A carbazole alkaloid analogue, its preparation method and application

Abstract

The application discloses a compound shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, co-crystal or solvate thereof, takes natural product antiostatin A7 with a neuroprotective effect as a guide, synthetizes structural analogs, and modifies C1 and C2 substituents to construct a series of novel carbazole derivatives. In the preparation process, anhydrous ethanol is used as a solvent, Aldol condensation and concentrated sulfuric acid dehydration are integrated into one-pot operation, high-purity intermediates are obtained, raw materials are easy to obtain, and operation is simple, and the synthesis efficiency is improved. The compound provided by the application can inhibit neural cell ferroptosis and has no obvious toxicity. In an animal MCAO model, the compound shows a good ischemic stroke protection effect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a carbazole compound, its preparation method, and its application. Background Technology

[0002] Stroke is a disease caused by various factors that damage cerebrovascular vessels, resulting in focal or systemic brain tissue damage. It is characterized by high incidence, high disability rate, high recurrence rate, and high mortality rate, and is one of the leading causes of death and long-term disability worldwide, imposing a heavy economic and care burden on society and families. Clinically, it is mainly divided into two categories: hemorrhagic stroke and ischemic stroke, with ischemic stroke being the most prevalent type, accounting for over 70% of cases.

[0003] Currently, the main drugs used in the clinical treatment of ischemic stroke fall into three categories: thrombolytics, antiplatelet agents, and neuroprotective agents, each playing a crucial role in restoring cerebral blood flow, inhibiting thrombus progression, and reducing neurological damage. However, existing clinical drugs have limitations to varying degrees, such as strict dosing windows, potential bleeding risks, and hepatotoxicity and nephrotoxicity, all of which affect medication use to varying degrees. The clinical need for stroke-related drugs urgently requires the discovery of new targets and new drugs.

[0004] Pathological studies have shown a close link between neurological diseases and ferroptosis in neurons, and targeted inhibition of ferroptosis can provide an effective intervention for neurological diseases. Our research group previously reported a class of alkaloids with a carbazole core structure, namely antiozatin compounds. Among them, compounds such as Antiostatin A7 can inhibit ferroptosis induced by the ferroptosis modeler erastin in various neurons, including PC12 and HT-22, demonstrating good neuroprotective effects. In this invention, a series of novel carbazole alkaloids based on the structural characteristics of natural antiozatin were designed and synthesized through a rational synthetic route. Some of the compounds involved in this invention exhibit low toxicity and good anti-ferroptosis activity, and can effectively reduce the area of ​​cerebral ischemia-induced injury in a mouse MCAO model. The structural formulas of the antiostatin compounds are as follows:

[0005] Therefore, it is particularly important to develop a carbazole alkaloid analog with neuroprotective effects. Summary of the Invention

[0006] This invention provides a novel, low-toxicity, and highly active neuroprotective agent that can be used alone or in combination with other drugs for the treatment and recovery of central nervous system diseases such as ischemic stroke. The specific technical solution is as follows: This invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof. (I) Wherein, R1 is selected from one of the following groups: C 1-6 Alkyl, pyridyl, pyrazinyl, furanyl, benzofuranyl, benzothiophenyl, thiophenyl, thiazolyl, phenyl substituted with one or more X groups, thiophenyl substituted with one or more X groups; wherein the X group is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, or halogen; R2 is H or CH3.

[0007] As a preferred option, when R1 is C 1-6 When R1 is an alkyl group, the alkyl group is methyl or n-hexyl; when R1 is a substituted phenyl group, the X group thereon is independently selected from methyl, methoxy, trifluoromethyl, cyano, chlorine, or fluorine; when R1 is pyridyl or pyrazinyl, it is 2-pyridyl or 2-pyrazinyl; when R1 is furanyl or benzofuran substituent, it is 2-furanyl or 2-benzofuranyl; when R1 is thiazolyl, it is 2-thiazolyl; when R1 is thienyl, it is 2-thienyl; when R1 is benzothienyl, it is... 2-Benzothienyl; when R1 is alkylthiophenyl, it is selected from 3-methyl-2-thiophenyl, 4-methyl-2-thiophenyl, or 3,4-dimethyl-2-thiophenyl; when R1 is methoxythiophenyl, it is 4-methoxy-2-thiophenyl; when R1 is halothiophenyl, it is selected from 3-bromo-2-thiophenyl, 4-bromo-2-thiophenyl, 5-bromo-2-thiophenyl, 5-chloro-2-thiophenyl, 4,5-dichloro-2-thiophenyl, or 2,5-dichloro-3-thiophenyl.

[0008] Furthermore, preferably, when R1 is an alkoxyphenyl substituted with X, the alkoxyphenyl is selected from 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl; when R1 is a phenyl substituted with X and the phenyl is substituted with one or more substituents selected from fluorine, chlorine, trifluoromethyl, or cyano, the phenyl is 4-cyanophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 4-cyanophenyl, 2-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, or 2,3-dichlorophenyl.

[0009] Further, R1 is methyl, n-hexyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-pyridyl, 2-pyrazinyl, 2-furanyl, 2 -Benzofuranyl, 2-thiazolyl, 2-thienyl, 2-benzothienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 3,4-dimethyl-2-thienyl, 4-methoxy-2-thienyl, 3-bromo-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 4,5-dichloro-2-thienyl, 2,5-dichloro-3-thienyl.

[0010] Furthermore, the compound shown in formula (I) or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate has a structure shown in any one of k1-k61:

[0011] Preferably, the structure is one of the following compounds:

[0012] The present invention also provides a method for synthesizing the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic or solvate, wherein the preparation method is as follows: (1) The compound shown in formula (II), the compound shown in formula (III), and basic substance A are dissolved in organic solvent A, and a condensation reaction is carried out at -20~50 °C (preferably -10~20 °C, more preferably 0~10 °C) for 0.5~24 hours. After the reaction is completed, acidic substance A is added, and the reaction is carried out at 40~180 °C (preferably 50~90 °C). The mixture undergoes a dehydration reaction at ℃ (1~24 hours, preferably 2~8 hours), is cooled to room temperature, and a solid precipitates after standing. It is then filtered, the residue is washed with anhydrous ethanol, and the residue is collected to obtain the compound shown in formula (IV). The molar ratio of the compound shown in formula (II), the compound shown in formula (III), basic substance A, and acidic substance A is 1:0.8~3.0:0.05~2.0:0.5~5.0 (preferably 1:1.0~2.0:0.1~1.0:1.0~2.0, more preferably 1:1.0~1.2:0.05~0.2:1.0~1.2). (2) The compound of formula (IV) and the compound of formula (V) obtained in step (1) are dissolved in organic solvent B with basic substance B and undergo a cyclization reaction at 30~180 °C (preferably 40~90 °C, more preferably 56 °C) for 1~24 hours (preferably 1~8 hours). The crude product is obtained by vacuum concentration and purified by column chromatography to obtain the compound of formula (I). The molar ratio of the compound of formula (IV), the compound of formula (V) and basic substance B is 1:0.8~3.0:0.5~3.0 (preferably 1:1.0~2.0:1.0~2.0).

[0013] Furthermore, the organic solvent A in step (1) or the organic solvent B in step (2) is an alcohol solvent, wherein the alcohol solvent is methanol, ethanol or isopropanol (preferably anhydrous ethanol).

[0014] Furthermore, the alkaline substance A mentioned in step (1) is sodium hydroxide, potassium hydroxide, or DBU (preferably sodium hydroxide).

[0015] Furthermore, the acidic substance A mentioned in step (1) is sulfuric acid, phosphoric acid, polyphosphoric acid or hydrochloric acid (preferably concentrated sulfuric acid).

[0016] Furthermore, the alkaline substance B mentioned in step (2) is sodium hydroxide, potassium hydroxide, or DBU (preferably DBU).

[0017]

[0018] In formula (III), R1 is the same as R1 in the compound shown in formula (I), R1 in formula (IV) is the same as R1 in the compound shown in formula (I), and R1 in formula (V) is the same as R1 in the compound shown in formula (I).

[0019] The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic or solvate thereof in the preparation of a medicament for inhibiting ferroptosis of nerve cells.

[0020] Some of the compounds provided in this invention have shown good inhibitory effects on neuronal ferroptosis in RSL3-induced neuronal cell ferroptosis models and animal models of stroke, and have good prospects for the development of anti-ferroptosis neuroprotective drugs. Figure 1 ).

[0021] Most of the compounds provided in this invention showed significant inhibitory effects on neuronal ferroptosis in the RSL3-induced HT22 cell ferroptosis model, with a significant increase in neuronal cell survival rate and an average half-maximal concentration (EC50). 50 All are at a low level. Figure 2 ).

[0022] Regarding cytotoxicity, most compounds showed no significant cytotoxicity to HT22 cells, and some compounds even exhibited certain cell proliferation activity, demonstrating a good safety window. Figure 3 ).

[0023] In a focal cerebral ischemia-reperfusion injury (MCAO) model in male SD rats, compared with the model group, the MCAO+k17 group and the MCAO+k34 group showed a significant reduction in cerebral infarction area. Among them, the MCAO+k17 group showed a greater reduction in cerebral infarction area than the MCAO+k34 group, demonstrating that compounds k17 and k34 have good protective effects against ferroptosis in vivo. Figure 4 , 5 ).

[0024] The innovation of this invention lies in: 1. This invention uses aniostatin A7, a natural product with neuroprotective effects, as a lead compound. Systematic substitutions were made at its C1 position to introduce cyclic structures such as aromatic rings, five-membered heterocycles, and aromatic heterocycles. Simultaneously, parallel modifications of the C2 position, including methylation and unmethylation, were performed to construct a series of novel carbazole derivatives. This provides a rich structural basis for in-depth exploration of the structure-activity relationship of different substituents in the carbazole skeleton against ferroptosis.

[0025] 2. High-efficiency preparation and purification: A one-step high-efficiency preparation process was developed—using anhydrous ethanol as a solvent, the Aldol condensation and concentrated sulfuric acid dehydration are integrated into a "one-pot" operation. The product crystallizes directly from the reaction solution, and only filtration and drying are needed to obtain a high-purity intermediate, eliminating the column chromatography or recrystallization steps required in traditional routes. This method uses readily available raw materials, is simple to operate, significantly improves synthesis efficiency, and overcomes the technical bottleneck of complex natural product structures that are difficult to synthesize in total.

[0026] 3. Green solvents and flexible catalysis: The entire process uses low-toxicity and inexpensive anhydrous ethanol to replace traditional toxic solvents such as benzene or halogenated hydrocarbons; in the cyclization reaction of step (2), both organic base DBU and inorganic base NaOH / KOH can be used for efficient catalysis, providing a dual option for high-yield preparation in the laboratory and cost control in industrialization.

[0027] 4. The carbazole derivatives described in this invention exhibit significant inhibitory activity in the ferroptosis cell model, and some compounds show better activity than the parent compound Antiostatin A7, while exhibiting lower cytotoxicity.

[0028] The beneficial effects of this invention include: 1. This invention successfully obtained a novel carbazole analog with significant anti-ferroptosis activity, which not only retains the inhibitory ability of antiosaturin compounds on the ferroptosis pathway, but also overcomes the defects of limited natural sources, complex structure making total synthesis difficult, poor bioavailability, and high cytotoxicity, thus advancing the drug development process of this type of compound.

[0029] 2. This invention provides a new candidate drug direction for stroke, a disease with high incidence and high disability rate and a lack of effective neuroprotective drugs, enriches the pipeline of neuroprotective drugs based on the mechanism of ferroptosis inhibition, and has potential clinical translational application value. Attached Figure Description

[0030] Figure 1 For compound (1) M) Anti-ferroptosis neuroprotective activity.

[0031] Figure 2 ECMO of some compounds in RSL3-induced ferroptosis in HT22 cells 50 value.

[0032] Figure 3 For compound (10 M) Cytotoxicity.

[0033] Figure 4 TTC staining results of brain slices from a focal cerebral ischemia-reperfusion (MCAO) model in male SD rats.

[0034] Figure 5 The percentage of cerebral infarction area in each group of rats. Detailed Implementation

[0035] Example 1: Synthesis of compound k1

[0036] Place 1 eq. of 4-fluoroacetophenone in a 25 ml round-bottom flask, add 4 ml of anhydrous ethanol solution to dissolve it completely, and stir well under ice bath conditions. Add 0.1 eq. of NaOH and stir for 5-10 minutes. Add 1.1 eq. of o-nitrobenzaldehyde in small batches, and after complete dissolution, remove the ice bath and react at room temperature for 2-3 hours. Monitor the reaction by TLC. Add 1 eq. of concentrated sulfuric acid and transfer to a 90°C container. The mixture was heated to reflux in an oil bath for 2-3 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, the rotor was removed, and the mixture was allowed to precipitate. The precipitate was filtered and washed with anhydrous ethanol. The precipitate was collected to obtain the α,β-unsaturated ketone compound represented by formula (Ⅳ). The yield was 51%.

[0037] The α,β-unsaturated ketone compound of formula (Ⅳ) (1 eq.) and ethyl acetoacetate (1.1 eq.) were placed in a dry two-necked flask, dissolved in 5 mL of anhydrous EtOH, followed by the addition of DBU (1 eq.). Heating at C for 2-3 hours resulted in a clear, brownish-yellow solution, which was monitored by TLC. The crude product was concentrated under reduced pressure. Purification was achieved by column chromatography using 200-300 mesh silica gel, eluting with petroleum ether / dichloromethane = 3 / 2, yielding compound k1 in 30% yield. 1 H NMR (400 MHz, DMSO- d 6): d 11.00 (1H, s), 9.70 (1H, s), 7.88 (1H, d, J = 8.0 Hz), 7.71–7.67 (2H, m),7.48 (1H, d, J = 8.2 Hz), 7.43–7.33 (3H, m), 7.08 (1H, t, J = 7.6 Hz), 6.98(1H, s), 4.49 (2H, q, J = 7.2 Hz), 1.37 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.2, 162.0, 149.2, 141.2, 134.1, 131.1, 130.6, 126.8, 125.9,121.7, 120.7, 120.0, 118.4, 116.0, 115.1, 111.8, 111.2, 61.0, 14.2. HR-ESI-MS: calcd for C 21 H 17 FNO3 + [M + H] + , 350.1187; found 350.1192.

[0038] Example 2 Synthesis of compound k2

[0039] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-nonanone (1.1 eq.) in a yield of 30%. d 11.31 (1H, s), 9.84 (1H, s), 7.96 (1H, d, J = 8.1 Hz), 7.49 (1H, d, J =8.3 Hz), 7.34 (1H, t, J = 7.5 Hz), 7.05 (1H, t, J = 7.8 Hz), 6.89 (1H, s), 4.47 (2H, q, J = 7.4 Hz), 2.88 (2H, t, J = 7.8 Hz), 1.69–1.65 (2H, m), 1.38(3H, t, J = 7.2 Hz), 1.32–1.23 (8H, m), 0.85 (3-H, t, J = 7.2 Hz). 13 C NMR (100 MHz, DMSO-) d 6): d 168.9, 150.7, 140.6, 132.5, 130.0, 125.4, 122.3, 121.1,118.7, 118.0, 115.0, 111.4, 108.2, 60.9, 31.3, 30.8, 29.3, 28.9, 28.7, 22.1,14.2, 14.0. HR-ESI-MS: calcd for C 22 H 28 NO3+ [M + H] + , 354.2064; found 354.2067.

[0040] Example 3 Synthesis of compound k3

[0041] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylthiophene (1.1 eq.) in a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6): d 11.07 (1H, s), 9.69 (1H, s), 7.85 (1H,d, J = 8.2 Hz), 7.74 (1H, d, J = 5.0 Hz), 7.67 (1H, d, J = 3.7 Hz), 7.58 (1H,d, J = 8.2 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.33 (1H, t, J = 4.5 Hz), 7.15–7.10(2H, m), 4.49 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.9, 148.6, 141.2, 139.2, 130.2, 128.6, 126.6, 126.4, 126.1,121.5, 120.6, 120.6, 120.2, 118.7, 114.1, 112.1, 112.0, 61.0, 14.2. HR-ESI-MS: calcd for C 19 H 16 NO3S + [M + H] + , 338.0845; found 338.0849.

[0042] Example 4 Synthesis of compound k4

[0043] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylfuran (1.1 eq.) in a yield of 34%.1 H NMR (400 MHz, DMSO- d 6): d 11.03 (1H, s), 9.71 (1H, s), 7.92 (1H,dd, J = 0.6, 1.8 Hz), 7.87 (1H, d, J = 8.1 Hz), 7.65 (1H, d, J = 8.2 Hz, 8-H), 7.43–7.38 (2H, m), 7.24 (1H, dd, J = 0.8, 3.5 Hz), 7.14–7.10 (1H, m), 6.78 (1H, dd, J =1.6, 1.8 Hz), 4.49 (2H, q, J = 7.2 Hz), 1.38 (3H, t, J = 7.1Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.0, 150.4, 148.7, 143.3, 141.2, 128.5,126.2, 121.5, 120.8, 120.4, 118.7, 116.3, 112.3, 112.1, 111.9, 110.4, 108.4,61.0, 14.2. HR-ESI-MS: calcd for C 19 H 16 NO4 + [M + H] + , 322.1074; found 322.1079.

[0044] Example 5 Synthesis of compound k5

[0045] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylthiazol (1.1 eq.) in a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6): d 11.39 (s, 1H), 9.80 (s, 1H), 8.13 (d, J = 3.2 Hz, 1H), 7.91 (d, J= 3.3 Hz, 1H), 7.83–7.78 (m, 2H), 7.53 (s, 1H), 7.44–7.40 (m, 1H), 7.16–7.12 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.38 (t, J =7.1 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6): d 167.5, 165.7, 147.8, 144.0, 141.1,129.8, 126.5, 121.2, 121.0, 120.2, 119.9, 119.0, 117.2, 115.0, 112.7, 112.6,61.2, 14.2. HR-ESI-MS: calcd for C 18 H 15 N2O3S + [M + H] + , 339.0798; found339.0799.

[0046] Example 6 Synthesis of compound k6

[0047] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 4'-trifluoromethylacetophenone (1.1 eq.) in a yield of 26%. 1 H NMR (400 MHz, DMSO- d 6): d 11.12 (1H, s), 9.75 (1H, s), 7.95(2H, d, J = 8.3 Hz), 7.91–7.87 (3H, m), 7.49 (1H, d, J = 8.2 Hz), 7.40–7.36(1H, m), 7.13–7.11 (1H, m), 7.07 (1H, s), 4.51 (2H, q, J = 7.1 Hz), 1.39 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.0, 148.9, 141.9, 141.3,131.0, 129.4, 128.3, 127.8, 126.1, 126.0, 124.4, 121.6, 120.6, 120.2, 118.6,115.1, 112.3, 111.8, 61.0, 14.2. HR-ESI-MS: calcd for C 22 H 17 F3NO3 + [M + H] + ,400.1155; found 400.1154.

[0048] Example 7 Synthesis of compound k7

[0049] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylpyridine (1.1 eq.) in a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6): d 11.68 (1H, s), 9.69 (1H, s), 8.87 (1H,d, J = 4.7 Hz), 8.06–7.99 (2H, m), 7.88 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J =8.2 Hz), 7.62 (1H, s, 7.48–7.45 (1H, m), 7.42–7.38 (1H, m), 7.14–7.10 (1H,m), 4.52 (2H, q, J = 7.2 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.0, 155.6, 149.2, 148.3, 140.8, 137.6, 131.5, 126.1, 123.1,122.5, 121.4, 121.0, 120.7, 120.0, 118.5, 113.7, 113.1, 112.1, 61.1, 14.2.HR-ESI-MS: calcd for C 20 H 17 N2O3+ [M + H] + , 333.1234; found 333.1235.

[0050] Example 8 Synthesis of compound k8

[0051] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylpyrazine (1.1 eq.) in a yield of 30%. 1 H NMR (400 MHz, DMSO- d 6): d 11.55 (1H, s), 9.75 (1H, s), 9.30 (1H,d, J = 1.5 Hz), 8.88 (1H, dd, J = 1.6, 2.6 Hz), 8.71 (1H, d, J = 2.6 Hz), 7.86 (1H, dd, J = 1.1, 8.1 Hz), 7.71–7.69 (2H, m), 7.43–7.40 (1H, m), 7.16–7.12 (1H, m), 4.52 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100MHz, DMSO- d 6): d 167.8, 151.2, 148.0, 143.8, 143.0, 142.8, 141.0, 131.5,126.3, 121.3, 120.9, 120.4, 120.0, 118.8, 114.8, 113.4, 112.2, 61.2, 14.2.HR-ESI-MS: calcd for C 19 H 16 N3O3 + [M + H] + , 334.1186; found 334.1193.

[0052] Example 9 Synthesis of compound k9

[0053] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with o-chloroacetophenone (1.1 eq.) in a yield of 25%. 1H NMR (400 MHz, DMSO- d 6): d 10.85 (1H, s), 9.68 (1H, s), 7.88 (1H, d, J = 7.8 Hz), 7.70–7.66 (1H, m), 7.57–7.50 (3H, m), 7.43 (1H, d, J = 8.0 Hz),7.36–7.32 (1H, m), 7.11–7.07 (1H, m), 6.89 (1H, s), 4.51 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.2, 148.3, 141.0,136.4, 132.6, 131.8, 131.6, 130.0, 129.9, 127.6, 125.9, 125.2, 121.6, 120.6,119.4, 118.3, 115.9, 111.8, 111.6, 61.0, 14.2. HR-ESI-MS: calcd for C 21 H 17 ClNO3 + [M + H] + , 366.0891; found 336.0896.

[0054] Example 10 Synthesis of compound k10

[0055] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-methoxyacetophenone (1.1 eq.) in a yield of 27%. 1 H NMR (400 MHz, DMSO- d 6): d 11.03 (1H, s), 9.72 (1H, s), 7.89 (1H,d, J= 8.0 Hz), 7.53–7.49 (2H, m), 7.38–7.34 (1H, m), 7.24–7.20 (2H, m), 7.11–7.05 (2H, m), 7.02 (1H, s), 4.50 (2H, q, J = 7.1 Hz), 3.86 (3H, s), 1.38(3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.3, 159.6, 149.2, 141.2,139.2, 131.0, 130.3, 127.7, 125.9, 121.7, 120.7, 120.7, 120.0, 118.4, 115.0,113.8, 113.7, 111.9, 111.3, 61.0, 55.2, 14.2. HR-ESI-MS: calcd for C 22 H 20 NO4 + [M + H] + , 362.1387; found 362.1394.

[0056] Example 11 Synthesis of compound k11

[0057] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with o-trifluoromethylacetophenone (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.76 (1H, s), 9.67 (1H, s), 7.95(1H, dd, J = 1.4, 8.0 Hz), 7.88 (1H, d, J = 8.1 Hz), 7.84–7.80 (1H, m), 7.76–7.22 (1H, m), 7.53 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.36–7.32(1H, m), 7.11–7.07 (1H, m), 6.86 (1H, s), 4.51 (2H, q, J= 7.1 Hz), 1.39 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.2, 148.0, 141.0, 136.1,132.6, 132.4, 132.1, 128.8, 127.9, 126.3, 125.9, 125.1, 124.1, 121.6, 120.5,119.1, 118.3, 115.9, 111.7, 111.5, 61.0, 14.2. HR-ESI-MS: calcd for C 22 H 17 F3NO3 + [M + H] + , 400.1155; found 400.1160.

[0058] Example 12 Synthesis of compound k12

[0059] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylbenzofuran (1.1 eq.) in a yield of 43%. 1 H NMR (400 MHz, DMSO- d 6): d 11.25 (1H, s), 9.79 (1H, s), 7.86(1H, d, J = 8.0 Hz), 7.79–7.77 (2H, m), 7.71 (1H, d, J = 7.3 Hz), 7.70 (1H, s), 7.61 (1H, s), 7.48–7.40 (2H, m), 7.36–7.32 (1H, m), 7.19–7.14 (1H, m), 4.51 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d167.7, 154.1, 152.6, 148.2, 141.3, 129.4, 128.7, 126.4, 125.0, 123.5,121.4, 121.3, 121.1, 120.3, 119.0, 115.2, 113.7, 112.1, 111.6, 111.5, 104.4,61.3, 14.2. HR-ESI-MS: calcd for C 23 H 18 NO4 + [M + H] + , 372.1230; found 372.1234.

[0060] Example 13 Synthesis of compound k13

[0061] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylbenzothiophene (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 11.26 (1H, s), 9.77 (1H, s), 8.07(1H, dd, J =1.3, 7.5 Hz), 8.00–7.98 (2H, m), 7.86 (1H, d, J = 8.0 Hz), 7.61(1H, d, J = 8.2 Hz), 7.50–7.40 (3H, m), 7.26 (1H, s), 7.17–7.13 (1H, m), 4.51(2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.8, 148.4, 141.3, 140.5, 139.2, 138.7, 130.6, 126.3, 124.9, 124.9, 124.1,123.1, 122.4, 121.4, 120.7, 120.6, 119.7, 118.9, 114.6, 112.9, 112.0, 61.1,14.2. HR-ESI-MS: calcd for C23 H 18 NO3S + [M + H] + , 388.1002; found 388.1006.

[0062] Example 14 Synthesis of compound k14

[0063] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with p-cyanoacetophenone (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 11.14 (1H, s), 9.75 (1H, s), 8.07–8.04 (2H, m), 7.90–7.86 (3H, m), 7.50 (1H, d, J = 8.2 Hz), 7.41–7.37 (1H, m), 7.14–7.10 (1H, m), 7.06 (1H, s), 4.51 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.0, 148.8, 142.6, 141.3, 133.0,130.9, 129.6, 126.2, 125.6, 121.5, 120.6, 120.3, 118.9, 118.7, 115.1, 112.7,111.8, 110.5, 61.1, 14.2. HR-ESI-MS: calcd for C 22 H 17 N2O3 + [M + H] + , 357.1234;found 357.1237.

[0064] Example 15 Synthesis of compound k15

[0065] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with p-methoxyacetophenone (1.1 eq.) in a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6): d10.99 (1H, s), 9.69 (1H, s), 7.93 (1H,d, J = 8.0 Hz), 7.64–7.60 (2H, m), 7.52 (1H, d, J = 8.2 Hz), 7.37–7.33 (1H,m), 7.17–7.14 (2H, m), 7.11–7.07 (1H, m), 6.99 (1H, s), 4.51 (2H, q, J = 7.1Hz), 3.85 (3H, s), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.4, 159.1, 149.6, 141.2, 131.1, 130.0, 129.7, 127.9, 125.7, 121.8, 120.8,119.9, 118.3, 114.8, 114.6, 111.9, 110.4, 61.0, 55.3, 14.2. HR-ESI-MS: calcdfor C 22 H 20 NO4 + [M + H] + , 362.13868; found 362.1376.

[0066] Example 16 Synthesis of compound k16

[0067] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with o-methoxyacetophenone (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.66 (1H, s), 9.63 (1H, s), 7.90 (1H,d, J = 8.1 Hz), 7.51–7.43 (2H, m), 7.37–7.30 (2H, m), 7.22 (1H, dd, J =1.0, 8.5 Hz), 7.12 (1H, td, J =1.1, 7.4 Hz), 7.09–7.05 (1H, m), 6.90 (1H, s), 4.50(2H, q,J = 7.1 Hz), 3.75 (3H, s), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.5, 156.7, 148.8, 140.8, 132.0, 130.9, 129.6, 126.3, 125.6,125.5, 121.7, 120.7, 120.6, 118.9, 118,0, 116.2, 111.7, 111.5, 110.7, 60.9,55.3, 14.2. HR-ESI-MS: calcd for C 22 H 20 NO4 + [M + H] + , 362.13868; found362.1381.

[0068] Example 17 Synthesis of compound k17

[0069] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-methylthiophene (1.1 eq.) in a yield of 37%. 1 H NMR (400 MHz, DMSO- d 6): d 11.03 (1H, s), 9.71 (1H, s), 7.86(1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 3.5 Hz),7.41–7.37 (1H, m), 7.14–7.10 (2H, m), 7.00 (1H, dd, J =1.3, 3.6 Hz), 4.49(2H, q, J = 7.1 Hz), 2.55 (3H, s), 1.37 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.0, 148.8, 141.2, 140.0, 136.9, 130.1, 126.9, 126.4, 126.1,121.6, 120.7, 120.6, 120.5, 118.7, 113.7, 112.1, 111.5, 61.0, 15.1, 14.2. HR-ESI-MS: calcd for C 20 H 18 NO3S + [M + H] + , 352.10019; found 352.0992.

[0070] Example 18 Synthesis of compound k18

[0071] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetylthiophene (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 11.01 (1H, s), 9.73 (1H, s), 7.96 (1H,dd, J = 1.3, 2.9 Hz), 7.93 (1H, d, J = 8.1 Hz), 7.80 (1H, dd, J = 2.9, 5.0Hz), 7.59–7.54 (2H, m), 7.40–7.36 (1H, m), 7.15 (1H, s), 7.13–7.09 (1H, m), 4.51 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.3, 149.3, 141.2, 138.0, 130.9, 127.7, 127.2, 125.9, 123.8, 122.8,121.8, 120.8, 120.2, 118.5, 114.5, 112.0, 111.0, 61.0, 14.2. HR-ESI-MS: calcdfor C 19 H 16 NO3S + [M + H]+ , 338.08454; found 338.0843.

[0072] Example 19 Synthesis of compound k19

[0073] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-chloro-6-fluoroacetophenone (1.1 eq.) in a yield of 27%. 1 H NMR (400 MHz, DMSO- d 6): d 10.99 (1H, s, 9-NH), 9.70 (1H, s,3-OH), 7.87 (1H, d, J = 8.0 Hz, 5-H), 7.62–7.54 (2H, m, 8, 3'-H), 7.46–7.34 (3H, m, 7, 4', 5'-H), 7.13–7.09 (1H, m, 6-H), 6.91 (1H, s, 2-H), 4.51 (2H, q, J = 7.1 Hz, 12-H), 1.39 (3H, t, J = 7.1 Hz, 13-H). 13 C NMR (100 MHz, DMSO- d 6): d 168.0, 160.3, 148.1, 140.9, 134.2, 132.0. 131.1, 126.1, 125.8, 124.4,121.5, 120.5, 119.6, 118.5, 118.1, 116.3, 115.0, 112.7, 111.5, 61.1, 14,2.HR-ESI-MS: calcd for C 21 H 16 ClFNO3 + [M + H] + , 384.0797; found 384.0800.

[0074] Example 20 Synthesis of compound k20

[0075] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-chloro-4-fluoroacetophenone (1.1 eq.) in a yield of 29%. 1 H NMR (400 MHz, DMSO- d 6): d11.16 (1H, s), 8.61 (1H, dd, J =1.0, 8.4 Hz), 7.89 (1H, s), 7.46–7.34 (4H, m), 7.23–7.15 (2H, m), 7.06 (1H, s), 4.72 (2H, q, J = 7.2 Hz), 1.60 (3H, t, J = 7.2 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 171.3, 162.8, 157.4, 140.7, 134.3, 132.7, 132.3, 132.1, 129.1,126.6, 125.6, 122.6, 120.6, 119.3, 117.9, 117.6, 115.0, 111.1, 106.4, 62.1,14.6. HR-ESI-MS: calcd for C 21 H 16 ClFNO3 + [M + H] + , 384.0797; found 384.0801.

[0076] Example 21 Synthesis of compound k21

[0077] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,3-dichloroacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.91 (1H, s), 9.71 (1H, s), 7.88 (1H,d, J = 8.0 Hz), 7.79 (1H, dd, J = 1.7, 7.9 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.48 (1H, dd, J = 1.8, 7.7 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.38–7.34 (1H, m), 7.12–7.08 (1H, m), 6.90 (1H, s), 4.51 (2H, q, J= 7.1 Hz), 1.39 (3H, t, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.1, 148.3, 141.0, 138.8, 132.4,131.4, 131.0, 130.4, 130.4, 128.6, 126.0, 124.9, 121.6, 120.5, 119.4, 118.4,115.5, 112.2, 111.5, 61.0, 14.2. HR-ESI-MS: calcd for C 21 H 16 Cl2NO3 + [M + H] + ,400.05018; found 400.0502.

[0078] Example 22 Synthesis of compound k22

[0079] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,5-dichloroacetophenone (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.95 (1H, s), 9.71 (1H, s), 7.87 (1H,d, J = 8.1 Hz), 7.72–7.70 (1H, m), 7.63–7.60 (2H, m), 7.42 (1H, d, J = 8.0Hz), 7.38–7.34 (1H, m), 7.12–7.08 (1H, m), 6.91 (1H, s), 4.51 (2H, q, J = 7.1Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.1, 148.2,141.0, 138.1, 132.0, 131.6, 131.5, 131.5, 131.3, 129.8, 126.0, 123.7, 121.6,120.5, 119.5, 118.4, 115.7, 112.4, 111.5, 61.1, 14.2. HR-ESI-MS: calcd forC 21 H 16 Cl2NO3 + [M + H] + , 400.05018; found 400.0500.

[0080] Example 23 Synthesis of compound k23

[0081] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,4-dichloroacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.92 (1H, s), 9.72 (1H, s), 7.89–7.85 (2H, m), 7.61 (1H, dd, J = 2.1, 8.3 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.41 (1H,d, J = 8.1 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.10 (1H, t, J = 7.5 Hz), 6.90 (1H,s), 4.51 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.1, 148.4, 141.0, 135.4, 133.8, 133.7, 133.1, 131.6, 129.3,127.8, 126.0, 124.0, 121.6, 120.6, 119.4, 118.4, 115.7, 112.2, 111.5, 61.1,14.2. HR-ESI-MS: calcd for C21 H 16 Cl2NO3 + [M + H] + , 400.05018; found 400.0500.

[0082] Example 24 Synthesis of compound k24

[0083] Place 1 eq. of 4-fluoroacetophenone in a 25 ml round-bottom flask, add 4 ml of anhydrous ethanol solution to dissolve it completely, and stir well under ice bath conditions. Add 0.1 eq. of NaOH and stir for 5-10 minutes. Add 1.1 eq. of o-nitrobenzaldehyde in small batches until completely dissolved, then remove the ice bath and react at room temperature for 2-3 hours. Monitor the reaction by TLC. Add 1 eq. of concentrated sulfuric acid and transfer to a 90°C container. The mixture was heated to reflux in an oil bath for 2-3 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, the rotor was removed, and the mixture was allowed to precipitate. The precipitate was filtered and washed with anhydrous ethanol. The precipitate was collected to obtain the α,β-unsaturated ketone compound represented by formula (Ⅳ). The yield was 51%.

[0084] The α,β-unsaturated ketone compound of formula (Ⅳ) (1 eq.) and ethyl propionyl acetate (1.1 eq.) were placed in a dry two-necked flask, dissolved in 5 mL of anhydrous EtOH, followed by the addition of DBU (1 eq.). Heating at C for 2-3 hours resulted in a clear, brownish-yellow solution, which was monitored by TLC. The crude product was concentrated under reduced pressure. Purification was achieved by column chromatography using 200-300 mesh silica gel, eluting with petroleum ether / dichloromethane = 3 / 2, yielding compound k24 in 29% yield. 1 H NMR (400 MHz, DMSO- d 6): d 10.55 (1H, s), 10.34 (1H, s), 8.20 (1H, d, J = 8.2 Hz), 7.46–7.39 (5H, m), 7.31 (1H, t, J = 7.8 Hz), 7.08 (1H, t, J = 7.8 Hz), 4.60 (2H, q, J = 7.2 Hz),2.10 (3H, s), 1.44 (3H, t, J = 7.0 Hz). 13 C NMR (100 MHz, DMSO- d 6): d170.0,161.9, 151.4, 140.7, 132.9, 132.8, 131.7, 129.4, 125.2, 123.1, 122.8, 121.1,118.1, 116.4, 115.9, 111.6, 108.1, 61.4, 14.2, 13.8. HR-ESI-MS: calcd forC 22 H 19 FNO3 + [M + H] + , 364.1343; found 364.1339.

[0085] Example 25 Synthesis of compound k25

[0086] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylthiophene (1.1 eq.) in a yield of 34%. 1 H NMR (400 MHz, DMSO- d 6): d 10.71 (1H, s), 10.08 (1H, s), 8.13(1H, dd, J = 1.1, 8.2 Hz), 7.83 (1H, dd, J = 1.2, 5.2 Hz), 7.49 (1H, d, J =8.2 Hz), 7.35–7.31 (2H, m), 7.23 (1H, dd, J = 1.2, 3.4 Hz), 7.11–7.07 (1H,m), 4.58 (2H, q, J = 7.1 Hz), 2.21 (3H, s), 1.43 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO-) d 6): d 169.6, 150.2, 140.6, 136.3, 133.7, 128.6, 127.9, 127.5,125.4, 124.6, 122.8, 122.1, 121.0, 118.3, 116.5, 111.7, 109.9, 61.5, 14.2,14.1. HR-ESI-MS: calcd for C 20 H 17NO3S [M + H] + , 352.1002; found 352.1001.

[0087] Example 26 Synthesis of compound k26

[0088] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylfuran (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.90 (1H, s), 9.94 (1H, s), 8.08 (1H,dd, J = 1.0, 8.0 Hz), 7.95 (1H, dd, J =0.8, 1.84 Hz), 7.57 (1H, d, J = 8.2Hz), 7.37–7.33 (1H, m), 7.12–7.08 (1H, m), 6.87 (1H, dd, J =0.8, 3.4 Hz), 6.79 (1H, dd, J =1.8, 3.4 Hz), 4.57 (2H, q, J = 7.1 Hz), 2.36 (3H, s), 1.43(3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.4. 149.6, 148.8, 143.5,140.6, 132.1, 125.5, 123.2, 122.5, 120.7, 118.4, 118.2, 117.1, 111.9, 111.8,111.5, 110.5, 61.5, 14.3, 14.1. HR-ESI-MS: calcd for C 20 H 17 NO4 [M + H] + ,336.1230; found 336.1229.

[0089] Example 27 Synthesis of compound k27

[0090] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 4'-trifluoromethylacetophenone (1.1 eq.), with a yield of 26%. 1 H NMR (400 MHz, DMSO- d 6): d 10.60 (1H, s), 10.21 (1H, s),8.17 (1H, d, J = 8.2 Hz), 7.96 (2H, d, J = 8.0 Hz), 7.64 (2H, d, J = 7.9 Hz), 7.42 (1H, d, J = 8.0 Hz), 7.34–7.30 (1H, m), 7.11–7.07 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.09 (3H, s), 1.44 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.8, 141.0, 140.8, 132.4, 130.6, 128.5, 128.4, 125.8, 125.4,124.4, 122.9, 122.6, 121.0, 118.2, 116.7, 111.5, 109.0, 61.4, 14.1, 13.7. HR-ESI-MS: calcd for C 23 H 18 F3NO3 [M + H] + , 414.1312; found 414.1315.

[0091] Example 28 Synthesis of compound k28

[0092] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with o-chloroacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.61 (1H, s), 10.20 (1H, s), 8.18 (1H,d, J= 8.2 Hz), 7.72–7.69 (1H, m), 7.60–7.53 (2H, m), 7.42–7.39 (2H, m), 7.34–7.29 (1H, m), 7.11–7.07 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.02 (3H, s), 1.45 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.8, 150.6, 140.7,135.3, 133.0, 132.5, 131.6, 130.1, 129.8, 127.9, 127.3, 125.3, 123.2, 122.9,121.1, 118.2, 116.5, 111.5, 109.0, 61.4, 14.2, 13.5. HR-ESI-MS: calcd forC 22 H 18 ClNO3 [M + H] + , 380.1048; found 380.1048.

[0093] Example 29 Synthesis of compound k29

[0094] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-methoxyacetophenone (1.1 eq.) in a yield of 19%. 1 H NMR (400 MHz, DMSO- d 6): d 10.52 (1H, s), 10.36 (1H, s),8.20 (1H, d, J = 8.2 Hz), 7.51 (1H, t, J = 8.1 Hz), 7.46 (1H, d, J = 8.0 Hz),7.32–7.28 (1H, m), 7.10–7.06 (2H, m), 6.96–6.94 (2H, m), 4.60 (2H, q, J = 7.1Hz), 3.83 (3H, s), 2.12 (3H, s), 1.45 (3H, t, J = 7.1 Hz). 13C NMR (100 MHz, DMSO- d 6): d 170.0, 159.5, 151.5, 140.7, 137.9, 132.6, 130.3, 130.0, 125.2,123.1, 122.6, 121.7, 121.1, 118.1, 116.4, 114.9, 113.5, 111.6, 107.8, 61.4,55.1, 14.2, 13.8. HR-ESI-MS: calcd for C 23 H 21 NO4 [M + H] + , 376.1543; found376.1547.

[0095] Example 30 Synthesis of compound k30

[0096] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with o-trifluoromethylacetophenone (1.1 eq.) in 18% yield. 1 H NMR (400 MHz, DMSO- d 6): d 10.57 (1H, s), 10.17 (1H, s),8.17 (1H, d, J = 8.2 Hz), 7.99 (1H, dd, J = 1.3, 8.2 Hz), 7.88–7.84 (1H, m),7.79–7.75 (1H, m), 7.40 (1H, d, J = 7.5 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.32–7.28 (1H, m), 7.10–7.06 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 1.94 (3H, s), 1.45(3H, t, J = 7.2 Hz). 13 C NMR (100 MHz, DMSO- d 6): d169.7, 150.3, 140.7, 135.2,133.1, 133.1, 132.0, 128.9, 128.1, 127.1, 126.5, 125.2, 123.9, 123.4, 122.9,120.9, 118.1, 116.1, 111.3, 109.0, 61.4, 14.1, 13.9. HR-ESI-MS: calcd forC 23 H 18 F3NO3 [M + H] + , 414.1312; found 414.1320.

[0097] Example 31 Synthesis of compound k31

[0098] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylbenzofuran (1.1 eq.) in a yield of 43%. 1 H NMR (400 MHz, DMSO- d 6): d 11.08 (1H, s), 9.88 (1H, s), 8.10(1H, d, J = 8.0 Hz), 7.79 (1H, dd, J = 1.3, 8.1 Hz), 7.74 (1H, dd, J = 1.0, 8.0 Hz), 7.54 (1H, d, J = 8.1 Hz), 7.44–7.40 (1H, m), 7.39–7.34 (2H, m), 7.30(1H, s), 7.15–7.11 (1H, m), 4.59 (2H, q, J = 7.1 Hz), 2.42 (3H, s), 1.44 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d169.1, 154.5, 151.2, 149.1,140.7, 132.8, 128.4, 125.7, 124.6, 124.5, 123.1, 122.4, 121.3, 120.7, 118.5,117.5, 117.2, 111.9, 111.7, 111.7, 108.3, 61.5, 14.4, 14.1. HR-ESI-MS: calcdfor C 24 H 18 NO4 [M + H] + , 386.1387; found 386.1389.

[0099] Example 32 Synthesis of compound k32

[0100] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetylbenzothiophene (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 10.89 (1H, s), 10.05 (1H, s),8.14 (1H, d, J = 8.2 Hz), 8.08 (1H, dd, J = 1.8, 7.3 Hz), 7.98 (1H, dd, J =1.8, 7.2 Hz), 7.55 (1H, s), 7.50–7.43 (3H, m), 7.35–7.31 (1H, m), 7.13–7.09(1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.28 (3H, s), 1.45 (3H, t, J = 7.1 Hz). 13 CNMR (100 MHz, DMSO- d 6): d 169.4, 149.9, 140.7, 140.3, 140.1, 137.1, 133.5,125.5, 125.3, 124.6, 124.5, 124.5, 124.1, 122.7, 122.4, 121.6, 120.9, 118.4,116.6, 111.6, 110.5, 61.5, 14.1, 14.1. HR-ESI-MS: calcd for C24 H 20 NO3 + [M + H] + ,401.1086; found 402.1157.

[0101] Example 33 Synthesis of compound k33

[0102] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with p-cyanoacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.60 (1H, s), 10.20 (1H, s), 8.16(1H, d, J = 8.2 Hz), 8.07–8.05 (2H, m), 7.63–7.61 (2H, m), 7.41 (1H, d, J =8.1 Hz), 7.34–7.30 (1H, m), 7.12–7.08 (1H, m), 4.59 (2H, q, J = 7.1 Hz), 2.09(3H, s), 1.44 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.6,141.8, 140.8, 132,9, 132.3, 131.0, 128.3, 125.5, 122.9, 122.6, 121.0, 118.9,118.3, 116.7, 111.5, 110.8, 109.3, 61.5, 14.2, 13.8. HR-ESI-MS: calcd forC 23 H 20 N2O3 + [M + H] + , 373.1390; found 373.1386.

[0103] Example 34 Synthesis of compound k34

[0104] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with p-methoxyacetophenone (1.1 eq.) in a yield of 35%. 1H NMR (400 MHz, DMSO- d 6): d 10.50 (1H, s), 10.43 (1H, s),8.21 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 8.1 Hz), 7.34–7.27 (3H, m), 7.18–7.13 (2H, m), 7.09–7.05 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 2.11(3H, s), 1.45 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 170.2, 158.9,151.9, 140.7, 133.1, 130.8, 130.5, 128.6, 125.1, 123.2, 122.8, 121.2, 118.1,116.3, 114.4, 111.7, 107.4, 61.4, 55.2, 14.2, 13.9. HR-ESI-MS: calcd forC 23 H 22 NO4 + [M + H] + , 376.15433; found 376.1536.

[0105] Example 35 Synthesis of compound k35

[0106] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-methylthiophene (1.1 eq.) in a yield of 37%. 1 H NMR (400 MHz, DMSO- d 6): d 10.73 (1H, s), 10.12 (1H, s),8.14 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.34–7.30 (1H, m), 7.11–7.07 (1H, m), 7.00 (1H, s), 4.58 (2H, q, J= 7.1 Hz), 2.57 (3H, s), 2.23 (3H,s), 1.43 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.4,140.7, 140.6, 133.9, 133.7, 128.5, 126.2, 125.4, 124.5, 122.9, 122.5, 121.0,118.3, 116.4, 111.8, 109.5, 61.5, 15.0, 14.2, 14.1. HR-ESI-MS: calcd forC 21 H 20 NO3S + [M + H] + , 366.1158; found 366.1161.

[0107] Example 36 Synthesis of compound k36

[0108] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetylthiophene (1.1 eq.) in a yield of 32%. 1 H NMR (400 MHz, DMSO- d 6): d 10.58 (1H, s), 10.35 (1H, s), 8.20(1H, d, J = 8.2 Hz), 7.81 (1H, dd, J = 2.9, 4.9 Hz), 7.70 (1H, dd, J = 1.3, 2.9 Hz), 7.49 (1H, d, J = 8.2 Hz), 7.33–7.29 (1H, m), 7.24 (1H, dd, J = 1.3,4.9 Hz), 7.10–7.06 (1H, m), 4.59 (2H, q, J = 7.1 Hz), 2.17 (3H, s), 1.44 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d170.0, 151.4, 140.6, 136.2,133.1, 129.1, 126.7, 125.6, 125.3, 125.2, 123.2, 123.1, 121.2, 118.1, 116.4,111.7, 108.0, 61.5, 14.2, 14.0. HR-ESI-MS: calcd for C 20 H 18 NO3S + [M + H] + ,352.1002; found 352.1000.

[0109] Example 37 Synthesis of compound k37

[0110] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-chloro-6-fluoroacetophenone (1.1 eq.), with a yield of 27%. 1 H NMR (400 MHz, DMSO- d 6): d 10.66 (1H, s), 10.23 (1H, s),8.18 (1H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 2.4, 9.0 Hz), 7.48–7.39 (3H, m), 7.35–7.31 (1H, m), 7.12–7.08 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.03 (3H, s), 1.45 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.8, 162.0, 150.6,140.7, 134.1, 133.1, 132.8, 131.8, 126.3, 125.4, 123.5, 123.0, 121.1, 118.2,117.1, 116.5, 115.2, 111.4, 109.2, 61.5, 14.2, 13.5. HR-ESI-MS: calcd forC 22 H 18 ClFNO3 + [M + H] +, 398.09538; found 398.0948.

[0111] Example 38 Synthesis of compound k38

[0112] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-chloro-4-fluoroacetophenone (1.1 eq.), with a yield of 29%. 1 H NMR (400 MHz, DMSO- d 6): d 10.66 (1H, s), 10.23 (1H, s),8.18 (1H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 2.4, 9.0 Hz), 7.48–7.39 (3H, m), 7.35–7.31 (1H, m), 7.12–7.08 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.03 (3H, s), 1.45 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.8, 162.0, 150.6,140.7, 134.1, 133.1, 132.8, 131.8, 126.3, 125.4, 123.5, 123.0, 121.1, 118.2,117.1, 116.5, 115.2, 111.4, 109.2, 61.5, 14.2, 13.5. HR-ESI-MS: calcd forC 22 H 18 ClFNO3 + [M + H] + , 398.09538; found 398.0948.

[0113] Example 39 Synthesis of compound k39

[0114] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,3-dichloroacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d10.70 (1H, s), 10.16 (1H, s),8.16 (1H, d, J = 8.2 Hz), 7.82 (1H, dd, J = 1.5, 8.1 Hz), 7.56 (1H, t, J =7.9 Hz), 7.40–7.37 (2H, m), 7.35–7.31 (1H, m), 7.12–7.08 (1H, m), 4.60 (2H,q, J = 7.1 Hz), 2.02 (3H, s), 1.44 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.3, 140.7, 137.7, 132.4, 132.3, 131.3, 130.6, 130.4,128.9, 126.7, 125.5, 123.1, 122.9, 121.1, 118.3, 116.7, 111.4, 109.6, 61.5,14.2, 13.5. HR-ESI-MS: calcd for C 22 H 18 Cl2NO3 + [M + H] + , 414.06583; found414.0666.

[0115] Example 40 Synthesis of compound k40

[0116] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,5-dichloroacetophenone (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.74 (1H, s), 10.16 (1H, s),8.16 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 1.2, 8.8 Hz), 7.64 (1H, dd, J =2.5, 8.7 Hz), 7.53 (1H, d, J = 2.4 Hz), 7.41 (1H, d,J = 8.1 Hz), 7.35–7.31(1H, m), 7.12–7.08 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.04 (3H, s), 1.44 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.3, 140.7, 137.1,132.4, 132.3, 132.0, 131.4, 131.3, 130.1, 125.7, 125.5, 123.3, 122.9, 121.1,118.3, 116.7, 111.4, 109.7, 61.5, 14.2, 13.6. HR-ESI-MS: calcd for C 22 H 18 Cl2NO3 + [M + H] + , 414.0658; found 414.0658.

[0117] Example 41 Synthesis of compound k41

[0118] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,4-dichloroacetophenone (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.69 (1H, s), 10.18 (1H, s),8.16 (1H, d, J = 8.2 Hz), 7.89 (1H, dd, J = 1.9 Hz), 7.63 (1H, dd, J = 2.0, 8.2 Hz), 7.44 (1H, dd, J = 8.4 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.35–7.31 (1H,m), 7.12–7.08 (1H, m), 4.60 (2H, q, J = 7.1 Hz), 2.03 (3H, s), 1.44 (3H, t, J = 7.1 Hz).13 C NMR (100 MHz, DMSO- d 6): d 169.7, 150.4, 140.7, 134.3, 134.3,133.9, 133.0, 132.5, 129.4, 128.1, 126.0, 125.5, 123.3, 122.9, 121.1, 118.3,116.6, 111.4, 109.5, 61.5, 14.2, 13.5. HR-ESI-MS: calcd for C 22 H 18 ClNO3 + [M +H] + , 414.06583; found 414.0658.

[0119] Example 42 Synthesis of compound k42

[0120] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-4-methylthiophene (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.88 (1H, s), 9.66 (1H, s), 7.88(1H, d, J = 8.1 Hz), 7.64 (1H, d, J = 5.1 Hz), 7.50 (1H, dt, J = 8.1, 1.1Hz), 7.36 (1H, ddd, J = 8.1, 7.1, 1.1 Hz), 7.13 (1H, d, J = 5.1 Hz), 7.10(1H, ddd, J = 8.1, 7.1, 1.1 Hz), 6.97 (1H, d, J = 2.6 Hz), 4.50 (2H, q, J =7.1 Hz), 2.15 (4H, s), 1.39 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.0, 148.3, 141.0, 135.4, 132.3, 132.0, 130.8, 126.0, 125.5, 121.6, 120.6,120.0, 119.6, 118.4, 116.5, 112.0, 111.8, 61.0, 14.5, 14.1. HR-ESI-MS: calcdfor C 20 H 18 NO3S + [M + H] + , 352.10019; found 352.0995.

[0121] Example 43 Synthesis of compound k43

[0122] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-3-methylthiophene (1.1 eq.) in a yield of 30%. 1 H NMR (400 MHz, DMSO- d 6): d 10.89 (1H, s), 9.67 (1H, s), 7.86(1H, d, J = 8.1 Hz), 7.64 (1H, d, J = 5.1 Hz), 7.50 (1H, d, J = 8.1 Hz), 7.36(1H, ddd, J = 8.1, 7.0, 1.1 Hz), 7.13 (1H, d, J = 5.1 Hz), 7.10 (1H, ddd, J =8.1, 7.0, 1.1 Hz), 6.97 (1H, d, J = 2.7 Hz), 4.50 (2H, q, J = 7.1 Hz), 2.15(3H, s), 1.38 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d168.0, 148.3,141.0, 135.4, 132.3, 132.0, 130.8, 129.7, 126.0, 125.6, 121.5, 120.6, 119.9,119.6, 118.4, 116.5, 112.0, 111.8, 61.0, 14.5, 14.2. HR-ESI-MS: calcd forC 20 H 18 NO3S + [M + H] + , 352.10019; found 352.1007.

[0123] Example 44 Synthesis of compound k44

[0124] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,3-dimethyl-5-acetylthiophene (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.99 (1H, s), 9.68 (1H, s),7.86 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 8.1 Hz), 7.43 – 7.35 (2H, m), 7.11(1H, ddd, J = 8.1, 7.1, 1.1 Hz), 7.07 (1H, s), 4.48 (2H, q, J = 7.1 Hz), 2.41(3H, s), 2.23 (3H, s), 1.37 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6): d 168.0, 148.8, 141.2, 134.4, 134.1, 133.1, 130.0, 129.3, 126.0, 121.6, 120.7,120.7, 120.49, 118.68, 113.44, 112.03, 111.30, 60.99, 14.17, 13.62, 12.81.HR-ESI-MS: calcd for C 21 H 20 NO3S+ [M + H] + , 366.11584; found 366.1153.

[0125] Example 45 Synthesis of compound k45

[0126] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-chlorothiophene (1.1 eq.) in a yield of 30%. 1 H NMR (400 MHz, DMSO- d 6): d 11.12 (1H, s), 9.73 (1H, s), 7.83(1H, d, J = 8.0 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.9 Hz), 7.40(1H, td, J = 8.0, 6.9, 1.2 Hz), 7.35 (1H, d, J = 3.9 Hz), 7.13 (1H, td, J =7.5, 6.9, 1.2 Hz), 7.08 (1H, s), 4.49 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.7, 148.4, 141.3, 138.3, 130.2,128.2, 126.4, 126.3, 121.4, 120.7, 120.5, 118.9, 114.0, 112.7, 112.1, 61.1,14.2. HR-ESI-MS: calcd for C 19 H 15 ClNO3S + [M + H] + , 372.04557; found 372.0459.

[0127] Example 46 Synthesis of compound k46

[0128] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-bromothiophene (1.1 eq.) in a yield of 29%. 1 H NMR (400 MHz, DMSO- d 6): d 11.11 (1H, s), 9.72 (1H, s), 7.84(1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.46 (2H, dd), 7.40 (1H, ddd, J = 8.2, 7.1, 1.2 Hz), 7.12 (1H, ddd, J = 8.2, 7.1, 1.2 Hz), 7.09 (1H, s), 4.49 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.8, 148.5, 141.3, 140.9, 131.7, 130.2, 127.4, 126.3, 121.4, 120.7,120.5, 118.9, 118.9, 114.0, 112.7, 112.1, 111.6, 61.1, 14.2. HR-ESI-MS: calcdfor C 19 H 15 BrNO3S + [M + H] + , 415.99505; found 415.9949.

[0129] Example 47 Synthesis of compound k47

[0130] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-4-bromothiophene (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 11.15 (1H, s), 9.72 (1H, s), 7.86(1H, d, J = 1.2 Hz), 7.83 (1H, d,J = 8.1 Hz), 7.66 (1H, d, J = 1.2 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.41 (1H, ddd, J = 8.1, 7.0, 1.2 Hz), 7.14 (1H, s), 7.13(1H, ddd, J = 8.1, 7.0, 1.2 Hz), 4.49 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.7, 148.3, 141.3, 140.8, 130.1,128.3, 126.3, 124.0, 121.4, 120.7, 120.5, 118.9, 118.61, 113.8, 113.0, 112.0,110.0, 61.1, 14.2. HR-ESI-MS: calcd for C 19 H 15 BrNO3S + [M + H] + , 415.99505;found 415.9950.

[0131] Example 48 Synthesis of compound k48

[0132] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-3-bromothiophene (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 11.01 (1H, s), 9.70 (1H, s), 7.89(1H, d, J = 5.4 Hz), 7.84 (1H, d, J = 8.1 Hz), 7.49 (1H, d, J = 8.1 Hz), 7.37(1H, ddd, J = 8.1, 7.0, 1.2 Hz), 7.33 (1H, d, J= 5.4 Hz), 7.11 (1H, ddd, J =8.1, 7.0, 1.2 Hz), 7.01 (1H, s), 4.50 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.8, 147.8, 141.0, 133.7, 131.9,130.9, 128.2, 126.2, 121.4, 120.4, 119.8, 118.6, 117.8, 116.6, 113.24, 111.8,110.1, 61.1, 14.2. HR-ESI-MS: calcd for C 19 H 15 BrNO3S + [M + H] + , 415.99505;found 415.9954.

[0133] Example 49 Synthesis of compound k49

[0134] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetyl-2,5-dichlorothiophene (1.1 eq.) in a yield of 33%. 1 H NMR (400 MHz, Chloroform- d ): d 11.07 (1H, s), 8.57(1H, dd, J = 8.3, 1.0 Hz), 8.44 (1H, s), 7.49 (1H, d, J = 1.0 Hz), 7.48 (1H,ddd, J = 8.3, 3.2, 1.0 Hz), 7.30 – 7.19 (2H, m), 7.13 (1H, s), 4.71 (2H, q, J= 7.2 Hz), 1.60 (3H, t, J = 7.2 Hz). 13 C NMR (100 MHz, Chloroform- d ): d170.9,157.4, 140.8, 136.2, 131.2, 127.0, 125.9, 125.8, 125.7, 125.1, 123.1, 122.6,121.8, 119.7, 115.5, 111.4, 106.8, 62.2, 14.5. HR-ESI-MS: calcd forC 19 H 14 Cl2NO3S + [M + H] + , 406.00660; found 406.0068.

[0135] Example 50 Synthesis of compound k50

[0136] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetyl-2,5-dichlorothiophene (1.1 eq.) in a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6): d 11.03 (1H, s), 9.71 (1H, s),7.86 (1H, d, J = 8.1 Hz), 7.48 (1H, dt, J = 8.2, 1.0 Hz), 7.41 – 7.34 (2H,m), 7.11 (1H, ddd, J = 8.1, 7.0, 1.1 Hz), 7.00 (1H, s), 4.50 (2H, q, J = 7.1Hz), 1.38 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 167.9, 148.1,141.0, 135.3, 131.5, 128.7, 126.2, 125.6, 123.2, 121.5, 120.5, 119.9, 118.6,118.6, 115.6, 112.8, 111.7, 61.1, 14.2. HR-ESI-MS: calcd for C 19 H 14 Cl2NO3S + [M+ H] +, 406.00660; found 406.0060.

[0137] Example 51 Synthesis of compound k51

[0138] Following the steps of Example 1, 4-fluoroacetophenone (1.1 eq.) was replaced with 1-(5-methoxythiophene-2-yl)acetophenone (1.1 eq.) in a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6): d 11.03 (1H, s), 9.67 (1H, s),7.86 (1H, d, J = 8.1 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.38 (1H, ddd, J = 8.3,7.0, 1.2 Hz), 7.34 (1H, d, J = 4.0 Hz), 7.11 1H, (ddd, J = 8.1, 7.0, 1.1 Hz),7.01 (1H, s), 6.52 (1H, d, J = 4.0 Hz), 4.48 (2H, q, J = 7.1 Hz), 3.96 (3H,s), 1.37 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 168.01, 165.9,148.9, 141.2, 130.1, 126.0, 125.0, 124.8, 121.6, 120.7, 120.5, 118.7, 113.1,112.1, 111.0, 105.3, 61.0, 60.4, 14.2. HR-ESI-MS: calcd for C 20 H 18 NO4S + [M + H] + , 368.09511; found 368.0949.

[0139] Example 52 Synthesis of compound k52

[0140] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-4-methylthiophene (1.1 eq.) in a yield of 27%. 1 H NMR (400 MHz, DMSO- d 6): d 10.66 (1H, d, J = 4.4 Hz), 10.07(1H, s), 8.14 (1H, d, J = 8.2 Hz), 7.70 (1H, d, J = 5.2 Hz), 7.47 (1H, dt, J = 8.2, 1.0 Hz), 7.32 (1H, ddd, J = 8.2, 7.0, 1.0 Hz), 7.17 (1H, d, J = 5.2Hz), 7.09 (1H, ddd, J = 8.2, 7.0, 1.0 Hz), 4.59 (2H, q, J = 7.1 Hz), 2.12(3H, s), 1.96 (3H, s), 1.44 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.6, 150.1, 140.6, 136.0, 133.9, 130.6, 130.3, 126.1, 125.4, 125.3, 122.8,121.4, 121.0, 118.3, 116.2, 111.7, 109.9, 61.5, 14.2, 14.0, 13.8. HR-ESI-MS:calcd for C 21 H 20 NO3S + [M + H] + , 366.11584; found 366.1161.

[0141] Example 53 Synthesis of compound k53

[0142] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-3-methylthiophene (1.1 eq.) in a yield of 28%. 1H NMR (400 MHz, DMSO- d 6): d 10.66 (1H, s), 10.06 (1H, s),8.13 (1H, d, J = 8.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.47 (1H, dt, J = 8.2, 1.0 Hz), 7.32 (1H, ddd, J = 8.2, 7.0, 1.0 Hz), 7.17 (1H, d, J = 5.1 Hz), 7.09(1H, ddd, J = 8.2, 7.0, 1.0 Hz), 4.59 (2H, q, J = 7.1 Hz), 2.12 (3H, s), 1.96(3H, s), 1.44 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.6, 150.1,140.6, 136.0, 133.9, 130.5, 130.3, 126.1, 125.4, 125.3, 122.8, 121.4, 121.0,118.2, 116.2, 111.7, 109.9, 61.4, 14.1, 13.9, 13.7. HR-ESI-MS: calcd forC 21 H 20 NO3S + [M + H] + , 366.11584; found 366.1159.

[0143] Example 54 Synthesis of compound k54

[0144] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2,3-dimethyl-5-acetylthiophene (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.69 (1H, s), 10.10 (1H, s), 8.13 (1H, d, J= 8.2 Hz), 7.50 (1H, dt, J = 8.2, 1.0 Hz), 7.32 (1H, ddd, J = 8.2, 7.0, 1.0 Hz), 7.08 (1H, ddd, J = 8.2, 7.0, 1.0 Hz), 6.91 (1H, s), 4.58 (2H, q, J = 7.1 Hz), 2.42 (3H, s), 2.23 (3H, s), 2.22 (3H, s), 1.43 (3H,t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.6, 150.4, 140.5, 133.6,133.6, 133.4, 131.3, 125.3, 124.3, 122.8, 122.6, 121.0, 118.2, 116.3, 111.7,109.3, 61.4, 14.1, 14.0, 13.5, 12.8. HR-ESI-MS: calcd for C 22 H 22 NO3S + [M + H] + ,380.13149; found 380.1305.

[0145] Example 55 Synthesis of compound k55

[0146] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-chlorothiophene (1.1 eq.) in a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6): d 10.87 (1H, s), 9.95 (1H, s), 8.09(1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.38 – 7.30 (2H, m), 7.14 –7.06 (2H, m), 4.57 (2H, q, J = 7.1 Hz), 2.23 (3H, s), 1.42 (3H, t,J = 7.1Hz). 13 C NMR (100 MHz, DMSO- d 6): d 169.3, 149.5, 140.6, 135.6, 133.8, 128.9,128.7, 127.7, 125.6, 125.0, 122.6, 120.9, 120.4, 118.4, 116.6, 111.7, 110.9,61.5, 14.1, 14.0. HR-ESI-MS: calcd for C 20 H 17 ClNO3S + [M + H] + , 386.06122; found386.0615.

[0147] Example 56 Synthesis of compound k56

[0148] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-5-bromothiophene (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.86 (1H, s), 9.84 (1H, s), 8.09(1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 3.8 Hz), 7.34(1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.6 Hz), 7.07 (1H, d, J = 3.8 Hz), 4.57(2H, q, J = 7.1 Hz), 2.22 (3H, s), 1.42 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d169.3, 149.6, 140.6, 138.3, 133.7, 131.2, 129.7, 125.6, 124.9,122.6, 120.9, 120.5, 118.5, 116.6, 112.2, 111.7, 110.9, 61.5, 14.1, 14.1. HR-ESI-MS: calcd for C 20 H 17 BrNO3S + [M + H] + , 430.01070; found 430.0105.

[0149] Example 57 Synthesis of compound k57

[0150] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-4-bromothiophene (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, DMSO- d 6): d 10.84 (1H, s), 9.94 (1H, s), 8.09(1H, d, J = 8.1 Hz), 7.96 (1H, d, J = 1.3 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.34(1H, ddd, J = 8.1, 7.0, 1.3 Hz), 7.26 (1H, d, J = 1.4 Hz), 7.10 (1H, ddd, J =8.1, 7.0, 1.3 Hz), 4.56 (2H, t, J = 7.1 Hz), 2.21 (3H, s), 1.41 (3H, d, J =7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d169.3, 149.5, 140.6, 138.3, 133.6,130.5, 125.6, 125.3, 124.8, 122.6, 120.8, 120.4, 118.4, 116.6, 111.6, 110.9,109.3, 61.5, 14.1, 14.0. HR-ESI-MS: calcd for C 20 H 17 BrNO3S + [M + H] + ,430.01070; found 430.0108.

[0151] Example 58 Synthesis of compound k58

[0152] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 2-acetyl-3-bromothiophene (1.1 eq.) in a yield of 26%. 1 H NMR (400 MHz, DMSO- d 6): d 10.83 (1H, s), 9.86 (1H, s), 8.08(1H, d, J = 8.1 Hz), 7.95 (1H, d, J = 5.4 Hz), 7.45 (1H, dt, J = 8.1, 1.0Hz), 7.37 (1H, d, J = 5.4 Hz), 7.34 (1H, ddd, J = 8.1, 7.0, 1.0 Hz), 7.10(1H, ddd, J = 8.1, 7.0, 1.0 Hz), 4.58 (1H, d, J = 7.1 Hz), 2.12 (3H, s), 1.43(3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d169.2, 149.1, 140.6, 133.7,132.4, 130.5, 128.9, 122.5, 120.8, 119.2, 118.4, 116.5, 111.6, 111.4, 61.5,14.1, 13.8. HR-ESI-MS: calcd for C 20 H 16 BrNO3S + [M + H] + , 430.01070; found430.0106.

[0153] Example 59 Synthesis of compound k59

[0154] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetyl-2,5-dichlorothiophene (1.1 eq.) in a yield of 24%. 1 H NMR (400 MHz, Chloroform- d ): d 11.56 (1H, s), 8.51 (1H, dd, J = 8.4, 1.0 Hz), 8.06 (1H, s), 7.46 – 7.35 (2H, m), 7.20 (1H, ddd, J = 8.4, 5.2, 3.1 Hz), 6.95 (1H, s), 4.69 (2H, q, J = 7.1 Hz), 2.35 (3H, s), 1.58 (3H, t, J = 7.1 Hz). 13 C NMR (100 MHz, DMSO- d 6): d 171.6, 156.2, 140.0,134.1, 133.1, 127.9, 126.2, 125.9, 125.7, 125.3, 124.5, 122.5, 122.2, 119.3,117.8, 111.0, 106.4, 62.1, 14.5, 14.0. HR-ESI-MS: calcd for C 20 H 16 Cl2NO3S + [M +H] + , 420.02225; found 420.0226.

[0155] Example 60 Synthesis of compound k60

[0156] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 3-acetyl-2,5-dichlorothiophene (1.1 eq.) in a yield of 28%. 1 H NMR (400 MHz, DMSO- d 6): d 10.88 (1H, s), 10.02 (1H, s), 8.12 (1H, d, J = 8.2 Hz), 7.45 (1H, dt, J = 8.2, 1.0 Hz), 7.35 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.27 (1H, s), 7.10 (1H, ddd, J = 8.2, 7.0, 1.2 Hz),4.58 (2H, q, J = 7.1 Hz), 2.14 (3H, s), 1.43 (3H, t, J = 7.1 Hz). 13 C NMR (101MHz, DMSO- d 6): d 169.4, 149.8, 140.6, 134.5, 132.8, 128.8, 125.8, 125.6,124.4, 124.2, 122.7, 121.0, 120.5, 118.3, 116.6, 111.4, 110.4, 61.5, 14.2,13.7. HR-ESI-MS: calcd for C 20 H 16 NO3S + [M + H] + , 420.02225; found 420.0217.

[0157] Example 61 Synthesis of compound k61

[0158] Following the steps of Example 24, 4-fluoroacetophenone (1.1 eq.) was replaced with 1-(5-methoxythiophene-2-yl)acetophenone (1.1 eq.) in a yield of 36%. 1 H NMR (400 MHz, DMSO- d 6): d10.79 (1H, s), 10.09 (1H, s), 8.13 (1H, d, J = 8.2 Hz), 7.50 (1H, dt, J = 8.2, 1.0 Hz), 7.33 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.09 (1H, ddd, J = 8.2, 7.0, 1.1 Hz), 6.85 (1H, d, J =3.8 Hz), 6.49 (1H, d, J = 3.9 Hz), 4.58 (2H, q, J = 7.1 Hz), 3.96 (3H, s), 2.26 (3H, s), 1.43 (3H, t, J = 7.1 Hz). 13 C NMR (101 MHz, DMSO- d 6): d 169.6,166.5, 150.3, 140.5, 134.0, 126.5, 125.4, 124.9, 122.8, 122.2, 121.8, 121.0,118.3, 116.4, 111.7, 109.6, 104.3, 61.4, 60.2, 14.1, 14.1. HR-ESI-MS: calcdfor C 21 H 20 NO4S + [M + H] + , 382.11076; found 382.1104.

[0159] Performance Test 1: Cytotoxicity Assay

[0160] Experimental method: MTT assay

[0161] Cell line: Mouse hippocampal neuron cells HT22

[0162] HT22 cells in the logarithmic growth phase were harvested and treated at a rate of 4 × 10⁻⁶. 3Cells were seeded at a density of [number] cells / well in 96-well plates. The plates were incubated at 37 °C with 5% CO2 for approximately 24 h to ensure cell adhesion. The test compounds were then diluted to 10 µM with DMEM complete culture medium (10% FBS, 1% penicillin-dextrose antibody), and the mixture was shaken to ensure thorough mixing. The 96-well plates were removed, the supernatant was discarded, and 100 µL of the prepared compound solution (k1, k9, k14, k15, k16, k17, k18, k19, k20, k21, k22, k23, k25, k28, k33, k34, k35, k36, k37, k38, k39, k40, k41) was added to each well, with four replicates per group. The control and blank groups were incubated with the same volume of culture medium. The plates were then incubated at 37 °C with 5% CO2 for 24 h. Under light-protected conditions, dilute 5 mg / mL MTT solution with DMEM basal medium to a final concentration of 0.5 mg / mL. Remove the 96-well plate, discard the medium, add 100 µL of the diluted MTT solution, and incubate at 37 °C, 5% CO2 for 4 h. Carefully aspirate the supernatant, add 100 µL of DMSO to each well, and shake at 500 rpm for 10 min. Measure the OD value at 490 nm using a microplate reader, and calculate the cell viability using the following formula: Cell viability (%) = (Experimental group OD value - Mean OD value of blank group) / (Mean OD value of control group - Mean OD value of blank group) × 100%.

[0163] Experimental results: The experimental results show that ( Figure 3 Most of the compounds provided by this invention did not show significant cytotoxicity to HT22 cells at a concentration of 10 μM, and some compounds also showed certain cell proliferation effects, demonstrating a good safety window.

[0164] Performance Test 2: Protective Activity Test

[0165] Experimental method: MTT assay

[0166] Cell line: Mouse hippocampal neuron cells HT22

[0167] HT22 cells in the logarithmic growth phase were harvested and treated at a rate of 4 × 10⁻⁶. 3Cells were seeded at a density of [number] cells / well in 96-well plates. After incubation at 37 °C and 5% CO2 for 24 h, the model group was treated with DMEM complete culture medium diluted to 1 µM of the ferroptosis inducer RSL3. The experimental group was treated with a mixture of RSL3 and compounds (k1, k9, k15, k16, k17, k18, k19, k20, k21, k22, k23, k28, k34, k35, k36, k37, k38, k39, k40, k41) at a final concentration of 1 µM (chemical screening: 1 µM, EC). 50 Tests: 2 µM, 1 µM, 0.5 µM, 0.25 µM, 0.125 µM, 0.0625 µM). The positive control group was treated with a mixture of 1 µM RSL3 and 0.5 µM Fer-1. The control and blank groups were treated with the same volume of culture medium, with four replicates per group. The culture medium was discarded, and 100 µL of diluted MTT solution was added. The cells were incubated at 37 °C with 5% CO2 for 4 h. The supernatant was carefully aspirated, and 100 µL of DMSO was added to each well. The cells were shaken at 500 rpm for 10 min. The OD value at 490 nm was measured using a microplate reader. Cell viability was calculated using the following formula: Cell viability (%) = (Experimental group OD value - Mean OD value of blank group) / (Mean OD value of control group - Mean OD value of blank group) × 100%. After calculating cell viability based on OD values, the EC50 of the drug was calculated using GraphPad Prism software. 50 value.

[0168] Experimental results: At a concentration of 1 μM, most of the compounds provided in this invention significantly improved the survival rate of HT22 cells with RSL3 injury, with cell survival rates exceeding 80%. The neuroprotective activity of some compounds was comparable to that of the positive control drug Fer-1 (0.5 μM). Figure 1 The half-maximal effective concentration (EC50) of most compounds. 50 All were below 1.0 μM. Among them, compounds k17 and k34 were representative, EC... 50 The values ​​were 0.2406 μM and 0.5258 μM, respectively. Figure 2 ).

[0169] Performance Test 3: Cerebral Ischemia-Reperfusion Model Experiment

[0170] SPF-grade healthy male SD rats, weighing 250–300 g, were housed in a temperature- and humidity-controlled environment with free access to food and water. After acclimatization, they were randomly divided into sham-operated, model, and drug-treated groups. A middle cerebral artery occlusion (MCAO) model was established in rats using the Longa suture method to simulate cerebral ischemia-reperfusion injury. Rats were anesthetized via intraperitoneal injection and fixed in a supine position. Except for the sham-operated group, the common carotid artery and external carotid artery were ligated in all other groups. After clamping the distal end of the internal carotid artery, a suture plug was inserted through the stump of the external carotid artery to block the middle cerebral artery and induce focal cerebral ischemia. In the sham-operated group, the corresponding vessels were simply dissected and sutured without inserting a suture plug. The occlusion was released 1.5 hours later, and after blood reperfusion, 40 mg / kg of the drugs (K17, K34) was administered intraperitoneally once. The sham-operated and model groups received an equal volume of physiological saline. After the rats regained consciousness, neurological deficits were assessed using the Longa 5-point scoring system, and brain tissue was subsequently harvested for TTC staining.

[0171] Experimental results: Compared with the model group, the cerebral infarction area was significantly reduced in both the MCAO+k17 group and the MCAO+k34 group. Among them, the MCAO+k17 group showed a greater reduction in cerebral infarction area than the MCAO+k34 group, demonstrating that compounds K17 and K34 have good protective effects against ferroptosis in vivo. Figure 4 , 5 ).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic or solvate thereof; (I) in, R1 is selected from one of the following groups: C 1-6 Alkyl, pyridyl, pyrazinyl, furanyl, benzofuranyl, benzothiophenyl, thiophenyl, thiazolyl, phenyl substituted with one or more X groups, thiophenyl substituted with one or more X groups; wherein the X group is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, or halogen; R2 is H or CH3.

2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, R1 is methyl, n-hexyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-pyridyl, 2-pyrazinyl, 2-furanyl, 2-benzene Furanyl, 2-thiazolyl, 2-thienyl, 2-benzothienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 3,4-dimethyl-2-thienyl, 4-methoxy-2-thienyl, 3-bromo-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 4,5-dichloro-2-thienyl, or 2,5-dichloro-3-thienyl.

3. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The structure is one of the following compounds: 。 4. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The structure is one of the following compounds: 。 5. A method for synthesizing the compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The preparation method is as follows: (1) The compound shown in formula (II), the compound shown in formula (III), and the basic substance A are dissolved in organic solvent A and undergo a condensation reaction at -20~50 °C. After the reaction is completed, acidic substance A is added and a dehydration reaction is carried out at 40~180 °C. After cooling to room temperature, a solid is precipitated by standing. The solid is filtered and the residue is washed with anhydrous ethanol. The residue is collected to obtain the compound shown in formula (IV). The molar ratio of the compound shown in formula (II), the compound shown in formula (III), the basic substance A, and the acidic substance A is 1:0.8~3.0:0.05~2.0:0.5~5.

0. (2) The compound of formula (IV) and the compound of formula (V) obtained in step (1) are dissolved in organic solvent B with basic substance B and undergo a cyclization reaction at 30~180 °C. The crude product is obtained by vacuum concentration and purified by column chromatography to obtain the compound of formula (I). The molar ratio of the compound of formula (IV), the compound of formula (V) and basic substance B is 1:0.8~3.0:0.5~3.

0.

6. A method for synthesizing the compound of formula (I) as described in claim 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The organic solvent A mentioned in step (1) or the organic solvent B mentioned in step (2) is an alcohol solvent, wherein the alcohol solvent is methanol, ethanol or isopropanol.

7. A method for synthesizing the compound of formula (I) as described in claim 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The alkaline substance A mentioned in step (1) is sodium hydroxide, potassium hydroxide, or DBU.

8. A method for synthesizing the compound of formula (I) as described in claim 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The acidic substance A mentioned in step (1) is sulfuric acid, phosphoric acid, polyphosphoric acid or hydrochloric acid.

9. A method for synthesizing the compound of formula (I) as described in claim 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, or solvate thereof, characterized in that, The alkaline substance B mentioned in step (2) is sodium hydroxide, potassium hydroxide, or DBU; In formula (III), R1 is the same as R1 in the compound shown in formula (I), R1 in formula (IV) is the same as R1 in the compound shown in formula (I), and R1 in formula (V) is the same as R1 in the compound shown in formula (I).

10. The use of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic or solvate thereof, in the preparation of a medicament for inhibiting ferroptosis of nerve cells.

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