0171] Hz,1H),7.58(s,1H),7.54-7.45(m,2H),7.39(dq,J=13.7,8.2,6.6Hz,2H),6.12(s,1H),5.11 (dd, J=8.5, 3.4Hz, 1H), 4.48 (dd, J=9.9, 3.1Hz, 1H), 4.23 (q, J=8.9, 8.1Hz, 1H), 2.53 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ158.17,143.00,142.76,139.80,133.64,132.95,130.10,127.53,126.42,125.22,108.50,74.81,69.56,13.86.

[0172] Example 21

[0173] Preparation method of (R)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (21)

[0174] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3'-fluoroacetophenone (4.77 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.78 g), with a yield of 54%.

[0175] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.05 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (829.06 mg), with a yield of 78%.

[0176] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 mg, 1 mmol), and a white solid (R)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (177.74 mg) is obtained, with a yield of 59%.

[0177] mp202~203℃; 1 H NMR (400MHz, DMSO-d6) δ10.77-10.52(m,1H),8.21(h,J=5.9,5.4Hz,1H),7.49(t,J=6.7Hz,1H),7.43-7.38(m,1H),7.35(s,1H),7.33(s,1H),7. 12(d,J=8.9Hz,1H),6.05(d,J=70.1Hz,1H),5.17-5.08(m,1H),4.47(dd,J=10.1,3.5Hz,1H),4.21(q,J=9.3,8.5Hz,1H),2.52(d,J=3.4Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ162.12(d, 1 J C-F =248Hz), 158.19, 143.45(d, 3 JC-F =10Hz),142.77,139.81,133.60,130.15(d, 3 J C-F =9Hz), 122.54(d, 4 J C-F =3Hz), 114.32(d, 2 J C-F =16Hz), 113.32(d, 2 J C-F =22Hz),108.48,74.84,69.58,13.84.

[0178] Example 22

[0179] Preparation method of (S)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (22)

[0180] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3'-fluoroacetophenone (4.77 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.87 g), with a yield of 55%.

[0181] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.05 g, 3 mmol), the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), and methanol (18 mL), to obtain a gray solid (S)-3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (735.77 mg), with a yield of 69%.

[0182] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (353.40 mg, 1 mmol), to obtain a white solid (S)-1-(2-(3-fluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (148.36 mg), with a yield of 50%.

[0183] mp201~202℃; 1 H NMR (400MHz, DMSO-d6) δ10.63 (s, 1H), 8.22 (q, J = 6.0

[0184] Hz,1H),7.58-7.46(m,1H),7.46-7.38(m,1H),7.34(d,J=8.8Hz,2H),7.14(d,J=8.8Hz,1H),6.08(s ,1H),5.12(dd,J=8.5,3.3Hz,1H),4.48(dd,J=10.0,3.3Hz,1H),4.23(q,J=8.8Hz,1H),2.53(s,3H). 13 C NMR(100MHz,DMSO-d6)δ162.19(d, 1 J C-F =241Hz), 158.23, 143.44(d, 3 J C-F =7Hz),142.82,139.80,133.64,130.19(d, 3 J C-F =8Hz), 122.57(d, 4 J C-F =3Hz), 114.35(d, 2 J C-F =20Hz), 113.35(d, 2 J C-F =22Hz),108.51,74.89,69.62,13.87.

[0185] Example 23

[0186] Preparation method of (R)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (23)

[0187] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-difluoroacetophenone (5.17 g, 22 mmol) and DMF (90 mL), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.71 g), with a yield of 50%.

[0188] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (1.11 g, 3 mmol), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (793.29 mg), with a yield of 71%.

[0189] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (371.39 mg, 1 mmol), to obtain a white solid (R)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (210.23 mg), with a yield of 60%.

[0190] mp221~222℃; 1 H NMR (400MHz, DMSO-d6) δ10.63 (s, 1H), 8.22 (dt, J=

[0191] 6.6,3.4Hz,1H),7.58(dd,J=11.8,8.2Hz,1H),7.53-7.39(m,2H),7.36(d,J=8.4Hz,1H),6.19(s ,1H),5.10(dd,J=8.5,3.3Hz,1H),4.47(dd,J=10.1,3.3Hz,1H),4.25-4.16(m,1H),2.53(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.17,149.25(dd, 1 J C-F =245Hz, 2 J C-F=13Hz), 148.80(dd, 1 J C-F =245Hz, 2 J C-F =13Hz),142.78,139.84,138.32(dd, 3 J C-F =9Hz, 4 J C-F =4Hz), 133.65, 123.32(dd, 3 J C-F =7Hz, 4 J C-F =3Hz), 117.20(d, 2 J C-F =17Hz), 115.68(d, 2 J C-F =18Hz),108.47,74.73,69.11,13.86.

[0192] Example 24

[0193] Preparation method of (S)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (24)

[0194] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-difluoroacetophenone (5.17 g, 22 mmol) and DMF (90 mL), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.68 g), with a yield of 50%.

[0195] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.11 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (784.38 mg), with a yield of 70%.

[0196] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (371.39 mg, 1 mmol), to obtain a white solid (S)-1-(2-(3,4-difluorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (215.48 mg), with a yield of 62%.

[0197] mp221~222℃; 1 H NMR (400MHz, DMSO-d6) δ10.63 (s, 1H), 8.22 (dd, J=

[0198] 6.5,2.5Hz,1H),7.57(dd,J=11.8,8.1Hz,1H),7.52-7.40(m,2H),7.36(d,J=8.4Hz,1H),6.17(s,1 H), 5.10 (dd, J=8.6, 3.4Hz, 1H), 4.47 (dd, J=10.1, 3.4Hz, 1H), 4.21 (t, J=8.8Hz, 1H), 2.53 (s, 3H). 13 C NMR(100MHz,DMSO-d6)δ158.17,149.24(dd, 1 J C-F =245Hz, 2 J C-F =13Hz), 148.79(dd, 1 J C-F =245Hz, 2 J C-F =12Hz),142.78,139.84,138.32(dd, 3 J C-F =9Hz, 4 J C-F =4Hz), 133.65, 123.31(dd, 3 J C-F =7Hz, 4 J C-F =3Hz), 117.19(d, 2 J C-F =17Hz), 115.68(d, 2 J C-F =18Hz),108.46,74.73,69.10,13.85.

[0199] Example 25

[0200] Preparation method of (R)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (25)

[0201] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-dimethoxyacetophenone (5.70 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.95 g), with a yield of 50%.

[0202] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.18 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (815.04 mg), with a yield of 69%.

[0203] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (395.46 mg, 1 mmol), to obtain a white solid (R)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (177.49 mg), with a yield of 50%.

[0204] mp224~225℃; 1 H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.21 (d, J = 6.4

[0205] Hz,1H),7.49(d,J=6.7Hz,1H),7.10(s,1H),6.99(d,J=8.4Hz,1H),6.93(d,J=8.3Hz,1H),5.85(s,1H),5 .01(d,J=8.2Hz,1H),4.41(d,J=9.4Hz,1H),4.21(t,J=9.3Hz,1H),3.75(d,J=10.5Hz,6H),2.53(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.27,148.57,148.27,142.77,139.75,133.70,1 32.81,118.55,111.53,110.36,108.44,75.29,70.03,55.60,55.49,13.90.

[0206] Example 26

[0207] Preparation method of (S)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (26)

[0208] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-dimethoxyacetophenone (5.70 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (4.03 g), with a yield of 51%.

[0209] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.18 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (775.89 mg), with a yield of 65%.

[0210] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (395.46 mg, 1 mmol), to obtain a white solid (S)-1-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (181.06 mg), with a yield of 51%.

[0211] mp221~222℃; 1 H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.21 (d, J = 6.4

[0212] Hz,1H),7.49(d,J=6.7Hz,1H),7.10(s,1H),6.99(d,J=8.5Hz,1H),6.93(d,J=8.3Hz,1H),5.85(s,1H),5 .01(d,J=8.2Hz,1H),4.41(d,J=9.4Hz,1H),4.21(t,J=9.3Hz,1H),3.75(d,J=10.5Hz,6H),2.53(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.27,148.57,148.27,142.77,139.75,133.70,1 32.81,118.55,111.53,110.36,108.44,75.29,70.03,55.60,55.49,13.90.

[0213] Example 27

[0214] Preparation method of (R)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (27)

[0215] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-dichloroacetophenone (5.89 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (4.15 g), with a yield of 52%.

[0216] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.20 g, 3 mmol), the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), and methanol (18 mL), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (839.30 mg), with a yield of 69%.

[0217] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (404.29 mg, 1 mmol), to obtain a white solid (R)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (170.75 mg), with a yield of 49%.

[0218] mp224~225℃; 1 H NMR (400MHz, DMSO-d6) δ10.64-10.60(m,1H),8.23(dd,J=6.9,2.9Hz,1H),7.77(d,J=2.4Hz,1H),7.64(dd,J=8.3,2.7Hz,1H),7. 52(s,1H),7.51(s,1H),6.18(s,1H),5.11(dd,J=8.3,3.5Hz,1H),4.48(dd,J=10.2,3.3Hz,1H),4.29-4.18(m,1H),2.53(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.16,142.76,141.71,139.86,133.65,130.88,130.37,130.05,128.65,126.92,108.48,74.56,69.03,13.87.

[0219] Example 28

[0220] Preparation method of (S)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (28)

[0221] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 2-bromo-3',4'-dichloroacetophenone (5.89 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (3.82 g), with a yield of 48%.

[0222] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridine-4(1H)-one is replaced with 3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-oxoethyl)-2-methylpyridine-4(1H)-one (1.20 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-methylpyridine-4(1H)-one (839.30 mg), with a yield of 69%.

[0223] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (404.29 mg, 1 mmol), to obtain a white solid (S)-1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (176.01 mg), with a yield of 50%.

[0224] mp223~224℃; 1 H NMR (400MHz, DMSO-d6) δ10.71-10.54(m,1H),8.23(dd,J=6.7,2.1Hz,1H),7.78(s,1H),7.65(dd,J=8.3,1.9Hz,1H),7.54 -7.48(m,2H),6.19(s,1H),5.11(dd,J=8.4,3.4Hz,1H),4.49(dd,J=10.2,3.3Hz,1H),4.23(t,J=9.3Hz,1H),2.53(s,3H). 13C NMR (100MHz, DMSO-d6) δ158.16,142.76,141.71,139.86,133.64,130.88,130.37,130.05,128.64,126.91,108.48,74.55,69.02,13.86.

[0225] Example 29

[0226] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(naphth-2-yl)ethyl)-2-methylpyridin-4(1H)-one (29)

[0227] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-2'-naphthylacetophenone (5.46 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-2-methyl-1-(2-(naphth-2-yl)-2-oxoethyl)pyridin-4(1H)-one (3.97 g), with a yield of 52%.

[0228] (2) The operation steps are the same as those in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-(naphthyl-2-yl)-2-oxoethyl)pyridin-4(1H)-one (1.15 g, 3 mmol), yielding a gray solid (R)-3-(benzyloxy)-1-(2-(naphthyl-2-yl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (832.60 mg), with a yield of 72%.

[0229] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-(naphth-2-yl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (385.46 mg, 1 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(naphth-2-yl)ethyl)-2-methylpyridin-4(1H)-one (175.19 mg) is obtained, with a yield of 53%.

[0230] mp203~204℃; 1 H NMR (400MHz, DMSO-d6) δ10.71 (d, J=26.8Hz, 1H),

[0231] 8.27(dd,J=6.8,2.3Hz,1H),8.16(s,1H),8.05-7.89(m,3H),7.75(d,J=8.6Hz,1H),7.69-7.63(m,1H),7. 57(dt,J=5.9,2.5Hz,2H),5.75(dd,J=8.2,4.9Hz,1H),5.06-4.96(m,1H),4.96-4.86(m,1H),2.54(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.14,142.78,140.73,134.70,133.65,132.98,132.54,12 8.51,128.06,127.65,127.25,126.92,126.72,125.30,108.96,73.63,60.07,14.07.

[0232] Example 30

[0233] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(naphth-2-yl)ethyl)-2-methylpyridin-4(1H)-one (30)

[0234] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with 2-bromo-2'-naphthylacetophenone (5.46 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-2-methyl-1-(2-(naphth-2-yl)-2-oxoethyl)pyridin-4(1H)-one (3.73 g), with a yield of 49%.

[0235] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-(naphthyl-2-yl)-2-oxoethyl)pyridin-4(1H)-one (1.15 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-(naphthyl-2-yl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (823.35 mg), with a yield of 71%.

[0236] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-(naphthyl-2-yl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (385.46 mg, 1 mmol), and a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(naphthyl-2-yl)ethyl)-2-methylpyridin-4(1H)-one (187.13 mg) is obtained, with a yield of 56%.

[0237] mp203~204℃; 1 H NMR (400MHz, DMSO-d6) δ10.73 (s, 1H), 8.27 (d, J = 6.7

[0238] Hz,1H),8.16(s,1H),8.02-7.92(m,3H),7.75(d,J=8.6Hz,1H),7.65(d,J=6.8Hz,1H),7.58(dd,J=6.5,3 .3Hz,2H),5.75(dd,J=8.2,4.9Hz,1H),5.01(t,J=9.7Hz,1H),4.91(dd,J=11.7,4.8Hz,1H),2.54(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.13,142.77,140.73,134.70,133.66,132.98,132.54,12 8.51,128.05,127.65,127.24,126.92,126.72,125.29,108.95,72.98,60.07,14.07.

[0239] Example 31

[0240] Preparation method of (R)-3-hydroxy-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (31)

[0241] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 3-(2-bromoacetyl)pyridine hydrobromide (4.38 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)pyridine-4(1H)-one (3.39 g), with a yield of 51%.

[0242] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)pyridin-4(1H)-one (1.00 g, 3 mmol), to obtain a gray solid (R)-3-(benzyloxy)-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (701.38 mg), with a yield of 70%.

[0243] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (R)-3-(benzyloxy)-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (336.39 mg, 1 mmol), and a white solid (R)-3-hydroxy-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (144.75 mg) is obtained, with a yield of 51%.

[0244] mp240~241℃; 1 H NMR (400MHz, DMSO-d6) δ10.77-10.57(m,1H),9.03(s,1H),8.86(d,J=5.5Hz,1H),8.67(d,J=8.1Hz,1H),8.25(d,J=6.6Hz,1H),8.05(dd,J=8.2,5. 5Hz,1H),7.50(d,J=6.7Hz,1H),6.63(s,1H),5.36(dd,J=7.0,3.8Hz,1H),4.62(dd,J=10.2,3.8Hz,1H),4.42(dd,J=10.1,7.2Hz,1H),2.53(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.12,143.15,142.75,141.69,140.86,140.23,140.15,133.70,126.53,108.52,73.69,67.49,13.90.

[0245] Example 32

[0246] Preparation method of (S)-3-hydroxy-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (32)

[0247] (1) The operation steps are the same as those in Example 1, except that 2-bromoacetophenone is replaced with 3-(2-bromoacetyl)pyridine hydrobromide (4.38 g, 22 mmol), yielding a yellow solid 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)pyridine-4(1H)-one (3.97 g), with a yield of 59%.

[0248] (2) The operation steps are the same as step (2) in Example 1, except that 3-(benzyloxy)-2-methyl-1-(2-oxo-2-phenylethyl)pyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)pyridin-4(1H)-one (1.00 g, 3 mmol), and the catalyst is replaced with (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (95.43 mg, 0.15 mmol), yielding a gray solid (S)-3-(benzyloxy)-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (699.36 mg), with a yield of 69%.

[0249] (3) The operation steps are the same as those in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with (S)-3-(benzyloxy)-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (336.39 mg, 1 mmol), to obtain a white solid (S)-3-hydroxy-1-(2-hydroxy-2-(pyridin-3-yl)ethyl)-2-methylpyridin-4(1H)-one (143.06 mg), with a yield of 51%.

[0250] mp240~241℃; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.04(s,1H),8.87(d,J=5.6Hz,1H),8.70(d,J=8.2Hz,1H),8.25(d,J=6.5Hz,1H),8.06(t,J=6.9Hz,1H), 7.50(d,J=6.6Hz,1H),6.92-6.43(m,1H),5.36(dd,J=6.9,3.7Hz,1H),4.63(dd,J=10.3,3.8Hz,1H),4.42(dd,J=10.2,6.9Hz,1H),2.53(s,3H). 13CNMR(100MHz,DMSO-d6)δ158.11,143.42,142.77,141.35,140.59,140.40,140.16,133.68,126.66,108.54,73.68,67.46,13.89.

[0251] Example 33

[0252] Preparation method of 3-hydroxy-2-methyl-1-phenylethylpyridin-4(H)-one (33):

[0253] (1) The operation steps are the same as those in Example 1 (1), except that 2-bromoacetophenone is replaced with β-bromoacetoethane (4.07 g, 22 mmol), and a yellow solid 3-(benzyloxy)-2-methyl-1-phenylethylpyridin-4(1H)-one (3.77 g) is obtained, with a yield of 59%.

[0254] (2) The operation steps are the same as step (3) in Example 1, except that (R)-3-(benzyloxy)-1-(2-hydroxy-2-phenylethyl)-2-methylpyridin-4(1H)-one is replaced with 3-(benzyloxy)-2-methyl-1-phenylethylpyridin-4(1H)-one (319.16 mg, 1 mmol), and a white solid 3-hydroxy-2-methyl-1-phenylethylpyridin-4(H)-one (116.93 mg) is obtained, with a yield of 51%.

[0255] mp231~232℃; 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 8.10 (d, J = 7.0

[0256] Hz,1H),7.34–7.24(m,4H),7.22(d,J=1.7Hz,1H),7.20(d,J=1.3Hz,1H),4.58(dd,J=8.1,6.7Hz,2H),3.10(t,J=7.4Hz,2H),2.51(s,3H). 13 C NMR (100MHz, DMSO-d6) δ158.62,142.85,141.43,138.08,136.59,129.05,128.60,127.02,110.49,56.74,35.41,12.41.

[0257] Example 34

[0258] The following are pharmacological experimental data for some of the compounds in this invention:

[0259] 1. Determination of the compound's chelating ability for iron ions

[0260] Based on the principles of spectrophotometry, an automated titration system is used to analyze pK. a The system includes: an automatic titrator, a pH meter, a UV-Vis spectrophotometer, and a computer with a pre-programmed VB interface.

[0261] pK a Titration: Add 45 mL (0.1 M) potassium chloride solution to a 50 mm path length cuvette to correct the baseline. Add 40 μL of saturated Na₂EDTA solution and 1.5 M hydrochloric acid to acidify to approximately pH 2. Add 20 μL of 50 mM DMSO solution of the analyte and stir at a constant speed. After the absorption spectrum stabilizes, begin automatic titration. Add 0.1 M KOH solution dropwise using an automatic burette, controlling the amount added to just increase the pH of the solution by 0.1 units. After the addition is complete, wait 30 seconds after the system has reached pH equilibrium, and then automatically acquire a full-wavelength spectrum. The system automatically repeats the automatic titration operation until the pH reaches the specified endpoint value.

[0262] Determination of Logβ1: Add 45 mL of 0.1 M potassium chloride solution to a 50 mm quartz cuvette to correct the baseline. Acidify with 1.5 M hydrochloric acid to approximately pH 2.1. Add 60 μL of 50 mM working solution and allow to stabilize for 2 min. Add acidic FeCl3 solution at a ratio of ligand / ferric ion = 1.1 / 1 and stir at a constant speed. After the OD value stabilizes, add a certain amount of 4 M HCl solution using an automatic burette to lower the pH by 0.1 units. Once the pH stabilizes, begin monitoring the spectrum. If the maximum value of the absorption curve also stabilizes, collect and save the entire spectral signal. Repeat the cycle until the specified pH value is reached.

[0263] Determination of Logβ2 and Logβ3: Add 45 mL of 0.1 M KCl solution to a quartz cuvette with a path length of 50 mm. Allow the spectrum to stabilize before baseline correction. Acidify with 1.5 M hydrochloric acid to approximately pH 2.5. Add a 50 mM solution of the analyte and allow to stabilize for 2 min. Add an acidic FeCl3 solution at a ligand / ferric ion ratio of 5:1 and stir at a constant speed. After the OD value stabilizes, add a certain amount of 0.1 M KOH solution using an automatic burette to raise the pH by 0.1 unit. After the pH stabilizes for 1 min, begin acquiring and saving a full-spectrum signal. Repeat this cycle until the specified pH value is reached.

[0264] The above criteria for determining pH stability are: when the pH value changes by no more than 0.001 within 3 seconds, the pH reading is considered stable. All data measured during the process are recorded and backed up using an internal Visual Basic program. The pH value is determined according to the above method. a1 pKa2 The values ​​of Logβ1, Logβ2, and Logβ3 are then used to fit and calculate pFe using HYSS software. 3+ .

[0265] The results showed that more than half of the pFe in Examples 1-32 3+ The values ​​are generally greater than 19, indicating that this series of compounds exhibits excellent iron ion chelating activity. In particular, Example 4 shows a high pFe... 3+ The value was 21.93, which is better than the iron chelating activity of the control drug Defriprone used in this experiment. Furthermore, it was found in the embodiments of this invention that the configuration of the compounds had little effect on the iron chelating ability results, indicating that this series of compounds also has great potential for further research.

[0266] Table 1. pFe of Examples 1-32 3+ value

[0267]

[0268]

[0269] a: Compounds were measured in 0.1M KCl.

[0270] b: Deferiprone reported in the literature Reference value (0.1 KCl).

[0271] 2. Determination of the antioxidant capacity of compounds

[0272] The antioxidant activity of the compounds was studied using two testing methods: ABTS and ORAC. The results of the two methods were combined to screen out compounds with better antioxidant activity.

[0273] 2.1ABTS

[0274] ABTS (2,2'-azido-bis-(3-ethylbenzodihydrothiazoline)-6-sulfonic acid) reacts directly with potassium persulfate (K2S2O8) to directly generate a stable cationic free radical (ABTS). ·+ At this point, the system turns green and has absorbance at 415 nm. The solutions used in the experiment were prepared as follows: (1) ABTS ·+ Preparation of stock solution: Accurately weigh ABTS and dissolve it in purified water to prepare 7mM, accurately weigh K2S2O8 and dissolve it in pure water to a concentration of 2.45mM, mix them in equal volumes, and react at room temperature and in the dark for 16h. After the reaction, centrifuge and dilute with PBS buffer (pH=7.4) to 100μM. (2) Preparation of Trolox and test compound solutions: Quinolone dimethacrylate (Trolox) was selected as a positive control. Accurately weigh Trolox and the compound to prepare a 10mM stock solution, and then dilute with PBS buffer to the required concentration. Set the parameters of the microplate reader, add 50μL of the above-prepared compound solutions of different concentrations to a 96-well plate using a pipette, and then add 150μL of ABTS solution to each well using a pipette. Shake for 30s, incubate at 30℃ for 6min, and measure the absorbance at 415nm. Each compound experiment was repeated three times. The data was fitted into GraphPad Prism 8.0 software to calculate the IC50 of the compound. 50 value.

[0275] The antioxidant results are shown in Table 2. It can be clearly seen that most compounds have stronger antioxidant capacity than Trolox, with 10 having the strongest antioxidant capacity (5.22±1.61). Based on the combined data, the S configuration has better antioxidant capacity than the R configuration.

[0276] Table 2. Antioxidant results of ABTS in Examples 1-31

[0277]

[0278]

[0279] 2.2 ORAC

[0280] The antioxidant capacity index (ORAC) detection method is a commonly used method in the field of antioxidant research. This method uses sodium fluorescein as a fluorescent indicator, 2,2'-azobisisobutylamidine dihydrochloride (AAPH) to provide peroxy free radicals, and the vitamin E water-soluble analog Trolox as a quantitative standard. The attenuation of fluorescence intensity by the antioxidant is used as the standard for its antioxidant capacity. (1) Preparation of standard solution Trolox and test sample solution: Accurately weigh the Trolox standard and compound to prepare a 10 mM concentration as the stock solution, and store it at -20℃ in the dark. Dilute the stock solution with phosphate buffer (PBS, pH=7.4) to a series of concentrations of 20, 40, 60, 80, and 100 μM. (2) Preparation of sodium fluorescein solution: Accurately weigh the sodium fluorescein and prepare a 10 mM stock solution with DMSO, and then dilute it with PBS to 65 nM. (3) Preparation of AAPH solution: Accurately weigh AAPH and directly prepare 20mM solution with PBS. Set the microplate reader parameters, prepare the solution as shown above, first add 40μL of different concentrations of the test compound or Trolox to the black 96-well plate using a pipette, then add 80μL of sodium fluorescein solution to the black 96-well plate using a multi-channel pipette, incubate at 37℃ and shake for 5min, and finally add 80μL of AAPH to the 96 wells within 1min using a multi-channel pipette, shake for 30s and then take the reading. Continuously measure the fluorescence intensity at an excitation wavelength (Ex) of 485nm and an emission wavelength (Em) of 538nm. Maintain the entire system at 37℃, measure the fluorescence intensity every 5min for 300min, and perform three parallel measurements for each group. The results are as follows. Figure 1 As shown.

[0281] The net area (net AUC) of the compound at different concentrations was calculated using GraphPad Prism 8.0 software. The ORAC equivalent (μmol / L Trolox eq.) of the test compound at different concentrations was calculated according to the regression equation. The ORAC results of two concentrations are shown in Table 3. The antioxidant activity of Example 24 was the highest.

[0282] Table 3 ORAC results for Examples 1-32

[0283]

[0284] Based on the combined antioxidant and iron chelating activities of ABTS and ORAC, Examples 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27, and 28 exhibited the best antioxidant and iron chelating activities. Since methods for inhibiting ferroptosis all address these two aspects, these compounds possess the potential to inhibit ferroptosis. Next, the inhibitory activity of Examples 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27, and 28 against erastin-induced ferroptosis will be investigated.

[0285] 3. Toxicity of the compound to HT22 cells

[0286] HT22 (mouse hippocampal neurons) are sensitive to ferroptosis. The toxicity of Examples 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27, and 28 to HT22 was first investigated to eliminate the influence of endogenous toxicity on the results. HT22 cells were seeded in 96-well plates (8000 cells / well) and cultured for 24 hours. The culture medium was discarded, and culture medium containing different concentrations of the drug was added. A blank control was set up with drug-free medium, and the cells were cultured for another 24 hours. Cell viability was determined by the MTT assay, and the results are shown below. Figure 2 As shown, the selected compound, like the positive control drug DFP, did not exhibit significant toxicity at 150 μM. While it showed some toxicity at 200 μM, cell viability remained above 90%. In conclusion, the compound showed virtually no significant toxicity to HT22 cells.

[0287] 4. Assay for the in vitro inhibitory activity against ferroptosis in HT22 cells

[0288] HT22 cells were seeded into 96-well plates (8000 cells / well) and cultured for 24 hours. The culture medium was then discarded, and medium containing different concentrations of the drug and medium containing erastin (10 μM) were added. The drug-free medium served as a blank control. Cells were cultured for another 24 hours. After 24 hours, cell viability was determined using the MTT assay, and EC50 was calculated using GraphPad Prism 8 software. 50 The results are shown in Table 4. It can be seen that all the compounds exhibited activity in inhibiting ferroptosis, and their activity was higher than that of the positive control drug DFP. If the compound lacks a hydroxyl group on its linkage chain, then EC... 50 A concentration greater than 500 μM indicates that the hydroxyl group is essential for improving anti-ferroptosis activity. Compared to CN128, the S-configuration compounds in the selected examples exhibited superior anti-ferroptosis activity. Among them, compound 24 showed the best anti-ferroptosis activity, more than 5 times that of DFP, indicating that this compound has the potential for further investigation.

[0289] Table 4 shows the inhibition of ferroptosis EC in the selected embodiments. 50 result

[0290]

[0291] Note: Compound 33 is the compound designed by patent CN 115850163 A, and CN128 is the compound designed by patent CN111170936A.

[0292] .

Claims

1. A 3-hydroxypyridine-4(H)-one derivative of formula (I) and a pharmaceutically acceptable salt thereof: In formula (I), R 1 is a C1-C6 straight-chain alkyl group, R 2 For , or ; each Y1, Z1is independently H, C1-C6linear or branched alkyl, C1-C6linear or branched alkoxy, C1-C6linear or branched haloalkyl, or halogen.

2. The 3-hydroxypyridine-4(H)-one derivative and pharmaceutically acceptable salt thereof according to Claim 1, wherein The 3-hydroxypyridine-4(H)-ketone derivatives have the following structure: 。 3. The 3-hydroxypyridine-4(H)-one derivative and pharmaceutically acceptable salt thereof according to Claim 1, wherein: ###00002### The 3-hydroxypyridine-4-one derivative is one of the following compounds: 。 4. The use of the 3-hydroxypyridine-4(H)-one derivatives as described in claim 3 and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating related diseases by inhibiting ferroptosis.

5. The use according to claim 4, wherein: The disease in question is either a neurodegenerative disease or acute renal failure.

6. The use according to claim 4, characterized in that: The 3-hydroxypyridine-4(H)-one derivatives are compounds 3, 4, 9, 10, 17, 18, 19, 20, 21, 22, 23, 24, 27 or 28.

7. Use according to claim 6, wherein: The 3-hydroxypyridine-4(H)-one derivative is compound 24.

8. The method for preparing the 3-hydroxypyridine-4(H)-one derivative as described in claim 1, characterized in that... The 3-hydroxypyridine-4(H)-ketone derivatives are prepared according to the following method: (1) The hydroxyl-protected pyridinone shown in formula a, the 2-bromoethylone compound shown in formula b, and potassium carbonate are dissolved in N,N-dimethylformamide and stirred at room temperature for 4 h. The resulting reaction solution A is post-treated to obtain compound c. The molar ratio of the hydroxyl-protected pyridinone shown in formula a, the 2-bromoethylone compound shown in formula b, and potassium carbonate is 1:1.1:1.

1. (2) Dissolve the compound of formula c described in step (1) in methanol, add a ruthenium catalyst, stir at room temperature for 1 h under nitrogen protection and room temperature, then add a mixed solution of triethylamine and formic acid dropwise. After the addition is complete, continue stirring at room temperature for 3 h to obtain reaction solution B, and perform post-treatment B. The molar ratio of the metal catalyst to the compound of formula c is 1:0.05~0.15; the molar ratio of the triethylamine, formic acid and the compound of formula c is 1:0.004:0.0024; the ruthenium catalyst is (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride or (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride; the post-treatment B is: concentrate the reaction solution B under reduced pressure to remove the solvent, extract with dichloromethane, wash with water, dry, and then react at a ratio of 2:1 and 1:

1. The target product was purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate. The eluent was collected, concentrated under reduced pressure, and dried to obtain compound d. (3) dissolving the compound of formula d obtained in step (2) in dichloromethane, slowly adding 1.0 mol / L boron trichloride solution in dichloromethane under nitrogen protection at -10°C, after dropping, continuing to react at -10°C for 30 min, transferring to room temperature and continuing to stir for 8-12 h, and then treating the obtained reaction liquid C to obtain the 3-hydroxypyridine-4(H)-one derivative shown in formula (I); the molar ratio of the compound of formula d to boron trichloride in the boron trichloride solution in dichloromethane in step (3) is 1:3-6; .

9. The method for preparing the 3-hydroxypyridine-4(H)-one derivative as described in claim 8, characterized in that: The volume of N,N-dimethylformamide in step (1) is 4-5 mL / mmol, calculated as the amount of the 2-bromoethylone compound represented by formula a. The post-treatment A in step (1) is as follows: the reaction solution A is poured into a separatory funnel, washed with water, extracted with ethyl acetate, dried, and purified by column silica gel chromatography with a mixed solution of dichloromethane and methanol in volume ratios of 100:1, 80:1, and 50:

1. The eluent of the target product is collected, concentrated under reduced pressure, and dried to obtain the compound shown in formula c. In step (2), the methanol content of compound c is 5-10 mL / mmol. The post-treatment B in step (2) is as follows: the reaction solution B is concentrated under reduced pressure to remove the solvent, extracted with dichloromethane, washed with water, dried, purified by column chromatography with a mixed solvent of petroleum ether and ethyl acetate in a ratio of 2:1 and 1:1, the eluent of the target product is collected, concentrated under reduced pressure and dried to obtain compound d.

10. The method for preparing the 3-hydroxypyridine-4(H)-one derivative as described in claim 8, characterized in that: The volume of dichloromethane mentioned in step (3) is 10-20 mL / mmol in terms of the amount of substance of compound d; The post-treatment C in step (3) is as follows: methanol A is added dropwise to the obtained reaction solution C to quench the reaction, the solvent is removed by vacuum distillation, methanol B is added dropwise at 65°C to dissolve the solid, after complete dissolution, the solution is naturally cooled to room temperature, diethyl ether is added, the solution is cooled at -20°C for 2 h, the solution is filtered, and the resulting filter cake is dried under vacuum to obtain the 3-hydroxypyridine-4(H)-ketone derivative shown in formula (Ⅰ); the volume ratio of methanol B to diethyl ether is 1:5.

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