A class of dextromethorphan or fenchol ester derivatives of 2-hydroxy nicotinic acid and their pharmaceutical uses

Abstract

This invention relates to a class of dextran or fentanyl ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses, belonging to the field of biomedical technology. The general structural formula of the derivatives of this invention is as follows, wherein R... 1 Selected from -H, -Cl, hydrocarbon groups with 1-8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, halophenyl, or -NR 4 R 5 ;R 4 R 5 Independently selected from -H or -CH3; R 2 Selected from -H, alkyl groups of 1-6 carbon atoms, acyl groups of 2-7 carbon atoms, or carbamoyl groups; R 3 The derivatives of this invention exhibit good anti-inflammatory effects; at high concentrations, they show lower cytotoxicity and are safer. They can be used to prepare drugs for treating inflammation and inflammation-related diseases such as stroke, neuropathic pain, depression, and Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to a class of dextranol or fentanyl ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses. Background Technology

[0002] Inflammation is a fundamental pathological process, primarily a defensive response, that occurs in biological tissues in response to stimuli such as trauma or infection. Local manifestations of inflammation include redness, swelling, heat, pain, and functional impairment, and systemic reactions such as fever and changes in peripheral blood leukocyte counts may also occur. Inflammation is a significant cause of many diseases, including cardiovascular disease, diabetes, cerebrovascular disease, Alzheimer's disease, and even cancer. Increasing research has revealed the important role of neuroinflammation in ischemic stroke. The mechanism of secondary injury after cerebral ischemia may be due to the production of intracranial inflammation following ischemic stroke; the inflammatory response accelerates the formation of ischemic damage and affects neuronal death and neural tissue regeneration. The neuroinflammatory response after cerebral ischemia is characterized by microglial activation, astrocyte activation, and an increase in inflammasomes. Microglia are rapidly activated within minutes of the acute phase of ischemic stroke, peaking 2-3 days after ischemia and persisting for several weeks. After a stroke, about 40% of patients will suffer from serious sequelae, causing them great pain. However, there are currently no drugs that can promote the repair of nerve function after a stroke.

[0003] Macrophages play a crucial role in initiating, maintaining, and resolving inflammatory responses. Lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria, possesses potent immunostimulatory capabilities. RAW264.7 macrophages, as a type of murine immune cell, are activated upon stimulation by external factors (such as LPS), secreting numerous inflammatory factors and generating an inflammatory response. The amount of inflammatory factors indirectly reflects the severity of inflammation, serving as a quantitative indicator of its intensity.

[0004] Dexborneol is a bicyclic monoterpene compound whose mechanism of action is to inhibit the expression of inflammatory factors during cerebral infarction, thereby reducing brain cell death. Dexborneol is poorly soluble in water, requiring the addition of large amounts of organic solvents when preparing an injectable solution, increasing the difficulty of drug formulation. Dexborneol is volatile and has an unpleasant odor, resulting in low oral bioavailability, further complicating oral drug delivery. ZL006-05 is a salicylate derivative of dexborneol, which has shown effects in animal models in reducing neurological damage after stroke, antidepressant effects, and treatment of neuropathic pain. It is currently in phase 3 clinical trials. However, ZL006-05 has poor water solubility and low oral bioavailability, making oral administration difficult.

[0005] Alzheimer's disease is another serious threat to human health. Literature reports that fentanyl significantly reduces the excessive accumulation of Aβ and neuronal death by stimulating FFAR2 signaling (a microbiome sensing mechanism), which can help protect the brain from Alzheimer's disease pathological damage. However, fentanyl is poorly soluble in water and has low oral bioavailability, further complicating the development of oral formulations.

[0006] Because long-term medication is required for neurological function repair after stroke and for diseases such as Alzheimer's disease, oral formulations are more suitable for clinical needs. Patent CN 116283588A discloses a class of 4-alkoxy-substituted 2,6-dihydroxybenzoic acid dextran or benzoyl esters and their pharmaceutical uses. However, these compounds have a relatively short half-life (less than 1 hour), and their oral bioavailability has not been significantly improved (approximately 5%). Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a class of dextranol or fentanyl ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses.

[0008] The first objective of this invention is to provide a class of dextromethorphanol or flavonol ester derivatives of 2-hydroxynicotinic acid, with the following general structural formula;

[0009]

[0010] Among them, R 1 Selected from -H, -Cl, hydrocarbon groups with 1-8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, halophenyl or -NR 4 R 5 ;R 4 R 5 Independently selected from -H or -CH3;

[0011] R 2 Selected from -H, alkyl groups with 1-6 carbon atoms, acyl groups with 2-7 carbon atoms, or carbamoyl groups;

[0012] R 3 Selected from or

[0013] X is selected from -CH= or -N=.

[0014] In one embodiment of the present invention, compounds selected from the following:

[0015]

[0016]

[0017] A second object of the present invention is to provide pharmaceutically acceptable salts of the dextran or flavonoid ester derivatives of 2-hydroxynicotinic acid described above. The phenolic hydroxyl groups present in the structure of the dextran or flavonoid ester derivatives of 2-hydroxynicotinic acid of the present invention are acidic and can form sodium or potassium salts, or complex salts with basic organic compounds such as basic amino acids or meglumine. The phenolic hydroxyl groups present in the structure can be etherified, esterified, or carbamated to become prodrugs. In vivo, these prodrugs can be metabolized to release the phenolic hydroxyl groups and exert pharmaceutical activity.

[0018] A third object of the present invention is to provide a class of pharmaceutical compositions in which the active ingredient is a dextranol or flavonol ester derivative of 2-hydroxynicotinic acid, or a pharmaceutically acceptable salt thereof.

[0019] A fourth object of the present invention is to provide a class of dextromethorphanol or flavonol ester derivatives of the aforementioned 2-hydroxynicotinic acid, a pharmaceutically acceptable salt of the dextromethorphanol or flavonol ester derivatives of the aforementioned 2-hydroxynicotinic acid, and the use of the aforementioned pharmaceutical compositions in the preparation of medicaments for treating inflammation and inflammation-related diseases.

[0020] In one embodiment of the present invention, the inflammation and inflammation-related diseases include one or more of stroke, neuropathic pain, depression, and Alzheimer's disease.

[0021] The technical solution of the present invention has the following advantages compared with the prior art:

[0022] (1) The dextran or fentanyl ester derivatives of 2-hydroxynicotinic acid described in this invention have a longer half-life and better oral bioavailability. Introducing a nitrogen atom onto the benzene ring and changing it to a pyridine or quinoline ring not only alters the skeletal structure and yields a novel structure, but more importantly, due to the reduced number of free phenolic hydroxyl groups in the molecule, this type of compound has a longer half-life (approximately 2 hours), resulting in a certain improvement in oral bioavailability (around 10%).

[0023] (2) The dextromethorphanol or flavonol ester derivatives of 2-hydroxynicotinic acid described in this invention have good anti-inflammatory effects; at high concentrations, they exhibit low cytotoxicity and are safer. They can be used to prepare drugs for treating inflammation and inflammation-related diseases such as stroke, neuropathic pain, depression, and Alzheimer's disease.

[0024] (3) The dextromethorphanol or flavonol ester derivatives of 2-hydroxynicotinic acid described in this invention have relatively good oral efficacy and are effective for depression and neuralgia, showing good pharmaceutical prospects. Attached Figure Description

[0025] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein:

[0026] Figure 1 The effect of acute-phase injection of compound 4 in Test Example 5 of this invention on the area of ​​cerebral infarction and neurological damage after stroke; the left figure shows the effect on the area of ​​cerebral infarction, and the right figure shows the effect on neurological damage.

[0027] Figure 2 This study demonstrates the dose-response relationship between compound 4 administered via gavage during the recovery period and neurological recovery after stroke in Example 6 of this invention.

[0028] Figure 3 This study examines the long-term effects of compound 4 administered via gavage during the recovery period in Example 7 of this invention on neurological recovery after stroke.

[0029] Figure 4 To test the inhibitory effect of compounds 4, 34, and 46 administered by gavage on neuropathic pain in Example 8 of this invention;

[0030] Figure 5 To test the effect of gavage administration of compound 4 in Example 9 of this invention on the behavior of a depressed mouse model;

[0031] Figure 6 This invention provides an example of the efficacy of compound 4 in improving motor function in Alzheimer's disease. Detailed Implementation

[0032] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0033] In this invention, unless otherwise stated, the statistical results in the specification are expressed as mean ± standard error, and statistical analysis was performed using SPSS 26.0 software. *p<0.05, **p<0.01, ***p<0.001.

[0034] Example 1: Synthesis of Compound 1 (2-hydroxy-6-methylnicotinic acid dexborneol ester)

[0035]

[0036] 0.78 g (5 mmol) of 2-hydroxy-6-methylnicotinic acid and 0.62 g (4 mmol) of dextroborneol were dissolved in 100 mL of dichloromethane. 1.54 g (7.5 mmol) of dicyclohexylcarbodiimide (DCC) and 0.12 g (1 mmol) of 4-dimethylaminopyridine (DMAP) were added, and the mixture was reacted at 55 °C for 6 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in 100 mL of ethyl acetate (EA), washed three times with 100 mL of saturated brine, and the organic layer was collected, dried, and purified by column chromatography at a ratio of petroleum ether (PE, 60 °C-90 °C):ethyl acetate (EA) = 30:1. The product was evaporated to dryness and then slurried to obtain a white solid. 1 HNMR(400MHz,DMSO-d6)δ11.95(s,1H),7.92(d,J=7.3Hz,1H),6.06(d,J=7.4H z,1H),4.86(m,J=9.9,3.5,1.9Hz,1H),2.32-2.23(m,1H),2.19(s,3H),2.07(m ,J=12.3,8.9,4.1Hz,1H),1.66(dd,J=14.5,4.2Hz,2H),1.20(m,J=15.5,8.0, 4.1Hz,3H),0.94(dd,J=13.6,3.5Hz,1H),0.86(s,3H),0.81(d,J=15.6Hz,6H); 13 C NMR (101MHz, DMSO-d6) δ165.25,160.27,153.01,145.76,104.32,79.45,49.10,47.93,44.84,37.01,33.88,28.18,27.38,20.07,19.21,14.02.

[0037] Example 2: Synthesis of Compound 2 (2-hydroxynicotinic acid dexborneol ester) references Compound 1, using 2-hydroxynicotinic acid and dexborneol as raw materials.

[0038]

[0039] White solid. 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),7.99(d,J=7.0Hz,1H),7.61(d,J=6.2Hz,1H),6.23(t,J=6.8Hz,1H),4.88(d,J=9.6Hz,1H),2.34-2.22(m,1H) ,2.05(d,J=11.0Hz,1H),1.66(dd,J=13.1,4.9Hz,3H),1.20(q,J=12.1,11 .0Hz,2H),0.95(d,J=13.8Hz,1H),0.86(s,3H),0.82(s,3H),0.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.30,159.66,145.45,141.42,120.98,104.76,79 .77,49.12,48.02,47.96,44.82,36.94,28.15,27.34,20.06,19.20,14.00.

[0040] Example 3: The synthesis of compound 3 (2-hydroxy-6-chloronicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-chloronicotinic acid and dexborneol as starting materials.

[0041]

[0042] White solid. 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.11(d,J=7.9Hz,1H),7.03(d,J=8.1Hz,1H),4.95(dt,J=9.5,2.8Hz,1H),2.32(ddt,J=13.8,9.7,4.0Hz,1 H),2.03(m,J=12.8,9.3,3.3Hz,1H),1.77-1.62(m,2H),1.34-1.14(m,2 H),1.02(dd,J=13.7,3.5Hz,1H),0.87(s,3H),0.83(s,3H),0.81(s,3H). 13 C NMR (101MHz, DMSO-d6) δ165.64,163.14,151.51,144.42,115.92,111.32,80.95,49.17,47.99,44.81,36.82,28.09,27.37,20.03,19.18,13.94.

[0043] Example 4: The synthesis of compound 4 (2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-trifluoromethylnicotinic acid and dexborneol as starting materials.

[0044]

[0045] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=7.8,0.8Hz,0H),7.39(d,J=7.7Hz,0H),4.98(m,J=10.0,3.5,2.0Hz,0H),2.42-2.26(m,0H),2. 11-1.88(m,0H),1.67(dt,J=8.7,4.2Hz,0H),1.39-1.13(m,0H),1.04(dd,J=13.7,3.5Hz,0H),0.87(s,0H),0.82(d,J=4.6Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ165.26,162.96,143.43,125.48,122.75,120.02,117.29,11 7.10,112.63,81.21,49.20,48.01,44.79,36.75,28.07,27.32,20.00,19.15,13.91. 19 F NMR(376MHz,DMSO-d6)δ-67.13.

[0046] Example 5: The synthesis of compound 5 (2-hydroxy-6-difluoromethylnicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-difluoromethylnicotinic acid and dexborneol as starting materials.

[0047]

[0048] White solid. 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.17(d,J=7.4Hz,1H),6.97(s,1H),6.77(d,J=54.2Hz,1H),2.30(d,J=12.5Hz,1H), 2.02(t,J=11.3Hz,1H),1.78-1.53(m,2H),1.38-1.14(m,2H),1.01(d,J=13.6Hz,1H),0.87(s,3H),0.82(d,J=7.5Hz,5H). 13C NMR (101MHz, DMSO-d6) δ165.50,143.48,80.80,49.19,48.01,44.78,36.81,32.36,28.10,27.33,20.05,19.19,13.97. 19 F NMR(376MHz,DMSO-d6)δ-117.61,-117.75.

[0049] Example 6: The synthesis of compound 6 (2-hydroxy-6-isopropylnicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-isopropylnicotinic acid and dexborneol as starting materials.

[0050]

[0051] White solid. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.96(d,J=7.4Hz,1H),6.11(d,J=7.5Hz,1H ),4.87(dt,J=9.8,2.8Hz,1H),2.77(p,J=6.9Hz,1H),2.27(ddt,J=13.7,10.0,3. 9Hz,1H),2.06(m,J=12.6,9.1,4.2Hz,1H),1.72-1.63(m,2H),1.30-1.16(m,2H), 1.15(s,1H),0.94(dd,J=13.6,3.4Hz,1H),0.86(s,3H),0.82(s,3H),0.78(s,3H). 13 CNMR(101MHz,DMSO-d6)δ165.17,161.98,160.42,145.90,117.69,100.72,79.4 7,49.10,47.93,44.83,37.01,32.00,28.17,27.35,21.61,20.05,19.19,13.99.

[0052] Example 7: The synthesis of compound 7 (2-hydroxy-6-isobutylnicotinic acid dexborneol ester) referenced compound 1, using 2-hydroxy-6-isobutylpropylnicotinic acid and dexborneol as starting materials.

[0053]

[0054] White solid. 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.95(d,J=7.3Hz,1H),6.06(d,J=7.5Hz,1H),4.86 (dt,J=10.2,3.2Hz,1H),2.33(d,J=7.3Hz,2H),2.30-2.22(m,1H),2.07(m,J=12.3,8.9, 4.0Hz,1H),1.90(dt,J=13.5,6.8Hz,1H),1.67(dq,J=14.9,4.3,3.8Hz,3H),1.27-1.15( m,2H),0.94(dd,J=13.6,3.5Hz,1H),0.86(s,3H),0.84(s,3H),0.82(s,5H),0.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.20,160.40,157.13,145.63,104.41,79.49,49.10,48.02,47 .95,44.83,41.78,37.00,33.88,28.55,28.17,27.38,24.99,22.43,20.08,19.21,14.02.

[0055] Example 8: The synthesis of compound 8 (2-hydroxy-6-isopentylnicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-isopentylpropylnicotinic acid and dexborneol as starting materials.

[0056]

[0057] White solid. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),7.94(d,J=7.3Hz,1H),6.09(d,J=7.4Hz,1H),4.86(dt ,J=9.5,2.8Hz,1H),2.47-2.45(m,2H),2.27(ddt,J=13.8,9.7,3.9Hz,1H),2.06(m,J=12.4,9 .0,4.0Hz,1H),1.65(dt,J=15.5,4.2Hz,2H),1.44(m,J=14.1,6.6Hz,3H),1.29-1.14(m,2H) ,0.94(dd,J=13.6,3.5Hz,1H),0.85(d,J=3.5Hz,5H),0.83(s,2H),0.82(s,3H),0.78(s,3H). 13C NMR(101MHz,DMSO-d6)δ165.20,160.40,157.21,145.77,117.28,103.46,79.45,49.09 ,47.93,44.83,37.75,37.01,30.96,28.17,27.64,27.37,22.69,20.06,19.20,14.01.

[0058] Example 9: The synthesis of compound 9 (2-hydroxy-6-phenylnicotinic acid dexborneol ester) references compound 1, using 2-hydroxy-6-phenylnicotinic acid and dexborneol as starting materials.

[0059]

[0060] White solid 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.09(s,0H),7.81(dd,J=6.7,2.9Hz,2 H),7.48(p,J=3.9Hz,3H),6.80(s,1H),4.93(dt,J=9.7,2.8Hz,1H),2.31(dd t,J=13.8,9.9,3.9Hz,1H),2.11-1.95(m,1H),1.79-1.60(m,2H),1.39-1.14 (m,2H),1.00(dd,J=13.7,3.5Hz,1H),0.88(s,3H),0.83(s,2H),0.82(s,2H). 13 C NMR(101MHz,DMSO-d6)δ165.57,161.15,144.71,133.96,131.14,129.44,127.81,7 9.99,49.17,47.98,44.84,36.97,33.88,28.16,27.39,24.99,20.07,19.21,14.02.

[0061] Example 10: Synthesis of Compound 10 (2-hydroxy-6-(2-phenyl)ethylnicotinic acid dexborneol ester) reference compound 1, using 2-hydroxy-6-(2-phenyl)ethylnicotinic acid and dexborneol as starting materials.

[0062]

[0063] White solid. 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),7.92(d,J=7.2Hz,1H),7.20(ddt,J=22.4,14.5,7.4Hz ,5H),6.08(d,J=7.2Hz,1H),4.86(d,J=9.7Hz,1H),2.86(dd,J=9.8,6.1Hz,2H),2.76(dd,J=9 .5,6.1Hz,2H),2.27(td,J=9.9,5.0Hz,1H),2.06(m,J=12.3,8.9,4.0Hz,1H),1.72-1.62(m, 3H),1.28-1.14(m,2H),0.94(dd,J=13.7,3.4Hz,1H),0.86(s,3H),0.82(s,3H),0.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.18,160.35,157.13,145.72,140.80,128.89,126.73,103.77,79.52,49.1 0,48.02,47.95,44.83,36.99,34.69,34.53,33.88,28.17,27.37,25.85,24.99,20.08,19.21,14.03.

[0064] Example 11 Synthesis of Compound 11 (2-Methoxy-6-methylnicotinic acid dexborneol ester)

[0065]

[0066] 0.29 g (1 mmol) of 2-hydroxy-6-methylnicotinic acid dexborneol ester was dissolved in 10 mL of dichloromethane, followed by the addition of 0.32 g (1.1 mmol) of dicycloamidinium (DBU) and 0.15 g (1.1 mmol) of dimethyl sulfate. The reaction was carried out at room temperature for 3 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in 100 mL of ethyl acetate (EA), washed three times with 100 mL of saturated brine, and the organic layer was collected, dried, and purified by column chromatography. The purified solid was obtained by column chromatography under the conditions of petroleum ether (PE, 60℃-90℃): ethyl acetate (EA) = 30:1. 1HNMR(400MHz,Chloroform-d)δ7.99(d,J=7.3Hz,1H),6.08(d,J=7.4Hz,1H),5.06(dt,J=10.1,2.8Hz,1H),3.55(s,3H),2.49-2.41(m,1H),2.39( s,3H),2.18(m,J=12.2,8.9,4.3Hz,1H),1.82-1.68(m,1H),1.38-1.21( m,3H),1.09(dd,J=13.8,3.5Hz,1H),0.93(s,3H),0.88(d,J=2.7Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ165.73,160.60,152.16,143.26,117.68,105.54,80 .59,49.06,47.88,45.07,37.01,31.80,28.19,27.49,21.82,19.84,19.03,13.73.

[0067] Example 12: The synthesis of compound 12 (2-methoxy-6-trifluoromethylnicotinic acid dexborneol ester) referenced compound 11, using 2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester and dimethyl sulfate as raw materials.

[0068]

[0069] A colorless, oily substance. 1 H NMR(400MHz,Chloroform-d)δ8.25(d,J=7.6Hz,1H),7.30(d,J=7.7Hz,1H),5.10(m,J=10.0,3.4,2.1Hz,1H),4.07(s,3H),2.53-2.35(m,1H ),2.07(m,J=13.3,9.5,4.4Hz,1H),1.86-1.68(m,2H),1.46-1.27(m,2H),1.10(dd,J=13.9,3.4Hz,1H),0.94(s,3H),0.90(d,J=1.7Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ164.69,162.39,148.41,148.06,142.18,122.29,119.56,118.15,112.82 ,112.79,112.76,112.73,81.78,54.62,49.13,47.96,45.01,36.97,28.11,27.30,19.77,18.96,13.63.

[0070] Example 13: Synthesis of Compound 13 (2-ethoxy-6-methylnicotinic acid dexborneol ester) reference compound 11, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and diethyl sulfate as starting materials.

[0071]

[0072] White solid. 1 H NMR(400MHz,Chloroform-d)δ7.95(d,J=7.5Hz,1H),6.04(d,J=7.4Hz,1H),5.04(dt,J=9.4,2.7Hz,1H),4.12(q,J=7.0Hz,2H),2.42(s,4H),2.40-2.33( m,0H),2.12(m,J=12.5,9.0,4.4Hz,1H),1.75-1.66(m,2H),1.31(q,J=7.1,6 .5Hz, 6H), 1.08 (dd, J=13.8, 3.4Hz, 1H), 0.92 (s, 3H), 0.87 (d, J=1.9Hz, 6H). 13 C NMR(101MHz,Chloroform-d)δ165.49,160.04,151.51,143.10,117.96,105.72,80.41 ,49.03,47.87,45.05,40.11,37.01,28.18,27.50,21.02,19.83,19.03,13.75,13.58.

[0073] Example 14: The synthesis of compound 14 (2-ethoxy-6-trifluoromethylnicotinic acid dexborneol ester) referenced compound 11, using 2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester and diethyl sulfate as starting materials.

[0074]

[0075] A colorless, oily substance. 1H NMR (400MHz, Chloroform-d) δ8.25(d,J=7.6Hz,1H),7.27(d,J=7.7Hz,1H),5.11(dt,J=9.9,2.8Hz,1H),4.51(q,J=7.0Hz,2H),2.46(ddt,J=13.8,9 .9,4.0Hz,1H),2.13(m,J=13.2,9.2,4.4Hz,1H),1.43(t,J=7.1Hz,3H),1 .35-1.23(m,2H),1.11(dd,J=13.8,3.5Hz,1H),0.94(s,3H),0.90(s,6H). 13 C NMR(101MHz,Chloroform-d)δ165.19,161.96,148.34,147.99,142.38,122.32,119.59,118.17 ,112.50,81.81,63.43,49.12,47.96,45.01,36.93,28.13,27.39,19.77,18.96,14.49,13.62. 19 F NMR(376MHz,Chloroform-d)δ-68.7.

[0076] Example 15 Synthesis of Compound 15 (2-Isopropoxy-6-methylnicotinic acid dexborneol ester)

[0077]

[0078] 290 mg of 2-hydroxy-6-methyl-nicotinic acid borneol ester was dissolved in a round-bottom flask with THF, followed by the addition of 228 mg of potassium carbonate and 132 mg of bromoethane. The mixture was reacted at room temperature for 5 h. After the reaction was complete, the filtrate was collected by suction filtration, evaporated to dryness, dissolved in 100 mL of ethyl acetate (EA), washed three times with 100 mL of saturated brine, and the organic layer was collected, dried, and purified by column chromatography. The filtrate was purified by column chromatography under the conditions of petroleum ether (PE, 60℃-90℃): ethyl acetate (EA) = 30:1 to obtain a colorless oily substance. 1H NMR(400MHz,Chloroform-d)δ8.03(d,J=7.6Hz,1H),6.71(d,J=7.6Hz,1H),5.50(p,J=6.1Hz,1H),5.07(dt,J=10.0,2.7Hz,1H),2.43(s,4H),2.20 (m,J=12.2,8.8,4.4Hz,1H),1.81-1.65(m,2H),1.36(d,J=6.4Hz,7H),1. 32-1.21(m,1H),1.09(dd,J=13.7,3.5Hz,1H),0.93(s,3H),0.89(s,6H). 13 C NMR(101MHz,Chloroform-d)δ166.66,161.32,160.71,141.82,115.02,111.74,80.73,68 .42,49.03,47.87,45.06,37.00,28.17,27.48,24.56,22.22,22.19,19.82,18.98,13.67.

[0079] Example 16: Synthesis of Compound 16 (2-isobutoxy-6-methylnicotinic acid dexborneol ester) reference compound 15, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and isobutyl bromide as starting materials.

[0080]

[0081] A colorless, oily substance. 1 H NMR(400MHz,Chloroform-d)δ8.03(d,J=7.6Hz,1H),6.72(d,J=7.7Hz,1H),5.09(dt,J=9.9,2.9Hz,1H),4.15(d,J=6.8Hz,2H),2.43(s,4H),2.14 (m,J=13.0,8.6,4.6Hz,2H),1.83-1.65(m,2H),1.39-1.21(m,2H),1.08( dd,J=13.8,3.5Hz,1H),1.01(d,J=6.6Hz,6H),0.93(s,3H),0.87(s,6H). 13C NMR(101MHz,Chloroform-d)δ166.05,161.97,160.78,141.64,115.28,111.41,80.59,72.79 ,49.04,47.92,45.03,36.95,28.17,28.00,27.45,24.52,19.83,19.63,19.58,18.98,13.68.

[0082] Example 17: Synthesis of Compound 17 (2-cyclohexyloxy-6-methylnicotinic acid dexborneol ester) reference compound 15, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and cyclohexyl bromide as starting materials.

[0083]

[0084] A pale yellow, oily substance. 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=7.6Hz,1H),6.86(d,J=7.7Hz,1H),5.15-5.09(m,1 H),4.95(dt,J=10.5,2.9Hz,1H),2.37(s,3H),2.31(td,J=10.0,4.6Hz,1H),2.05(dd d,J=12.8,9.2,4.2Hz,1H),1.91(dt,J=13.8,4.3Hz,2H),1.69(q,J=3.6Hz,2H),1.52 -1.16(m,10H),0.98(dd,J=13.7,3.5Hz,1H),0.87(s,3H),0.82(s,3H),0.81(s,3H). 13 CNMR(101MHz,DMSO-d6)δ166.05,160.86,160.58,142.04,116.05,111.95,80.30,75.39,73.33,49.1 1,47.98,44.78,36.89,31.99,28.19,27.40,26.86,25.75,24.70,24.03,21.72,20.06,19.16,14.00.

[0085] Example 18: Synthesis of Compound 18 (2-acetoxy-6-methylnicotinic acid dexborneol ester)

[0086]

[0087] 0.29 g (1 mmol) of 2-hydroxy-6-methylnicotinic acid dexborneol ester was dissolved in 10 mL of dichloromethane, followed by the addition of 0.15 g (1.5 mmol) of acetic anhydride and 0.10 g (1 mmol) of triethylamine. The reaction was carried out at room temperature for 3 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, and then purified by column chromatography using petroleum ether (PE, 60℃-90℃): ethyl acetate (EA) = 30:1 to obtain a white solid. 1 HNMR(400MHz,Chloroform-d)δ8.27(d,J=7.8Hz,1H),7.17(d,J=7.9Hz,1H),5.06(dt,J=9.8,2.9Hz,1H),2.58(s,2H),2.44(td,J=10.0,4.1Hz,1H),2 .38(s,3H),2.01(m,J=13.3,9.4,4.4Hz,1H),1.86-1.69(m,2H),1.40-1.1 9(m,2H),1.06(dd,J=13.9,3.5Hz,1H),0.93(s,3H),0.88(d,J=5.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ169.32,163.63,162.71,156.37,141.67,121.99,116.36 ,81.30,49.12,48.02,44.95,36.88,28.16,27.46,24.40,21.37,19.78,18.94,13.69.

[0088] Example 19: The synthesis of compound 19 (2-acetoxy-6-trifluoromethylnicotinic acid dexborneol ester) referenced compound 18, using 2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester and acetic anhydride as starting materials.

[0089]

[0090] A colorless oily substance with a yield of 80%. 1 H NMR (400MHz, Chloroform-d) δ8.54(d,J=7.9Hz,1H),7.71(d,J=7.8Hz,1H),5.10(m,J=10.0,3.6,2.2Hz,1H),2.56-2.41(m,1H),2.40(s ,3H),1.97(m,J=13.4,9.5,4.4Hz,1H),1.82-1.61(m,2H),1.44-1.18(m,3H),1.06(d,J=3.4Hz,1H),0.94(s,3H),0.89(d,J=4.0Hz,7H). 13C NMR(101MHz,Chloroform-d)δ168.76,162.60,156.81,150.09,149.73,143.17,124.57,122.70,121.83,119.09 ,119.06,119.03,116.37,112.80,82.38,49.18,48.10,44.89,36.80,28.13,27.41,21.22,19.74,18.91,13.67. 19 F NMR(376MHz,Chloroform-d)δ-68.1.

[0091] Example 20: The synthesis of compound 20 (2-propionyloxy-6-trifluoromethylnicotinic acid dexborneol ester) referenced compound 18, using 2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester and propionic anhydride as starting materials.

[0092]

[0093] A colorless, oily substance. 1 H NMR(400MHz,Chloroform-d)δ8.52(d,J=7.8Hz,1H),7.70(d,J=7.9Hz,1H),5.09 (dt,J=9.8,2.9Hz,1H),2.73(q,J=7.6Hz,2H),2.45(ddt,J=14.0,9.9,4.0Hz,1H) ,1.96(m,J=13.4,9.5,4.4Hz,1H),1.84-1.69(m,2H),1.47-1.30(m,2H),1.25(d ,J=7.5Hz,3H),1.08(dd,J=13.9,3.5Hz,1H),0.94(s,3H),0.89(d,J=4.7Hz,6H). 13 CNMR(101MHz,Chloroform-d)δ172.25,162.61,157.02,150.05,149.69,143.00,122.77,121.86,1 19.13,118.92,82.27,49.19,48.10,44.91,36.78,28.12,27.69,27.42,19.75,18.92,13.67,8.50. 19 F NMR(376MHz,Chloroform-d)δ-68.17.

[0094] Example 21: Synthesis of Compound 21 (2-Isobutyryloxy-6-methylnicotinic acid dexborneol ester) referenced Compound 15, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and isobutyric anhydride as starting materials.

[0095]

[0096] White solid. 1 HNMR(400MHz,Chloroform-d)δ8.23(d,J=7.8Hz,1H),7.15(d,J=7.7Hz,1H),5.18-4 .79(m,1H),2.91(p,J=7.0Hz,1H),2.57(s,3H),2.42(ddt,J=14.0,9.0,4.0Hz,1H),1 .99(m,J=13.5,9.3,4.4Hz,1H),1.84-1.66(m,2H),1.35(d,J=7.0Hz,7H),1.26(m,J =13.1,4.2Hz,2H),1.06(dd,J=14.1,3.5Hz,1H),0.93(s,3H),0.88(d,J=5.6Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ175.24,163.45,162.53,156.77,141.28,121.73,116.60,81 .00,49.13,48.01,44.97,36.87,34.21,28.13,27.47,24.45,19.79,18.98,18.70,13.70.

[0097] Example 22: The synthesis of compound 22 (2-cyclohexanoyloxy-6-methylnicotinic acid dexborneol ester) referenced compound 18, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and cyclohexylformyl chloride as starting materials.

[0098]

[0099] A colorless, oily substance. 1H NMR(400MHz,Chloroform-d)δ8.22(d,J=8.0Hz,1H),7.13(s,1H),5.03(dt,J=10.3,2.8Hz ,1H),2.64(ddt,J=11.7,7.3,3.7Hz,1H),2.56(s,3H),2.46-2.36(m,2H),2.25-2.11(m,3 H),2.05-1.90(m,2H),1.79(ddt,J=23.5,11.9,3.8Hz,3H),1.62(m,J=15.5,10.2,4.0Hz, 2H),1.38-1.21(m,6H),1.05(dd,J=14.0,3.5Hz,1H),0.93(s,3H),0.87(d,J=5.9Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ170.46,159.74,158.80,153.04,137.53,117.96,112.92,77.24,45.39,4 4.27,41.23,39.44,33.15,24.98,24.75,24.40,23.74,22.12,21.86,21.52,20.71,16.07,15.26,9.98.

[0100] Example 23 Synthesis of Compound 23 (2-N,N-dimethylcarbamoyloxy-6-methylnicotinic acid dexborneol ester)

[0101]

[0102] Add 30 mL of dichloromethane and 300 mg of triphosgene to 500 mg of 2-hydroxy-6-methylnicotinic acid borneol ester, then inject 0.5 mL of triethylamine. After reacting for 5 h, add dimethylamine directly without post-treatment. After reacting for 2 h, evaporate the dichloromethane solvent, add water and ethyl acetate for extraction, take the organic phase, dry it with anhydrous Na2SO4, evaporate the organic phase for column chromatography (PE:EA = 100:1), and obtain a white solid. 1H NMR(400MHz,Chloroform-d)δ8.23(d,J=7.8Hz,1H),7.13(d,J=7.8Hz,1H),5.0 7(dt,J=10.0,2.7Hz,1H),3.14(s,3H),2.99(s,3H),2.56(s,3H),2.42(ddt,J=1 3.9,10.0,4.0Hz,1H),2.01(m,J=13.3,9.3,4.4Hz,1H),1.83-1.68(m,2H),1.39 -1.20(m,3H),1.08(dd,J=14.0,3.6Hz,1H),0.92(s,3H),0.87(d,J=4.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ164.28,162.16,156.69,153.90,141.68,121.46,117.21 ,81.17,49.11,47.99,44.96,36.87,36.76,28.12,27.35,24.43,19.80,18.97,13.62.

[0103] Example 24 Synthesis of compound 24 (2-(4-methylpiperazinyl)formyloxy-6-trifluoromethylnicotinic acid dexborneol ester) hydrochloride

[0104]

[0105] 500 mg of 2-hydroxy-6-trifluoromethylnicotinic acid dextran was completely dissolved in 30 mL of acetone. 400 mg of 1-methylpiperazine-1-formyl chloride hydrochloride was added, followed by 2 equivalents of K2CO3. The mixture was heated under reflux for 12 h. The reaction was monitored by TLC, filtered, and the solvent was directly evaporated. Column chromatography (DCM:MeOH = 100:1) was performed to obtain 24300 mg of a colorless oily compound.

[0106] Compound 24 was dissolved in 10 mL of ethyl acetate and then reacted with 2 mol / L ethyl hydrochloride to form the salt of compound 24 hydrochloride. 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.65(d,J=7.8Hz,1H),8.03(d,J=8.2Hz,1H),5.01(d,J =9.8Hz,1H),4.38-3.90(m,2H),3.59(s,0H),3.09(d,J=32.7Hz,2H),2.76(s,3H),2.35(ddt, J=14.0,9.1,3.9Hz,1H),1.88(dt,J=13.1,6.9Hz,1H),1.70(dd,J=12.5,4.1Hz,2H),1.31(t, J=12.6Hz,1H),1.20(dt,J=11.4,5.7Hz,1H),1.04(dd,J=13.8,3.5Hz,1H),0.91-0.80(m,7H). 13 C NMR(101MHz,DMSO-d6)δ163.16,156.18,151.60,148.09,147.73,144.77,123.76,122.40,120.57,119.67,81.99, 70.34,52.14,49.68,49.28,48.16,44.71,42.58,41.95,41.15,36.45,32.05,28.09,27.29,20.03,19.17,13.86. 19 FNMR(376MHz,Chloroform-d)δ-68.82.

[0107] Example 25 Synthesis of compound 25 ((S)-2-(2-((methylamino)methyl)pyrrolidinyl)formyloxy-6-trifluoromethylnicotinic acid dexborneol ester)

[0108]

[0109] Compound 4 (500 mg, 1.46 mmol) was placed in a two-necked flask, 10 mL of DCM was added, followed by Cs₂CO₃ (1.42 g, 4.37 mmol). The flask was placed under N₂ protection and cooled to 0 °C in an ice bath. Triphosgene (172.59 mg, 0.58 mmol) in 10 mL of DCM was slowly added dropwise. After stirring for 10 min, the mixture was brought to room temperature and stirred at room temperature for 4 h. TLC monitoring showed that the reaction was not complete (obtaining a DCM solution of intermediate 25-1). Tert-butyl (S₂CO₃) was then added. 2-((methylamino)methyl)pyrrolidin-1-carbonate (936.53 mg, 4.37 mmol) was stirred at room temperature for 8 h; the reaction solution was washed with 50 mL of water and 50 mL of saturated brine, the organic layer was collected, evaporated to dryness, and subjected to column chromatography (DCM:MeOH = 100:1). The eluent was evaporated to dryness to give intermediate 25-2 as a transparent oily substance; it was dissolved in 10 mL of ethyl acetate, and 1.0 mL of 2 mol / L ethyl hydrochloride was added. The mixture was stirred at room temperature for 4 h to give a pale yellow solid. 1 H NMR(400MHz,Methanol-d4)δ8.68(d,J=7.9Hz,1H),7.93(dd,J=8.0,4.8Hz,1H),5.11 (d,J=10.1Hz,1H),4.06-3.56(m,3H),3.39(dd,J=45.3,8.1Hz,2H),3.25(s,2H),3.0 7(s,1H),2.50-2.38(m,1H),2.26(s,1H),2.18-1.98(m,3H),1.90-1.69(m,3H),1.46 (d,J=14.1Hz,1H),1.30(t,J=11.0Hz,1H),1.15(t,J=12.2Hz,1H),0.98-0.90(m,9H). 13 C NMR (101MHz, METHANOL-D4) δ163.27,163.02,156.58,156.48,154.68,152. 88,149.06,148.70,143.79,143.65,123.21,123.11,122.04,119.44,82.43 ,82.29,59.42,50.01,49.86,48.90,48.83,45.36,44.92,36.36,36.20,35.38,34.86,27.58,27.38,27.30,26.99,22.53,22.32,18.76,17.92,12.68.

[0110] Example 26: Synthesis of Compound 26 (2-hydroxy-6-methylnicotinic acid ferrugin ester) - Reference Compound 1, using 2-hydroxy-6-methylnicotinic acid and ferrugin as starting materials.

[0111]

[0112] White solid. 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),7.97(d,J=7.2Hz,1H),6.06(d,J=7.3Hz,1H),4.34(s,1H),2.19(s,3H),1.91-1.78(m,1H),1.66(d,J= 3.8Hz,1H),1.59(dd,J=10.3,6.7Hz,2H),1.38(dq,J=12.4,6.5,5.6Hz,1H),1.14(d,J=10.0Hz,1H),1.05(s,4H),0.99(s,3H),0.70(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.95,165.04,157.97,150.68,121.31,109.16,90.52 ,53.22,53.07,46.05,34.73,32.64,31.64,30.80,25.40,24.62,24.14,17.55.

[0113] Example 27: Synthesis of Compound 27 (2-hydroxy-6-chloronicotinic acid ferrugin ester) reference compound 1, using 2-hydroxy-6-chloronicotinic acid and ferrugin alcohol as raw materials.

[0114]

[0115] White solid. 1 H NMR (400MHz, Chloroform-d) δ11.64(s,1H),8.12(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),4.62(d,J=2.0Hz,1H),1.88-1.72( m,3H),1.65(dq,J=10.6,2.0Hz,1H),1.53(tt,J=12.9,4.7Hz,1H),1.30-1.21(m,2H),1.16(s,3H),1.09(s,3H),0.80(s,3H). 13 CNMR(101MHz,Chloroform-d)δ169.09,165.38,155.76,141.35,116.88,106 .84,88.80,48.69,48.33,41.45,40.00,29.65,26.86,25.87,20.30,19.52.

[0116] Example 28: Synthesis of Compound 28 (2-hydroxy-6-trifluoromethylnicotinic acid ferrugin ester) - Reference Compound 1, using 2-hydroxy-6-trifluoromethylnicotinic acid and ferrugin as starting materials.

[0117]

[0118] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=7.5Hz,1H),7.39(d,J=7.8Hz,1H),4.45(s,1H),1.79(td,J=11.2,5.4Hz,1H),1.67(d,J=3.9Hz,1H) ,1.60(q,J=6.1,3.6Hz,2H),1.44-1.34(m,1H),1.15(d,J=10.2Hz,1H),1.07(s,3H),1.05(d,J=2.5Hz,1H),1.02(s,3H),0.73(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.01,167.76,148.41,130.22,127.48,124.76,121.53,117.4 7,92.21,53.30,53.02,45.95,34.67,32.58,31.55,30.70,25.31,24.45,17.54,17.43.

[0119] Example 29: Synthesis of Compound 29 (2-hydroxynicotinic acid ferrugin ester) reference compound 1, using 2-hydroxynicotinic acid and ferrugin as raw materials.

[0120]

[0121] White solid. 1 H NMR(400MHz,Chloroform-d)δ8.26(dd,J=7.3,2.2Hz,1H),7.80-7.75(m,1H),6.42(t,J=6.8Hz,1H),4.57(d,J=1.9Hz,1H),1.91- 1.80(m,1H),1.75(d,J=4.4Hz,2H),1.63(dd,J=10.3,2.2Hz,1H),1.56-1.42(m,1H),1.25-1.10(m,5H),1.07(s,3H),0.83(s,3H). 13C NMR (101MHz, DMSO-d6) δ165.28,159.71,145.74,141.63,120.40,104.84,86.13,48.48,48.30,41.27,38.77,29.97,26.84,26.02,20.64,19.83.

[0122] Example 30: Synthesis of Compound 30 (2-ethoxy-6-methylnicotinic acid fumarate) reference compound 15, using 2-hydroxy-6-trifluoromethylnicotinic acid fumarate and ethyl bromide as starting materials.

[0123]

[0124] A colorless, oily substance. 1 H NMR(400MHz,Chloroform-d)δ8.25(d,J=7.6Hz,1H),7.27(d,J=7.7Hz,1H),5.05(d,J=9.2Hz,1H),4.51(q,J=7.0Hz,2H),2.36-2.26(m,1H),1. 91-1.83(m,1H),1.71-1.60(m,2H),1.43(t,J=7.1Hz,3H),1.24-1.13(m ,2H),1.06(dd,J=13.7,3.5Hz,1H),0.89(s,3H),0.83(d,J=4.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ165.19,161.96,148.34,147.99,142.38,122.32,119.59,118.17 ,112.50,89.81,63.43,48.86,48.67,41.46,39.98,29.69,27.09,25.88,20.49,19.52.14.49.

[0125] Example 31: The synthesis of compound 31 (2-propionyloxy-6-methylnicotinic acid camphenol ester) references compound 18, using 2-hydroxy-6-methylnicotinic acid dexborneol ester and propionic anhydride as starting materials.

[0126]

[0127] White solid. 1HNMR(400MHz,Chloroform-d)δ8.26(d,J=7.8Hz,1H),7.17(d,J=7.8Hz,1H),5.05(dt,J= 9.9,3.0Hz,1H),2.72(q,J=7.5Hz,2H),2.58(s,3H),2.43(ddt,J=14.2,9.5,4.1Hz,1H), 2.00(m,J=13.3,9.3,4.4Hz,1H),1.87-1.69(m,2H),1.37(td,J=12.6,12.2,5.7Hz,1H), 1.25(t,J=7.3Hz,5H),1.06(dd,J=14.1,3.5Hz,1H),0.93(s,3H),0.88(d,J=6.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ172.76,163.61,162.63,156.58,141.56,121.85,116.43,8 1.18,49.13,48.01,44.96,36.87,28.15,27.75,27.47,24.42,19.79,18.96,13.69,8.62.

[0128] Example 32 (Reference compound 25 for the synthesis of 2-(4-methylpiperazinyl)formyloxy-6-methylnicotinic acid fumarate), using 2-hydroxy-6-trifluoromethylnicotinic acid fumarate and 1-methylpiperazine as starting materials.

[0129]

[0130] White solid. 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=8.0Hz,1H),7.98(dd,J=7.9,2.1Hz,1H),4.48(s,1H), 3.57(dd,J=12.6,6.1Hz,2H),3.38(dd,J=11.6,6.5Hz,2H),2.38(d,J=6.1Hz,2H),2.34- 2.30(m,2H),2.18(s,3H),1.72(dd,J=12.0,4.8Hz,2H),1.63(d,J=9.8Hz,2H),1.44(td, J=12.7,12.2,5.9Hz,1H),1.19(d,J=9.8Hz,1H),1.09(s,4H),1.04(s,3H),0.73(s,3H). 13C NMR (101MHz, DMSO-d6) δ163.40,156.80,151.79,148.08,147.72,144.38,123.61,122.42,120.21,119.68,88. 07,54.26,48.58,48.20,45.96,44.76,43.95,41.22,32.32,32.32,29.93,26.73,26.00,20.49,19.63,16.71.

[0131] Example 33: Synthesis of Compound 33 (2-(N-methyl-2-(N-methyl)aminoethylamino)formyloxy-6-trifluoromethylnicotinic acid dexborneol ester) Referring to Compound 25, 2-hydroxy-6-trifluoromethylnicotinic acid dexborneol ester and methyl tert-butyl[2-(methylamino)ethyl]carbamic acid were used as starting materials, and Compound 33 and hydrochloric acid were used as starting materials to obtain Compound 33 hydrochloride.

[0132]

[0133] Oily substance. 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=40.9Hz,2H),8.63(t,J=8.2Hz,1H),8.01(ddd,J=7.9,4.4,1.3Hz,1H),5. 00(ddd,J=9.9,3.6,1.9Hz,1H),3.74(t,J=6.7Hz,1H),3.57(q,J=6.6Hz,1H),3.21-3.13(m,1H),3.11-3.01( m,3H),2.92(d,J=1.2Hz,1H),2.59-2.49(m,4H),2.34(ddt,J=13.9,9.0,3.9Hz,1H),1.96-1.83(m,1H),1.77 -1.64(m,2H),1.36-1.25(m,1H),1.24-1.13(m,2H),1.06(td,J=14.6,14.0,3.6Hz,1H),0.91-0.77(m,11H). 13CNMR(101MHz,DMSO-d6)δ168.10,167.96,161.22,161.07,158.05,157.38,128.74,128.61,127.20,125.05,124.47,86.69,86.62 ,54.03,52.91,51.11,50.49,49.77,49.49,41.51,41.18,40.45,40.40,37.83,37.72,36.45,32.83,32.06,24.76,23.90,18.60.

[0134] Example 34 Synthesis of compound 34 (2-(N-methyl-2-(N-methyl)aminoethylamino)formyloxy-6-trifluoromethylnicotinic acid dexborneol ester)

[0135]

[0136] Compound 4) 0.343 g (0.01 mol) was dissolved in 15 mL of DCM, (R)-(3-((tert-butyldimethylsilyl)oxy)butyric acid) 0.240 g (0.011 mol) and 4-dimethylaminopyridine (DMAP) 0.134 g (0.011 mol). After stirring at room temperature for 30 min, N,N'-dicyclohexylcarboimide (DCC) 0.2270 g (0.011 mol) was added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, the product was purified by silica gel column chromatography with PE:EA = 100:1 elution buffer. The product was dissolved in 10 mL of methanol solution, stirred at 0 °C for 10 min, and then 0.046 g (0.003 mol) of trimethylbromosilane was slowly added dropwise. After the addition was completed, the product was allowed to return to room temperature and reacted for 3 h. The reaction was monitored by TLC. After the reaction was complete, the product was purified by silica gel column chromatography with PE:EA = 20:1 elution buffer to obtain an oily substance. 1 H NMR(400MHz,Chloroform-d)δ8.55(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),5.09(dt,J=10 .0,3.0Hz,1H),4.50-4.40(m,1H),2.90-2.70(m,2H),2.45(ddt,J=14.1,9.4,3.9Hz,1H),1 .95(ddd,J=13.6,9.4,4.3Hz,1H),1.86-1.71(m,2H),1.47-1.36(m,1H),1.32(d,J=6.4Hz ,3H),1.30-1.22(m,1H),1.08(dd,J=13.8,3.4Hz,1H),0.93(s,3H),0.89(d,J=3.5Hz,6H). 13C NMR(101MHz,Chloroform-d)δ170.21,162.74,156.70,149.99,143.09,122.39,121.76,119.2 7,82.79,64.37,49.23,48.13,44.89,44.04,36.77,28.09,27.44,22.54,19.73,18.91,13.70.

[0137] Example 35: The synthesis of compound 35 (dextrin 2,4-dihydroxy-5-pyrimidinecarboxylate) was based on compound 1, using 2-methylmercapto-4-dihydroxy-5-pyrimidinecarboxylic acid and dextroborneol as starting materials.

[0138]

[0139] White solid. 1 H NMR (400MHz, Chloroform-d) δ11.64(s,1H),8.33(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),5.17(dt,J=10.0,2.8Hz,1H),2.49(ddt,J=14.1,9.7,3.9Hz ,1H),1.97(ddd,J=13.4,9.3,4.3Hz,1H),1.87-1.76(m,2H),1.50-1.27(m ,2H),1.12(dd,J=14.0,3.4Hz,1H),0.95(s,3H),0.91(s,3H),0.90(s,3H). 13 C NMR(101MHz,Chloroform-d)δ168.25,165.37,140.89,136.71,121.12,116.19, 112.28,83.81,49.35,48.17,44.87,36.72,28.07,27.39,19.71,18.91,13.68.

[0140] Example 36: The synthesis of compound 36 (2-hydroxy-6-cyanonicotinic acid dexborneol ester) reference compound 1, using 2-hydroxy-6-cyanonicotinic acid and dexborneol as starting materials.

[0141]

[0142] White solid. 1H NMR (400MHz, Chloroform-d) δ11.64(s,1H),8.33(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),5.17(dt,J=10.0,2.8Hz,1H),2.49(ddt,J=14.1,9.7,3.9Hz ,1H),1.97(ddd,J=13.4,9.3,4.3Hz,1H),1.87-1.76(m,2H),1.50-1.27(m ,2H),1.12(dd,J=14.0,3.4Hz,1H),0.95(s,3H),0.91(s,3H),0.90(s,3H). 13 C NMR(101MHz,Chloroform-d)δ168.25,165.37,140.89,136.71,121.12,116.19, 112.28,83.81,49.35,48.17,44.87,36.72,28.07,27.39,19.71,18.91,13.68.

[0143] Example 37: The synthesis of compound 37 (2-hydroxy-6-carboxynicotinic acid dexborneol ester) reference compound 1, using 2-hydroxy-6-carboxynicotinic acid and dexborneol as starting materials.

[0144]

[0145] In a 250 mL round-bottom flask, 14.8 g (200 mmol) of ethyl formate and 100 mL of tetrahydrofuran were added. 1,1-Dimethoxyacetone (23.6 g, 200 mmol) was added at room temperature, followed by 30% sodium methoxide (27 g). The mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The tetrahydrofuran phase was removed by vortexing. The product was washed twice with diethyl ether (50 mL) to give 15.0 g of intermediate 37-l, a yellow solid, with a yield of 56.8%.

[0146] Cyanoacetamide (8.8 g, 105 mmol), piperidine acetate (prepared by adding piperidine and 6 mL of water to 2 mL of acetic acid until the mixture is alkaline), and 100 mL of water were placed in a round-bottom flask, and then intermediate 37-l (15.0 g, 88 mmol) was added. The resulting mixture was heated under reflux for 5 h, and then cooled to room temperature. The mixture was acidified with hydrochloric acid while stirring until the mixture became acidic, and a solid precipitated. The crude product was filtered to obtain a crude product, which was recrystallized from a mixed solvent of ethanol and water to give 8.3 g of intermediate 37-2 as a white solid, with a yield of 41.52%.

[0147] A mixture of intermediate 37-2 (8.3 g, 42 mmol) and KOH aqueous solution (80% w / 150 mL) was added to a 250 mL pear-shaped flask and heated in an oil bath at 150 °C for 24 h. The reaction was then stopped, and the mixture was cooled to room temperature and poured into 300 mL of water. The pH was adjusted to 4 under ice bath conditions. The solid product was collected by filtration, washed, and dried. The crude product was recrystallized from acetic acid to give 7.5 g of intermediate 37-3, a grayish-white solid, in 81% yield.

[0148] In a 250 mL round-bottom flask, dextroborneol (5.0 g, 32.4 mmol) and 165 mL of dichloromethane were added. Intermediate 37-3 (4.4 g, 20.7 mmol) was added at room temperature, followed by DMAP (785 mg, 6.48 mmol). After stirring at room temperature for 10 min, DCC (10.0 g, 48.6 mmol) was added. The reaction was allowed to proceed for 8 h at room temperature. The reaction was monitored by TLC until complete. The organic phase dichloromethane was concentrated under vacuum, and ethyl acetate was added and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain 5.0 g of intermediate 37-4 as a white solid, with a yield of 48.8%.

[0149] Intermediate 37-4 (5.0 g, 14.3 mmol) was added to a 100 mL round-bottom flask, and 80 mL of acetic acid and water (acetic acid: water = 1:1) were added. The mixture was heated at 60°C and stirred overnight. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, and the organic phase was washed three times with water. The organic phase was collected and dried over anhydrous sodium sulfate. The obtained organic phase was concentrated under vacuum to obtain the crude product. The crude product was recrystallized from ethanol and water to give 3.2 g of white solid, with a yield of 74.4%. 1 H NMR (400MHz, Chloroform-d) δ9.90 (s, 1H), 8.34 (d, J = 7.7Hz, 1H), 7.43 (d, J = 7.5Hz, 1H), 5.15 (d, J = 9.8Hz, 1H), 2.48 (td, J = 10. 1,5.0Hz,1H),2.03(td,J=9.1,4.7Hz,1H),1.82-1.73(m,2H),1.46-1.28(m,2H),1.15-1.10(m,1H),0.95(s,3H),0.91(s,6H). 13 C NMR(101MHz,Chloroform-d)δ192.90,167.78,164.24,149.91,141.56,121.02, 113.47,83.07,49.30,48.12,44.91,36.79,28.09,27.39,19.75,18.95,13.70.

[0150] Example 38: Synthesis of Compound 38 (2-hydroxy-6-methylnicotinic acid dexborneol ester)

[0151]

[0152] Compound 37 (2.0 g, 6.6 mmol) was added to a 100 mL round-bottom flask, and ethanol was added to dissolve it in 35 mL. 300 mg of sodium borohydride was added in small portions, and the mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (dichloromethane / methanol = 50:1) to give 1.50 g of a white solid, with a yield of 74.6%. 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.01(d,J=7.5Hz,1H),6.27(d,J=7.4Hz ,1H),5.57(d,J=5.9Hz,1H),4.89-4.85(m,1H),4.31(d,J=5.8Hz,2H),2.27(d dd,J=9.8,5.9,3.0Hz,1H),2.06(td,J=8.6,4.1Hz,1H),1.63(t,J=4.4Hz,2H) ,1.27-1.18(m,2H),0.96-0.91(m,1H),0.86(s,3H),0.82(s,3H),0.79(s,3H). 13 C NMR (101MHz, DMSO-d6) δ165.31,159.96,156.76,145.63,118.02,101.53,59.83,49.11,47.94,44.83,36.99,28.18,27.37,20.07,19.21,14.03.

[0153] Example 39: Synthesis of Compound 39 (2-hydroxy-6-methylnicotinic acid dexborneol ester)

[0154]

[0155] Compound 37 (1.0 g, 3.3 mmol) was added to a 100 mL round-bottom flask, and 25 mL of ethanol was added to dissolve it. Hydroxylamine (165 mg, 4.95 mmol) was added at room temperature, and the reaction was carried out for 3 h at room temperature. The reaction was monitored by TLC until complete, yielding intermediate 39-1. Without purification, 25 mL of methanol was added to dissolve the intermediate. 300 mg of Pd / C was added, and the reaction was carried out under a hydrogen atmosphere for 6 h. The reaction was monitored by TLC until complete, and the organic phase (methanol) was concentrated under vacuum. The crude product was recrystallized from ethyl acetate to give 200 mg of a white solid. 1 HNMR(400MHz,Chloroform-d)δ8.16(d,J=7.3Hz,1H),6.39(d,J=7.8Hz,1H),5.08(d,J=9.7Hz,1H),3.89(s,2H),2.44(td,J=10. 4,5.4Hz,1H),2.15-2.08(m,1H),1.81-1.70(m,2H),1.41-1.26(m,2H),1.10(dd,J=13.8,3.5Hz,1H),0.93(s,3H),0.89(s,6H). 13 C NMR(101MHz,Chloroform-d)δ166.08,162.91,157.15,145.77,117.77,105.47 ,80.94,49.11,47.94,45.01,44.02,36.96,28.15,27.47,19.81,18.99,13.72.

[0156] Example 40: Synthesis of Compound 40 (2-hydroxy-6-methylnicotinic acid dexborneol ester)

[0157]

[0158] Compound 37 (1.0 g, 3.3 mmol) was added to a 100 mL round-bottom flask, and 25 mL of tert-butanol was added to dissolve it. Dimethyl dibutene (7 equivalents), sodium dihydrogen phosphate (4 equivalents), and sodium chlorite (1.3 eq / 27 equivalents) were added to the flask. The mixture was reacted at room temperature for 3 h, and the reaction was monitored by TLC until complete. Na₂SO₃ (1.3 equivalents) was added, and the temperature was maintained at 0 °C. The mixture was stirred at room temperature for 15 min. The pH was adjusted to 5 with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with EA (100 mL each). The organic phases were combined, and the crude product was subjected to silica gel column chromatography (dichloromethane / methanol = 30:1) to give 430 mg of a white solid, with a yield of 41.6%. 1H NMR (400MHz, DMSO-d6) δ8.04(d,J=7.3Hz,1H),6.84(d,J=7.3Hz,1H),4.99-4.75(m,1H),2.28(dq,J=8.5,4.8Hz,1H),2.07-1.9 8(m,1H),1.66(dt,J=8.7,4.1Hz,2H),1.25-1.11(m,2H),0.98(dd,J=13.8,3.6Hz,1H),0.86(s,3H),0.82(s,3H),0.80(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.21,162.16,159.43,144.66,123.31,106.62,97 .24,80.20,49.16,47.98,44.80,36.87,28.13,27.32,20.05,19.19,13.99.

[0159] Example 41: Synthesis of Compound 41 (dextrin 2-methylmercapto-4-hydroxy-5-pyrimidinecarboxylate) Reference Compound 1 was used as the starting material, with 2-methylmercapto-4-hydroxy-5-pyrimidinecarboxylic acid and dextroborneol.

[0160]

[0161] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),4.95-4.78(m,1H),2.46(s,3H),2.27(ddt,J=13.9,9.1,4.0Hz,1H),2.04(ddd,J=12.3,8.8,4.0 Hz,1H),1.74-1.57(m,2H),1.22(ddd,J=20.9,11.9,7.4Hz,2H),0.96(dd,J=13.7,3.6Hz,1H),0.85(s,3H),0.82(s,3H),0.78(s,3H). 13 C NMR (101MHz, DMSO-D6) δ164.24,80.00,49.12,47.95,44.83,36.91,28.11,27.35,20.05,19.19,13.96,13.59.

[0162] Example 42 Synthesis of compound 42 (dextrin 2-methyl-4-hydroxy-5-pyrimidinecarboxylate)

[0163]

[0164] Ethamidin hydrochloride (2.50 g, 26.44 mmol) was weighed and added to a reaction flask. An appropriate amount of anhydrous ethanol solution was added, and the mixture was transferred to an ice bath to cool to 0°C. 2 eq of anhydrous sodium ethoxide solution (3.60 g, 52.88 mmol) was added, followed by slow dropwise addition of 1 eq of diethyl ethoxymethylene malonate (5.72 g, 26.44 mmol). The mixture was stirred for 10 min, then transferred to an oil bath and heated to reflux at 80°C overnight. The reaction was monitored by TLC. The reaction was then transferred to room temperature, and a small amount of water was slowly added to quench the reaction. The ethanol in the reaction system was evaporated to dryness, dissolved in water, and the pH of the reaction solution was adjusted to 6 with 2 mol / L dilute hydrochloric acid. The reaction solution was extracted three times with ethyl acetate, and the lipid layer was washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solution was purified by column chromatography to obtain intermediate 42-2, a white solid.

[0165] Intermediate 42-2 was dissolved in an appropriate amount of anhydrous ethanol solution, and an excess of saturated sodium hydroxide aqueous solution was added. The mixture was heated to 60°C, and the reaction was monitored by TLC. The reaction was completed in 2 hours. The reaction was cooled to room temperature, the ethanol solution was evaporated, a small amount of water was added until the precipitated solid was dissolved, and 22 mol / L dilute hydrochloric acid solution was slowly added dropwise until a large amount of solid precipitated (approximately pH 6). The mixture was filtered and the filter cake was washed with a small amount of water. The filter cake was dried to obtain intermediate 42-3, a white solid.

[0166] Weigh intermediate 42-3 (400 mg, 2.60 mmol) into a reaction flask, add an appropriate amount of acetonitrile, then add 1 eq of dextroborneol (400.92 mg, 2.60 mmol) and 2.1 eq of NMI (447.16 mg, 5.45 mmol), stir for 30 min, add 1.2 eq of TCFH (875.41 mg, 3.12 mmol), react at room temperature, and stir overnight; evaporate the reaction solution to dryness, add an appropriate amount of DCM, water, and saturated brine to wash the reaction solution, dry with anhydrous sodium sulfate, and pass through a column chromatography to obtain a white solid with a yield of 52.21%. 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),4.89(d,J=9.7Hz,1H),2.30(s,4H),2.05(ddd,J=12.4,8.9,3.7Hz,1H) ,1.73-1.62(m,2H),1.29-1.17(m,2H),0.96(dd,J=13.7,3.4Hz,1H),0.86(s,3H),0.82(s,3H),0.79(s,3H). 13 C NMR (101MHz, DMSO-D6) δ164.95,164.33,159.56,158.93,115.37,80.02,49.13,47.96,44.82,36.91,28.13,27.34,22.00,20.06,19.19,13.98.

[0167] Example 43: The synthesis of compound 43 (dextrin 2-tert-butyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using tert-butylformamidinium hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0168]

[0169] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),4.89(d,J=9.8Hz,1H),2.28(t,J=12.2Hz,1H),2.04(d,J=12.3Hz,1 H),1.65(d,J=12.6Hz,2H),1.25(s,11H),0.97(d,J=13.8Hz,1H),0.85(s,3H),0.82(s,3H),0.79(s,3H). 13 C NMR (101MHz, DMSO-D6) δ172.90,164.03,158.62,115.70,79.99,49.14,47.97,44.83,38.17,36.90,28.22,28.10,27.32,20.04,19.19,13.94.

[0170] Example 44: Synthesis of Compound 44 (dexborneol 2-amino-4-hydroxy-5-pyrimidinecarboxylate) reference compound 42, using guanidine hydrochloride, diethyl ethoxymethylene malonate, and dexborneol as starting materials.

[0171]

[0172] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),4.83(d,J=9.3Hz,1H),2.24(tt,J=8.6,4.1Hz,1H),2.09(ddd,J=12.4,9.0,4.2 Hz,1H),1.71-1.59(m,2H),1.26-1.16(m,2H),0.91(dd,J=13.4,3.6Hz,1H),0.85(s,3H),0.82(s,3H),0.77(s,3H). 13 C NMR (101MHz, DMSO-D6) δ164.90,163.58,159.44,159.03,104.69,78.79,49.03,47.87,44.86,37.12,28.19,27.42,20.08,19.22,14.02.

[0173] Example 45: The synthesis of compound 45 (dextrin 2-cyclopropyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using cyclopropylformamidin hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0174]

[0175] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 4.87 (dt, J = 10.1, 2.6Hz, 1H), 2.26 (ddt ,J=13.7,8.6,4.0Hz,1H),2.03(ddd,J=12.4,8.9,4.0Hz,1H),1.94(tt,J=8.1 ,4.8Hz,1H),1.72-1.60(m,2H),1.22(qd,J=11.3,9.7,2.5Hz,2H),1.11-1.02 (m,4H),0.95(dd,J=13.5,3.4Hz,1H),0.85(s,3H),0.81(s,3H),0.77(s,3H). 13 C NMR(101MHz,DMSO-D6)δ169.76,164.21,160.00,158.91,114.09,79.80,49 .10,47.94,44.82,36.92,28.12,27.35,20.04,19.18,14.28,13.96,11.39.

[0176] Example 46: The synthesis of compound 46 (dextrin 2-isopropyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using isopropylformamidin hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0177]

[0178] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),4.89(d,J=9.7Hz,1H),2.84(p,J=6.9Hz,1H),2.33-2.23(m,1H),2.04(td,J=9.9,8.9,5.2Hz,1H ),1.73-1.61(m,2H),1.30-1.20(m,2H),1.15(d,J=6.9Hz,6H),0.97(dd,J=13.6,3.3Hz,1H),0.86(s,3H),0.83(s,3H),0.79(s,3H). 13C NMR(101MHz,DMSO-D6)δ171.84,164.18,159.34,159.30,115.66,79.98,49 .13,47.97,44.82,36.91,33.74,28.11,27.34,20.76,20.06,19.19,13.95.

[0179] Example 47: Synthesis of Compound 47 (dextrinol 2-ethyl-4-hydroxy-5-pyrimidinecarboxylate) was based on Compound 42, using propamidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0180]

[0181] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),4.89(d,J=9.8Hz,1H),2.56(q,J=7.8Hz,2H),2.29(d,J=12.2Hz,1H),2.03(d,J=11.6H z,1H),1.66(d,J=14.3Hz,2H),1.16(dt,J=15.8,9.4Hz,5H),0.96(d,J=13.7Hz,1H),0.86(s,3H),0.82(s,3H),0.78(s,3H). 13 CNMR(101MHz,DMSO-D6)δ168.67,164.26,159.18,115.53,80.00,49.12,47.96,44.83,36.91,28.27,28.12,27.34,20.05,19.18,13.96,11.58.

[0182] Example 48: The synthesis of compound 48 (dextrin 2-butyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using pentamidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0183]

[0184] White solid. 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),4.89(dt,J=9.4,2.5Hz,1H),2.55(t,J=7.5Hz,2H),2.28(ddt,J=13.7,8.7,3.8Hz,1H),2.05(ddd,J=12.6,8.9 ,3.9Hz,1H),1.63(qd,J=15.1,13.8,5.9Hz,4H),1.23(ddd,J=27.7,13.0, 6.9Hz, 4H), 0.97 (dd, J=13.7, 3.6Hz, 1H), 0.89-0.81 (m, 9H), 0.79 (s, 3H). 13 CNMR(101MHz,DMSO-D6)δ167.98,164.29,159.22,115.42,80.01,49.13,47.97,44.82,40.68,40.47,40 .26,40.05,39.84,39.63,39.42,36.91,34.50,29.22,28.12,27.35,22.07,20.07,19.20,14.12,13.98.

[0185] Example 49: The synthesis of compound 49 (dextrin 2-propyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using butamidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0186]

[0187] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),4.89(d,J=9.8Hz,1H),2.52(t,J=7.5Hz,2H),2.28(td,J=11.9,10.0,4.5Hz,1H),2.09-2.01 (m,1H),1.65(p,J=7.9,7.3Hz,4H),1.22(dt,J=21.4,11.5Hz,2H),0.97(dd,J=13.8,3.4Hz,1H),0.88-0.81(m,9H),0.79(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.75,164.26,159.19,115.46,80.02,49.12,47.95 ,44.82,36.90,36.62,28.12,27.34,20.60,20.04,19.18,13.91(d,J=9.1Hz).

[0188] Example 50: The synthesis of compound 50 (dextrin 2-phenyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using benzoamidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0189]

[0190] White solid. 1 HNMR (400MHz, DMSO-d6) δ8.61(s,1H),8.12(d,J=7.7Hz,2H),7.56(dt,J=32.2,7.5Hz,3H),4.94(d,J=9.6Hz,1H),2.31(t,J=11.2Hz,1 H),2.07(d,J=11.1Hz,1H),1.68(d,J=13.7Hz,2H),1.30-1.21(m,2H),1.01(d,J=13.8Hz,1H),0.88(s,3H),0.84(s,3H),0.82(s,3H). 13 C NMR(101MHz,DMSO-D6)δ164.23,161.56,160.44,159.04,133.12,132.29,129.31,12 8.90,115.21,80.17,49.18,47.99,44.85,36.93,28.13,27.37,20.06,19.21,13.99.

[0191] Example 51: The synthesis of compound 51 (dextrin 2-o-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using o-chlorobenzomididine hydrochloride, diethyl ethoxymethylidene malonate, and dextroborneol as starting materials.

[0192]

[0193] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.06(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),4.94(d,J=9.8Hz,1H),2.36-2.25(m,1H),2 .13-2.03(m,1H),1.67(d,J=13.6Hz,2H),1.29-1.20(m,2H),1.01(dd,J=13.7,3.2Hz,1H),0.87(s,3H),0.83(d,J=8.0Hz,6H). 13C NMR (101MHz, DMSO-D6) δ164.25,132.37,130.89,127.06,80.27,80.27,49.19,48.00,44.84,36.92,28.13,27.37,20.07,19.21,14.00.

[0194] Example 52: Synthesis of Compound 52 (dextrinol 2-p-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylate) was based on Compound 42, using p-chlorobenzamidinium hydrochloride, diethyl ethoxymethylimide malonate, and dextroborneol as starting materials.

[0195]

[0196] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.14(d,J=8.3Hz,2H),7.61(d,J=8.3Hz,2H),4.94(d,J=9.7Hz,1H),2.36-2.27(m,1H),2 .13-2.04(m,1H),1.74-1.63(m,2H),1.29-1.19(m,2H),1.01(dd,J=13.3,3.2Hz,1H),0.88(s,3H),0.84(s,3H),0.82(s,3H). 13 C NMR (101MHz, DMSO-D6) δ164.19,138.06,130.76,129.45,80.29,48.00,36.92,28.13,20.07,19.21,14.00.

[0197] Example 53: The synthesis of compound 53 (dextrin 2-m-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using m-chlorobenzamidinium hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0198]

[0199] White solid. 1H NMR (400MHz, DMSO-d6) δ8.62 (s, 1H), 8.18 (s, 1H), 8.09 (d, J = 7.9Hz, 1H), 7.67 (d,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),4.94(d,J=9.8Hz,1H),2.32(tt,J=10. 2,4.0Hz,1H),2.08(ddd,J=12.3,9.2,3.0Hz,1H),1.76-1.63(m,2H),1.31-1.2 2(m,2H),1.02(dd,J=13.7,3.3Hz,1H),0.88(s,3H),0.84(s,3H),0.82(s,3H). 13 C NMR (101MHz, DMSO-d6) δ164.13,134.10,132.72,131.24,128.60,127.55,80.34,49.19,48.00,44.84,36.91,28.12,27.36,20.06,19.20,13.99.

[0200] Example 54: The synthesis of compound 54 (dextrin 2-o-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using o-fluorobenzoamidine hydrochloride, diethyl ethoxymethylimide malonate, and dextroborneol as starting materials.

[0201]

[0202] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.73(t,J=7.6Hz,1H),7.62(q,J=7.1Hz,1H),7.42-7.31(m,2H),4.94(d,J=9.7Hz,1H),2.31(ddt,J=13. 8,8.8,3.9Hz,1H),2.15-2.00(m,1H),1.76-1.61(m,2H),1.29-1.18(m,2H),1.01(dd,J=13.8,3.4Hz,1H),0.87(s,3H),0.83(d,J=6.8Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ164.18,133.36,132.82,131.21,128.29,120.94,80.41,49.19,48.02,44.83,36.88,28.12,27.36,20.08,19.21,13.99.

[0203] Example 55: The synthesis of compound 55 (dextrin 2-p-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylate) was based on compound 42, using p-fluorobenzomididine hydrochloride, diethyl ethoxymethylimide malonate, and dextroborneol as starting materials.

[0204]

[0205] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.20(dd,J=8.5,5.4Hz,2H),7.37(t,J=8.7Hz,2H),4.93(d,J=9.7Hz,1H),2.30(tt,J=8.3,4.3Hz,1H) ,2.07(qd,J=8.6,5.7,3.2Hz,1H),1.77-1.60(m,2H),1.31-1.20(m,2H),1.01(dd,J=13.7,3.3Hz,1H),0.87(s,3H),0.83(d,J=7.8Hz,6H). 13 C NMR(101MHz,DMSO-D6)δ166.53,164.17,164.03,159.19,131.75,131.66,116.55 ,116.33,80.22,49.18,47.99,44.85,36.92,28.13,27.36,20.06,19.20,13.99.

[0206] Example 56: The synthesis of compound 56 (dextrin 2-m-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using m-fluorobenzomididine hydrochloride, diethyl ethoxymethylmethylene malonate, and dextroborneol as starting materials.

[0207]

[0208] White solid. 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.00(d,J=7.9Hz,1H),7.94(d,J=10.2Hz ,1H),7.58(q,J=7.4Hz,1H),7.46(dd,J=10.0,7.5Hz,1H),4.98-4.89(m,1H),2 .36-2.27(m,1H),2.07(td,J=10.7,8.9,5.8Hz,1H),1.74-1.63(m,2H),1.30- 1.19(m,2H),1.02(dd,J=13.8,3.4Hz,1H),0.88(s,3H),0.83(d,J=7.5Hz,6H). 13C NMR(101MHz,DMSO-D6)δ164.12,163.80,161.37,160.46,158.97,131.54,131.46,125.09,120.03 ,119.82,115.68,115.44,80.33,49.18,47.99,44.84,36.90,28.12,27.36,20.05,19.19,13.98.

[0209] Example 57: The synthesis of compound 57 (dextrin 2-o-bromophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using o-bromobenzomididine hydrochloride, diethyl ethoxymethylimide malonate, and dextroborneol as starting materials.

[0210]

[0211] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.74(d,J=7.8Hz,1H),7.57(d,J=7.7Hz,1H),7.48(dt,J=19.9,7.6Hz,2H),4.95(d,J=9.7Hz,1H), 2.31(s,1H),2.08(t,J=11.3Hz,1H),1.67(s,2H),1.27-1.20(m,2H),1.02(dd,J=13.8,3.1Hz,1H),0.88(s,3H),0.83(d,J=7.3Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ133.36,132.82,131.21,128.29,80.41,49.19,48.02, 44.83,40.04(dp,J=41.8,20.9Hz),36.88,28.12,27.36,20.08,19.21,13.99.

[0212] Example 58: The synthesis of compound 58 (dextrin 2-p-bromophenyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using p-bromobenzamide hydrochloride, diethyl ethoxymethylimide malonate, and dextroborneol as starting materials.

[0213]

[0214] White solid. 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.06(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),4.94(d,J=9.8Hz,1H),2.36-2.25(m,1H),2 .13-2.03(m,1H),1.67(d,J=13.6Hz,2H),1.29-1.20(m,2H),1.01(dd,J=13.7,3.2Hz,1H),0.87(s,3H),0.83(d,J=8.0Hz,6H). 13 C NMR (101MHz, DMSO-D6) δ164.25,132.37,130.89,127.06,80.27,80.27,49.19,48.00,44.84,36.92,28.13,27.37,20.07,19.21,14.00.

[0215] Example 59: The synthesis of compound 59 (dextrinol 2-m-tolyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using m-tolymidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0216]

[0217] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.94(d,J=19.8Hz,2H),7.41(d,J=5.0Hz,2H),4.93(d,J=9.7Hz,1H),2.35(s,3H),2.33-2.26(m, 1H),2.09(t,J=11.2Hz,1H),1.76-1.61(m,2H),1.25(dt,J=22.4,11.1Hz,2H),1.05-0.98(m,1H),0.88(s,3H),0.83(d,J=8.1Hz,6H). 13 C NMR(101MHz,DMSO-D6)δ164.22,138.69,133.78,129.40,129.24,126.07,80 .17,49.17,47.99,44.84,36.93,28.13,27.36,21.44,20.06,19.21,14.00.

[0218] Example 60: The synthesis of compound 60 (dextrinol 2-thiaphenyl-4-hydroxy-5-pyrimidinecarboxylate) was based on reference compound 42, using thiaphenimine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0219]

[0220] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),8.16(s,2H),4.93(d,J=9.8Hz,1H),2.31(t,J=11.7Hz,1H),2.08(t,J=10.9Hz,1H), 1.68(d,J=13.1Hz,2H),1.24(dt,J=20.5,10.6Hz,2H),1.00(dd,J=13.7,3.1Hz,1H),0.87(s,3H),0.82(d,J=8.9Hz,6H). 13 CNMR(101MHz,DMSO-D6)δ164.12,161.04,145.78,127.99,80.42,49.18,47.99,44.83,36.88,28.11,27.34,20.06,19.20,13.98.

[0221] Example 61: The synthesis of compound 61 (dextrinol 2-pyridyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using pyridine 3-formamidine hydrochloride, diethyl ethoxymethylene malonate, and dextroborneol as starting materials.

[0222]

[0223] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=4.7Hz,1H),8.65(s,1H),8.44(d,J=8.1Hz,1H),7.57(dd,J=8.0,4.7Hz,1H),5.02-4.87(m, 1H),2.08(s,1H),1.67(d,J=4.3Hz,2H),1.27(dd,J=26.2,12.2Hz,2H),1.06-0.98(m,1H),0.88(s,3H),0.83(d,J=7.3Hz,6H). 13 C NMR(101MHz,DMSO-D6)δ164.13,153.10,149.61,136.69,136.33,124.31,123.69,12 0.27,80.37,49.20,48.01,44.83,36.91,35.95,28.12,27.36,20.07,19.21,14.00.

[0224] Example 62: The synthesis of compound 62 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylate dexborneol ester) was based on compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylene malonate, and dexborneol as starting materials.

[0225]

[0226] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),4.89-4.75(m,1H),3.08(s,6H),2.25(s,1H),2.06(t,J=11.8Hz,1H),1.65( d,J=17.0Hz,2H),1.23(dd,J=25.4,11.7Hz,2H),0.93(d,J=13.7Hz,1H),0.86(s,3H),0.82(s,3H),0.77(s,3H). 13 C NMR (101MHz, DMSO-D6) δ162.09,78.80,49.07,47.88,44.85,37.84,37.11,28.17,27.41,20.08,19.22,14.03.

[0227] Example 63: The synthesis of compound 63 (2-isopropyl-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using isopropylformamidinium hydrochloride, diethyl ethoxymethylene malonate, and benzoyl alcohol as starting materials.

[0228]

[0229] White solid. 1 H NMR(400MHz,DMSO-d6)δ8.41(d,J=1.9Hz,1H),4.38(s,1H),2.32-2.29(m,3H),1.82(d,J=13.2Hz,1H) ,1.69-1.57(m,3H),1.45-1.36(m,1H),1.15(q,J=10.5Hz,2H),1.05(s,3H),1.00(s,3H),0.71(s,3H). 13 C NMR (400MHz, DMSO-D6) δ173.78,165.10,159.56,158.11,86.37,48.48,48.31,41.26,35.86,29.96,26.84,26.00,22.00,20.63,19.78.

[0230] Example 64: The synthesis of compound 64 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylate) referenced compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylene malonate, and benzoyl alcohol as starting materials.

[0231]

[0232] White solid. 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),4.37(s,1H),2.83(p,J=6.9Hz,1H),1.82(d,J=13.3Hz,1H),1.67(s,1H),1 .59(d,J=10.2Hz,2H),1.41(d,J=14.0Hz,1H),1.16(s,4H),1.14(s,3H),1.05(s,4H),1.00(s,3H),0.72(s,3H). 13 C NMR (400MHz, DMSO-D6) δ172.05,164.24,159.73,159.07,115.32,86.33,48.49,48.31,41.28,33.74,29.97,26.84,26.00,20.75,20.64,19.77.

[0233] Comparative Example 1

[0234]

[0235] Test Example 1: Determining the effect of the compound on the in vitro proliferation of RAW264.7 macrophages.

[0236] The cells were digested, counted, and a RAW264.7 cell suspension of 7 × 10⁶ cells was prepared. 4 Cells / mL, add 100 μL of cell suspension to each well of a 96-well cell culture plate; incubate at 37℃ in a 5% CO2 incubator for 24 h; dilute the drug with culture medium to the required working solution concentration, add 100 μL of the corresponding drug-containing culture medium to each well, and set up a negative control group; incubate at 37℃ in a 5% CO2 incubator for 24 h; add 20 μL of CCK-8 to each well, and continue incubation for 2-3 h; gently mix on a shaker for 10 min to remove air bubbles from the 96-well plate; λ = 450 nm, read the OD value of each well with a microplate reader, and calculate the inhibition rate; inhibition rate (%) = (OD value of negative control group - OD value of experimental group) / OD value of negative control group × 100%, the results are shown in Table 1:

[0237] Table 1. Inhibitory effect of compounds on the growth of RAW264.7 macrophages (6 μmol / L)

[0238] compound Inhibition rate compound Inhibition rate compound Inhibition rate compound Inhibition rate Celecoxib A Compound 16 B Compound 33 C Compound 50 B ZL006-05 A Compound 17 C Compound 34 C Compound 51 B Compound 1 B Compound 18 C Compound 35 B Compound 52 B Compound 2 B Compound 19 C Compound 36 B Compound 53 B Compound 3 B Compound 20 C Compound 37 B Compound 54 B Compound 4 B Compound 21 C Compound 38 B Compound 55 B Compound 5 B Compound 22 C Compound 39 B Compound 56 B Compound 6 B Compound 23 C Compound 40 B Compound 57 B Compound 7 B Compound 24 C Compound 41 B Compound 58 B Compound 8 B Compound 25 C Compound 42 B Compound 59 B Compound 9 B Compound 26 C Compound 43 B Compound 60 B Compound 10 B Compound 27 B Compound 44 B Compound 61 B Compound 11 B Compound 28 B Compound 45 B Compound 62 B Compound 12 C Compound 29 B Compound 46 B Compound 63 B Compound 13 C Compound 30 C Compound 47 B Compound 64 B Compound 14 C Compound 31 C Compound 48 B Compound 15 C Compound 32 C Compound 49 B

[0239] Note: A: 40%-50%, B: 10%-5%, C: 5%-0%.

[0240] As can be seen from Table 1, at higher concentrations (6 μmol / L), celecoxib and ZL006-05 exhibit strong cytotoxicity (40%-50%), while the compounds of this invention have cytotoxicity of less than 10%, indicating that they have better safety.

[0241] Effect of Compound 2 on Lipopolysaccharide-Induced Inflammatory Factors in RAW264.7 Macrophages

[0242] The cells were digested, counted, and a RAW264.7 cell suspension of 7 × 10⁶ cells was prepared. 4 Cells / mL, 100 μL of cell suspension was added to each well of a 96-well cell culture plate; incubated at 37°C in a 5% CO2 incubator for 24 h; the drug was diluted with culture medium to the required concentration, and 100 μL of the corresponding drug-containing culture medium was added to each well, with a negative control group set up; incubated at 37°C in a 5% CO2 incubator for 2 h; then 100 μg / L LPS was added and incubated for 24 h, the supernatant was collected, and the contents of IL-1β and TNF-α were detected according to the ELISA kit instructions, as shown in Table 2:

[0243] Table 2. Effects of compounds on lipopolysaccharide-induced inflammatory factors in RAW264.7 macrophages (1 μmol / L)

[0244] TNF-α IL-1β TNF-α IL-1β TNF-α IL-1β negative group 52.5 22.7 Compound 20 B D Compound 43 B D Model group 208.4 97.5 Compound 21 B D Compound 44 B D ZL006-05 A C Compound 22 B D Compound 45 B D Celecoxib C E Compound 23 B D Compound 46 C E Compound 1 B E Compound 24 B D Compound 47 B D Compound 2 B E Compound 25 B D Compound 48 B D Compound 3 B E Compound 26 C E Compound 49 B D Compound 4 C E Compound 27 C E Compound 50 B D Compound 5 C E Compound 28 C E Compound 51 B D Compound 6 C E Compound 29 C E Compound 52 B D Compound 7 C E Compound 30 B D Compound 53 B D Compound 8 C E Compound 31 B D Compound 54 B D Compound 9 C E Compound 32 B D Compound 55 B D Compound 10 C E Compound 33 B D Compound 56 B D Compound 11 B D Compound 34 B D Compound 57 B D Compound 12 B D Compound 35 B D Compound 58 B D Compound 13 B D Compound 36 B D Compound 59 B D Compound 14 B D Compound 37 B D Compound 60 B D Compound 15 B D Compound 38 B D Compound 61 B D Compound 16 B D Compound 39 B D Compound 62 B D Compound 17 B D Compound 40 B D Compound 63 B D Compound 18 B D Compound 41 B D Compound 64 B D Compound 19 B D Compound 42 B D

[0245] Note: Inflammatory factor measurement values: A: 200%-151%, B: 150%-101%, C: 100%-76%, D: 75%-51%, E: 50%-25%.

[0246] As can be seen from Table 2, ZL006-05, celecoxib, and the compound of the present invention have significant inhibitory effects on the increase of inflammatory factors in RAW264.7 macrophages induced by lipopolysaccharide, but the inhibitory effect of the compound of the present invention is significantly stronger than that of ZL006-05.

[0247] Test Example 3: Inhibition rate of carrageenan-induced paw edema in rats by intravenous injection of compound 3

[0248] Male SD rats (SPF grade, 6-8 weeks old, weighing 250-280g) were randomly divided into groups of 6. The normal control group and the model group were intravenously injected with an equal volume of solvent. Each drug group was intravenously injected with 20 μmol / kg of each compound. 0.5 h after drug administration, the normal control group received a subcutaneous injection of 100 μL of physiological saline into the hind limb toes, while the other groups received an injection of 100 μL of 1% carrageenan. The paw volume was measured at 0 h and 4 h after carrageenan injection, and the paw edema rate (%) was calculated. The results are shown in Table 3.

[0249] Table 3. Inhibitory effects of compounds on carrageenan-induced paw edema in rats.

[0250]

[0251]

[0252] Note: A: 1.50%-1.40%, B: 1.30%-1.20%, C: 1.20%-1.10%.

[0253] As shown in Table 3, ZL006-05, celecoxib, and the compound all exhibited significant inhibitory effects on carrageenan-induced paw edema in rats. However, the compound of this invention showed a significantly stronger inhibitory rate on rat paw edema than ZL006-05. This is because the electron cloud density on the pyridine ring of the compound of this invention is relatively low compared to the benzene ring, resulting in a stronger acidity of the hydroxyl group, which makes it easier to bind to the relevant drug target and achieve a stronger therapeutic effect.

[0254] Preliminary drug metabolism study of compound 4 in test example 5

[0255] Animals: SD rats / male, 3 rats per group;

[0256] Solvent: 5% DMSO / 20% PEG400 / 75% (30% Solutol in water);

[0257] Dosage: 2 mg / kg (IV), 10 mg / kg (PO);

[0258] Blood collection time: (1) Injection route: 0.0833h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h; (2) Gavage route: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h;

[0259] The test results are shown in Table 4:

[0260] Table 4 shows the PK experimental results for compound 4.

[0261] 2 mg / kg (iv) 10 mg / kg (po) T1 / 2 (hr) 3.34±0.31 2.51±0.97 AUC0-t(ng·hr / mL) 2888±417 2062±200 AUC0-∞(ng·hr / mL) 2909±432 2163±118 Bioavialibility (%) / 14.9

[0262] As shown in Table 4, preliminary drug metabolism studies of compound 4 indicate that its oral bioavailability is 14.9%.

[0263] Test Example 5: Neuroprotective effect of compound 4 administered in the acute phase on a rat model of ischemic stroke.

[0264] Preparation of a focal cerebral ischemia-reperfusion (MCAO) model: SD rats were anesthetized by intraperitoneal injection of 7% trichloroacetaldehyde hydrate (6 mL / kg). The anesthetized rats were fixed in a supine position on the operating table. A midline incision was made in the neck, and the subcutaneous tissue was bluntly dissected. The right common carotid artery, external carotid artery, and internal carotid artery were separated. The vagus nerve was gently dissected, and the external carotid artery was ligated and cut. The proximal end of the common carotid artery was clamped. An incision was made distal to the ligation suture of the external carotid artery, and a suture was inserted, passing through the bifurcation of the common carotid artery into the internal carotid artery. The suture was then slowly inserted until slight resistance was felt (approximately 20 mm from the bifurcation), thus blocking all blood supply to the middle cerebral artery. After 2.0 h of right-sided cerebral ischemia, the suture was gently removed, blood supply was restored, reperfusion was performed, the skin was sutured, and the area was disinfected.

[0265] SD rats were divided into three groups: a model group, a compound 4 (1 mg / kg) group, and a compound 4 (1 mg / kg) + edaravone (2 mg / kg) group. After establishing a cerebral ischemia model as described above, animals were randomly and equally assigned to each group in a single-blind manner. Animals experiencing abnormalities during surgery due to anesthesia or other complications were excluded. Following the dosage guidelines described above, the drug was administered intravenously immediately after ischemia-reperfusion. 24 hours after cerebral ischemia, neurological deficit symptoms were evaluated using a modified Bederson 5-point scale. Animals were then sacrificed, and their brains were harvested, stained, and photographed. The photographs were processed using ImageJ software, and the corresponding area of ​​the left brain and the area of ​​the non-infarcted lesion in the right brain were calculated using formulas to determine the percentage of infarct size. The results are as follows: Figure 1 As shown. From Figure 1 It can be seen that, compared with the model group, intravenous administration of compound 4 significantly improved the neurological deficit symptoms in the animals and significantly reduced the cerebral infarction area in the model animals. The efficacy of compound 4 + edaravone was even better.

[0266] Test Example 6: Dose-response relationship of oral administration of compound 4 during the recovery period on neuroprotective effect in a mouse model of permanent ischemic stroke.

[0267] Preparation of a photoinduced cerebral ischemia model: Photoinduced rose red to generate oxygen free radicals, damaging vascular endothelial cells and thus creating a focal cerebral ischemia model to simulate cerebral ischemia. Adult mice were anesthetized with 2% isoflurane gas, fixed on a stereotactic frame, and the skull was exposed through a midline scalp incision. Connective tissue was removed and the skull was dried. A 2mm diameter circular cold light source was vertically placed above the skull, with its center offset 1.5mm to the right from the anterior fontanelle. After intraperitoneal injection of rose red (100mg / kg) for 5 minutes, the intensity of the cold light source was adjusted to 12000Lux and irradiated for 15 minutes. After irradiation, the cold light source was removed, and the area was sutured and disinfected. Throughout the procedure, the animal's body temperature was maintained at 37±0.5℃ using a temperature-controlled infrared lamp. The sham-operated group was anesthetized, had their scalp cut open, and were injected with rose red, but did not receive cold light irradiation. After the surgery, the animals were returned to their respective cages and carefully monitored until they regained consciousness.

[0268] Administration: Compound 4 (10 mg / kg) is administered by gavage once daily for 5-11 days after surgery.

[0269] Animal behavior assessment: On days 4 and 12 post-surgery, the grid test was used to assess the neuromuscular strength and coordination of the rodents, and the cylinder test was used to assess their motor function and contralateral limb use. Test results are as follows: Figure 2 As shown. From Figure 2 It can be seen that, compared with the model group, the administration of compound 4 (10 mg / kg) by gavage once a day for 5-11 days after the operation significantly improved the neurological deficit symptoms in the animals, suggesting that it is effective for the recovery of stroke.

[0270] Test Example 7: Long-term neuroprotective effect of compound 4 administered orally during the recovery period on a mouse model of permanent ischemic stroke.

[0271] The animal model and administration time were the same as in test case 6, and the dosage was 10 mg / kg.

[0272] Animal behavioral assessment: On days 4, 12, 19, 26, and 33 post-surgery, the grid test was used to assess the neuromuscular strength and coordination of the rodents, and the cylinder test was used to assess their motor function and contralateral limb use. Test results are as follows: Figure 3 As shown. From Figure 3 It can be seen that, compared with the model group, the administration of compound 4 (10 mg / kg) by gavage once a day for 5-11 days after the operation significantly improved the neurological deficit symptoms in the animals, suggesting that it is effective for the recovery of stroke and has a long-term effect.

[0273] Test Example 8: Inhibitory effect of compounds 4, 34, and 46 administered by gavage on neuropathic pain.

[0274] Methods for establishing a neuropathic pain model: A neuropathic pain model was established using the spinal nerve ligation (SNL) method. Mice were anesthetized with an intraperitoneal injection of 2% chloral hydrate (0.2 mL / 10 g). After the righting reflex disappeared, the mice were fixed in a prone position. The model was established using the Kim and Chung method: A 3-5 cm long midline skin incision was bluntly dissected on the back of the mouse at the L4-S2 level. The paravertebral muscles were dissected down to the sixth lumbar vertebral process. The right L5 / L6 articular process was exposed and removed, and the L6 transverse process was partially bitten open to expose the right L4-L6 spinal nerves. The L5 nerve was gently dissected and tightly ligated with 5-0 silk suture. The incision was then sutured layer by layer, the skin was disinfected with iodine, and the animals were fed again. Postoperatively, the animals exhibited gait abnormalities. Apart from mild eversion and tucked toes, there were no other deformities in the operated hind limb.

[0275] Analgesic effect assay: C57BL / 6 mice (male, clean grade, 7-8 weeks old, weighing 22±2g) with a pre-determined baseline mechanical withdrawal response threshold were randomly divided into a compound 24 group and a solvent group. After SNL surgery, compounds 4, 34, and 46 (10mg / kg) were administered by gavage on postoperative day 7 for 3 consecutive days. The mechanical withdrawal response threshold was measured 4 hours after administration on day 3. The test results are shown below. Figure 4 As shown. From Figure 4 It can be seen that gavage administration of compounds 4, 34, and 46 all had significant analgesic effects.

[0276] Test Example 9: Effect of gavage administration of compound 4 on the behavior of a depressed mouse model.

[0277] Preparation of the chronic mild stress model: Chronic mild stress (CMS) includes wet cage, restraint stress, forced swimming, day-night reversal, inclined cage, no water or food, continuous light or continuous darkness, etc., for a total of 21 days.

[0278] C57BL / 6 mice were divided into a physiological control group, a model group, a compound 4 (2.5 mg / kg) group, a compound 4 (5 mg / kg) group, a compound 4 (10 mg / kg) group, and a ZL006-05 (30 mg / kg) group and a ZL006-05 (60 mg / kg) group. After a three-week stress period as described above, each group was administered the compound via gavage for 7 consecutive days. Stress stimulation was also applied during the administration period. The tail suspension test (TST) was performed after the last administration. The test results are as follows: Figure 5 As shown. From Figure 5 It can be seen that continuous gavage administration of compound 4 and ZL006-05 can significantly improve the immobility time of mice in the tail suspension test caused by CMS; the efficacy of compound 4 (10 mg / kg) and ZL006-05 (60 mg / kg) is comparable.

[0279] Test Example 10: Efficacy of Compound 4 in Improving Alzheimer's Disease (AD)

[0280] Laboratory animals: Zebrafish were all raised in fish tank water at 28℃;

[0281] Detection Method: Wild-type AB strain zebrafish, 4 days post-fertilization (4 dpf), were randomly selected and placed into 6-well plates, with 30 zebrafish treated in each well (experimental group). The samples were administered in aqueous solution. The positive control, donepezil hydrochloride, had a concentration of 3.33 μg / mL. The concentrations of compound 4 in the experimental groups were 0.100 μg / mL, 0.330 μg / mL, and 1.00 μg / mL, respectively. A normal control group and a model control group were also included, with a volume of 3 mL per well. Except for the normal control group, all other experimental groups were administered aluminum chloride hexahydrate in aqueous solution to establish a zebrafish AD model. After treatment at 28℃ for 1 day, 10 zebrafish from each experimental group were randomly transferred to 96-well plates, 200 μL / zebrafish, 1 zebrafish / well. Data were collected using a behavioral analyzer, and the total movement distance of the zebrafish was analyzed. The statistical analysis results of this index were used to evaluate the efficacy of the samples in improving AD. The results are as follows: Figure 6 As shown. From Figure 6 It can be seen that compound 4 has the effect of improving AD, specifically manifested in the recovery of motor dysfunction.

[0282] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A class of dextran or flavone ester derivatives of 2-hydroxynicotinic acid, characterized in that, The general formula for the structure is shown below; ， Among them, R 1 Selected from -H, -Cl, hydrocarbon groups with 1-8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, halophenyl or -NR 4 R 5 ;R 4 R 5 Independently selected from -H or -CH3; R 2 Selected from -H, alkyl groups with 1-6 carbon atoms, acyl groups with 2-7 carbon atoms, or carbamoyl groups; R 3 Selected from or ; X is selected from CH or N.

2. A class of dextranol or flavone ester derivatives of 2-hydroxynicotinic acid, characterized in that, Selected from the following compounds: 。 3. A pharmaceutically acceptable salt of a dextranol or flavonol ester derivative of 2-hydroxynicotinic acid as described in claim 1 or 2.

4. A class of pharmaceutical compositions, characterized in that, The active ingredient of the pharmaceutical composition is a pharmaceutically acceptable salt of dextranol or flavonol ester derivatives of 2-hydroxynicotinic acid as described in claim 1 or 2, or a dextranol or flavonol ester derivative of 2-hydroxynicotinic acid as described in claim 3.

5. The use of the dextranol or flavonol ester derivative of 2-hydroxynicotinic acid according to any one of claims 1 or 2, the pharmaceutically acceptable salt of the dextranol or flavonol ester derivative of 2-hydroxynicotinic acid according to claim 3, or the use of the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating inflammation and inflammation-related diseases.

6. The application according to claim 5, characterized in that, The inflammation and inflammation-related diseases mentioned are selected from one or more of stroke, neuropathic pain, depression, and Alzheimer's disease.

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