Class of dexborneol or fenchyl alcohol ester derivatives of 2-hydroxynicotinic acid and pharmaceutical uses thereof

Abstract

The present invention belongs to the technical field of biomedicine, and relates to a class of dexborneol or fenchyl alcohol ester derivatives of 2-hydroxynicotinic acid, and pharmaceutical uses thereof. The structural general formula of the derivatives is (1), R1 being selected from -H, -Cl, a hydrocarbon group having 1-8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, halogenated phenyl, or -NR4R5; R4, R5 are independently selected from -H or -CH3; R2 is selected from -H, an alkyl group having 1-6 carbon atoms, an acyl group having 2-7 carbon atoms, or a carbamoyl group; R 3 is selected from formula (a) or formula (b); X is selected from -CH= or -N=. The derivatives have good inflammation-inhibiting effects, and at high concentrations, they exhibit low cytotoxicity and are safer. The derivatives can be used for preparing a drug for treating inflammation and inflammation-related diseases such as stroke, neuropathic pain, depression and Alzheimer's disease.

Description

Dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a class of dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses. Background Art

[0002] Inflammation is a fundamental pathological process, primarily a defensive response, that occurs when biological tissues are stimulated by certain stimuli, such as trauma and infection. Local manifestations of inflammation include redness, swelling, heat, pain, and functional impairment, and are also accompanied by systemic reactions such as fever and changes in peripheral white blood cell counts. Inflammation is a major cause of many diseases, including cardiovascular disease, diabetes, cerebrovascular disease, Alzheimer's disease, and even cancer. A growing number of studies have identified a role for neuroinflammation in ischemic stroke. The mechanism of secondary injury after cerebral ischemia may be due to inflammation in the brain after ischemic stroke. This inflammatory response accelerates ischemic damage and impairs 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, approximately 40% of patients will suffer from serious sequelae, causing great pain to the patients. However, there is currently no drug that can promote the repair of neurological function after stroke.

[0003] During the inflammatory response, macrophages play an important role in initiating, maintaining, and resolving inflammatory responses. Lipopolysaccharide (LPS) is one of the main components of the cell wall of Gram-negative bacteria and has a strong immune-stimulating ability. RAW264.7 macrophages, a type of mouse-derived immune cell, are activated when stimulated by external factors (such as LPS), secreting numerous inflammatory factors and producing an inflammatory response. The amount of inflammatory factors can indirectly reflect the severity of inflammation and is a quantitative indicator of the severity of inflammation.

[0004] Dextromethorphanol is a bicyclic monoterpenoid compound whose mechanism of action is to inhibit the expression of inflammatory factors during cerebral infarction, thereby reducing brain cell death. Dextromethorphanol is poorly soluble in water, and when formulated into an injection, a large amount of organic solvent must be added, which increases the difficulty of preparing the drug for injection. Dextromethorphanol is volatile and has an unpleasant odor, and its oral bioavailability is low, which increases the difficulty of preparing oral formulations. ZL006-05 is a salicylate derivative of dextromethorphanol, which has shown effects in animal models such as reducing post-stroke neurological damage, combating depression, and treating neuropathic pain. It has currently entered 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 suggest that fenchol significantly reduces excessive Aβ accumulation and neuronal death by stimulating FFAR2 signaling (a microbiome-sensing mechanism), potentially protecting the brain from Alzheimer's pathological damage. However, fenchol is poorly soluble in water and has low oral bioavailability, which complicates its oral formulation.

[0006] Because long-term medication is required for post-stroke neurological restoration and Alzheimer's disease, oral formulations are more suitable for clinical needs. Patent CN 116283588A discloses a class of 4-alkoxy-substituted 2,6-dihydroxybenzyl dextranol or fenchol ester compounds and their pharmaceutical uses. However, these compounds have a relatively short half-life (less than 1 hour), and their oral bioavailability remains low (approximately 5%). Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a class of dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid and their pharmaceutical uses.

[0008] The first object of the present invention is to provide a class of dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid, the general structural formula of which is shown below:

[0009] Among them, R 1 -H, -Cl, a hydrocarbon group of 1 to 8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, a halogenated phenyl group or -NR 4 R 5 ; R 4 、R 5 Independently selected from -H or -CH3;

[0010] R 2 is selected from -H, an alkyl group of 1 to 6 carbon atoms, an acyl group of 2 to 7 carbon atoms, or a carbamoyl group;

[0011] R 3 Selected from

[0012] X is selected from -CH= or -N=.

[0013] In one embodiment of the present invention, the compound is selected from the following:

[0014] A second objective of the present invention is to provide pharmaceutically acceptable salts of the aforementioned dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid. The phenolic hydroxyl group present in the structure of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid of this invention is acidic and can form sodium and potassium salts, or complex salts with basic organic compounds such as basic amino acids and meglumine. The phenolic hydroxyl group present in the structure can be etherified, esterified, or carbamate-terminated to form prodrugs. These prodrugs can be metabolized in vivo to release the phenolic hydroxyl group, exerting their pharmacological activity.

[0015] The third object of the present invention is to provide a pharmaceutical composition, the active ingredient of which is the dextran or fenchol ester derivative of 2-hydroxynicotinic acid, or a pharmaceutically acceptable salt of the dextran or fenchol ester derivative of 2-hydroxynicotinic acid.

[0016] The fourth object of the present invention is to provide a class of dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid, pharmaceutically acceptable salts of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid, and the use of the pharmaceutical composition in the preparation of drugs for treating inflammation and inflammation-related diseases.

[0017] 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.

[0018] The technical solution of the present invention has the following advantages over the prior art:

[0019] (1) The dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid described in the present invention have a longer half-life and better oral bioavailability. By introducing a nitrogen atom into the benzene ring and changing the benzene ring to a pyridine ring or a quinoline ring, not only does this change the skeletal structure, but it also yields a novel structure. More importantly, due to the relatively low number of free phenolic hydroxyl groups in the molecule, the half-life of this compound is relatively long (approximately 2 hours), and oral bioavailability is significantly improved (approximately 10%).

[0020] (2) The dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid described herein have excellent anti-inflammatory effects and exhibit low cytotoxicity at high concentrations, making them 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.

[0021] (3) The dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid of the present invention have relatively good oral efficacy and are effective for depression and neuralgia, showing good medicinal prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0023] Figure 1 shows the effects of acute injection of Compound 4 in Test Example 5 of the present invention on cerebral infarction area and nerve damage after stroke; the left figure shows the effect on cerebral infarction area, and the right figure shows the effect on nerve damage;

[0024] FIG2 is a dose-effect relationship of compound 4 administered orally during the recovery period on post-stroke neurological recovery in Test Example 6 of the present invention;

[0025] FIG3 shows the long-term effect of oral administration of compound 4 in Test Example 7 of the present invention on post-stroke neurological recovery during the recovery period;

[0026] FIG4 shows the inhibitory effects of compounds 4, 34, and 46 on neuropathic pain after oral administration in Test Example 8 of the present invention;

[0027] FIG5 shows the effect of oral administration of Compound 4 in Test Example 9 of the present invention on the behavior of depression model mice;

[0028] FIG6 shows the efficacy of compound 4 in Test Example 10 of the present invention in improving the motor function of Alzheimer's disease. DETAILED DESCRIPTION

[0029] 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 the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0030] In the present 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.

[0031] Example 1 Synthesis of Compound 1 (2-hydroxy-6-methylnicotinate)

[0032] 0.78 g (5 mmol) of 2-hydroxy-6-methylnicotinic acid and 0.62 g (4 mmol) of borneol 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 completed, the filtrate was filtered and dried, then dissolved in 100 mL of ethyl acetate (EA). The mixture was washed three times with 100 mL of saturated brine. The organic layer was collected, dried, and sanded. The mixture was then passed through a column with petroleum ether (PE, 60°C-90°C): ethyl acetate (EA) = 30:1. The product was dried and slurried to obtain a white solid. 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),7.92(d,J=7.3Hz,1H),6.06(d,J=7.4Hz ,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-d 6) 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.

[0033] Example 2 Synthesis of Compound 2 (2-hydroxynicotinic acid borneol ester) Reference compound 1, using 2-hydroxynicotinic acid and borneol as raw materials

[0034] White solid. 1 H 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-d 6) 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.

[0035] Example 3 Synthesis of Compound 3 (2-hydroxy-6-chloronicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-chloronicotinic acid and borneol as raw materials

[0036] 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-d 6) 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.

[0037] Example 4 Synthesis of Compound 4 (2-hydroxy-6-trifluoromethyl nicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-trifluoromethyl nicotinic acid and borneol as raw materials

[0038] 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-d 6) δ165.26,162.96,143.43,125.48,122.75,120.02,117.29,117.10,112. 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.

[0039] Example 5 Synthesis of Compound 5 (2-hydroxy-6-difluoromethylnicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-difluoromethylnicotinic acid and borneol as raw materials

[0040] 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). 13 C 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.

[0041] Example 6 Synthesis of Compound 6 (2-hydroxy-6-isopropylnicotinate) Reference Compound 1, using 2-hydroxy-6-isopropylnicotinate and borneol as raw materials

[0042] 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). 13C NMR(101MHz,DMSO-d6)δ165.17,161.98,160.42,145.90,117.69,100.72,79.47 ,49.10,47.93,44.83,37.01,32.00,28.17,27.35,21.61,20.05,19.19,13.99.

[0043] Example 7 Synthesis of Compound 7 (2-hydroxy-6-isobutylnicotinate) Reference Compound 1, using 2-hydroxy-6-isobutylpropylnicotinate and borneol as raw materials

[0044] White solid. 1 H 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.

[0045] Example 8 Synthesis of Compound 8 (2-hydroxy-6-isopentylnicotinate) Reference Compound 1, using 2-hydroxy-6-isopentylpropylnicotinate and borneol as raw materials

[0046] White solid. 1H 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). 13 C 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.

[0047] Example 9 Synthesis of Compound 9 (2-hydroxy-6-phenylnicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-phenylnicotinic acid and borneol as raw materials

[0048] 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). 13C 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.

[0049] Example 10 Synthesis of Compound 10 (2-hydroxy-6-(2-phenyl)ethyl nicotinate) Reference Compound 1, using 2-hydroxy-6-(2-phenyl)ethyl nicotinate and borneol as raw materials

[0050] White solid. 1 H 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.

[0051] Example 11 Synthesis of Compound 11 (2-methoxy-6-methylnicotinate)

[0052] 0.29 g (1 mmol) of 2-hydroxy-6-methylnicotinate was dissolved in 10 mL of dichloromethane. 0.32 g (1.1 mmol) of dicyclic amidine (DBU) and 0.15 g (1.1 mmol) of dimethyl sulfate were added sequentially and allowed to react at room temperature for 3 h. After the reaction was complete, the filtrate was filtered and dried, then dissolved in 100 mL of ethyl acetate (EA). The mixture was washed three times with 100 mL of saturated brine. The organic layer was collected, dried, and sanded. Then, it was passed through a column with petroleum ether (PE, 60°C-90°C): ethyl acetate (EA) = 30:1 to produce a white solid. 1 H NMR(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.

[0053] Example 12 Synthesis of Compound 12 (2-methoxy-6-trifluoromethyl nicotinate) Reference Compound 11, using 2-hydroxy-6-trifluoromethyl nicotinate and dimethyl sulfate as raw materials

[0054] Colorless oil. 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). 13C 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.

[0055] Example 13 Synthesis of Compound 13 (2-ethoxy-6-methyl nicotinate) Reference Compound 11, using 2-hydroxy-6-methyl nicotinate and diethyl sulfate as raw materials

[0056] 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.

[0057] Example 14 Synthesis of Compound 14 (2-ethoxy-6-trifluoromethyl nicotinate) Reference Compound 11, using 2-hydroxy-6-trifluoromethyl nicotinate and diethyl sulfate as raw materials

[0058] Colorless oil. 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.

[0059] Example 15 Synthesis of Compound 15 (2-isopropoxy-6-methylnicotinate)

[0060] 290 mg of 2-hydroxy-6-methyl-bornyl nicotinate was dissolved in THF in an eggplant-shaped flask. Then, 228 mg of potassium carbonate and 132 mg of ethyl bromide were added and the mixture was allowed to react at room temperature for 5 h. After the reaction was complete, the filtrate was filtered, dried, and dissolved in 100 mL of ethyl acetate (EA). The mixture was washed three times with 100 mL of saturated brine. The organic layer was collected, dried, and sanded. The mixture was then passed through a column with a ratio of petroleum ether (PE, 60°C-90°C): ethyl acetate (EA) = 30:1 to obtain a colorless oil. 1 H 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.

[0061] Example 16 Synthesis of Compound 16 (2-isobutoxy-6-methyl nicotinate) Reference Compound 15, using 2-hydroxy-6-methyl nicotinate and isobutyl bromide as raw materials

[0062] Colorless oil. 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). 13 C 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.

[0063] Example 17 Synthesis of Compound 17 (2-cyclohexyloxy-6-methyl nicotinate) Reference Compound 15, using 2-hydroxy-6-methyl nicotinate and cyclohexyl bromide as raw materials

[0064] Pale yellow oil. 1H 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.

[0065] Example 18 Synthesis of Compound 18 (2-acetoxy-6-methylnicotinate)

[0066] Dissolve 0.29 g (1 mmol) of 2-hydroxy-6-methylnicotinate (dextrose-1-ol) in 10 mL of dichloromethane. Add 0.15 g (1.5 mmol) of acetic anhydride and 0.10 g (1 mmol) of triethylamine, and allow to react at room temperature for 3 h. After the reaction is complete, filter the filtrate, spin dry, and prepare sand. Pass the column with a mixture of petroleum ether (PE, 60°C-90°C): ethyl acetate (EA) = 30:1, yielding a white solid. 1 H NMR(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). 13C 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.

[0067] Example 19 Synthesis of Compound 19 (2-acetoxy-6-trifluoromethyl nicotinate) Reference Compound 18, using 2-hydroxy-6-trifluoromethyl nicotinate and acetic anhydride as raw materials

[0068] Colorless oil, yield 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). 13 C 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.

[0069] Example 20 Synthesis of Compound 20 (2-propionyloxy-6-trifluoromethyl nicotinate) Reference Compound 18, using 2-hydroxy-6-trifluoromethyl nicotinate and propionic anhydride as raw materials

[0070] Colorless oil. 1H 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 C NMR(101MHz,Chloroform-d)δ172.25,162.61,157.02,150.05,149.69,143.00,122.77,121.86,11 9.13,118.92,82.27,49.19,48.10,44.91,36.78,28.12,27.69,27.42,19.75,18.92,13.67,8.50. 19 F NMR(376MHz,Chloroform-d)δ-68.17.

[0071] Example 21 Synthesis of Compound 21 (2-isobutyryloxy-6-methyl nicotinate) Reference Compound 15, using 2-hydroxy-6-methyl nicotinate and isobutyric anhydride as raw materials

[0072] White solid. 1 H NMR(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). 13C 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.

[0073] Example 22 Synthesis of Compound 22 (2-cyclohexanoyloxy-6-methyl nicotinate) Reference Compound 18, using 2-hydroxy-6-methyl nicotinate and cyclohexylcarbonyl chloride as raw materials

[0074] Colorless oil. 1 H 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.

[0075] Example 23 Synthesis of Compound 23 (2-N,N-dimethylcarbamoyloxy-6-methylnicotinate)

[0076] To 500 mg of 2-hydroxy-6-methyl borneol nicotinate, 30 mL of dichloromethane and 300 mg of triphosgene were added, and 0.5 mL of triethylamine was injected. After the reaction for 5 h, dimethylamine was directly added without post-treatment. After the reaction for 2 h, the solvent dichloromethane was dried, and water and ethyl acetate were added for extraction. The organic phase was taken and dried over anhydrous Na2SO4. The organic phase was dried and subjected to column chromatography (PE:EA=100:1) to obtain a white solid. 1 H 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.

[0077] Example 24 Synthesis of Compound 24 (2-(4-methylpiperazinyl)formyloxy-6-trifluoromethylnicotinate) Hydrochloride

[0078] 500 mg of 2-hydroxy-6-trifluoromethylnicotinate was completely dissolved in 30 mL of acetone, 400 mg of 1-methylpiperazine-1-carbonyl chloride hydrochloride was added, and then 2 equivalents of K2CO3 were added. The reaction was heated under reflux for 12 h, monitored by plate spotting, filtered, and the solvent was directly dried by spin drying. The solution was purified by column chromatography (DCM:MeOH=100:1) to obtain 300 mg of Compound 24 as a colorless oil.

[0079] Compound 24 was dissolved in 10 mL of ethyl acetate and salified with 2 M hydrochloric acid in ethyl acetate to obtain 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 F NMR(376MHz,Chloroform-d)δ-68.82.

[0080] Example 25 Synthesis of Compound 25 ((S)-(2-(2-((methylamino)methyl)pyrrolidinyl)formyloxy-6-trifluoromethylnicotinate)

[0081] Compound 4 (500 mg, 1.46 mmol) was placed in a two-necked flask, and 10 mL of DCM was added. Cs2CO3 (1.42 g, 4.37 mmol) was added. The mixture was cooled to 0°C under N2 protection and slowly added dropwise with a 10 mL solution of triphosgene (172.59 mg, 0.58 mmol) in DCM. After stirring for 10 minutes, the mixture was allowed to cool to room temperature and stirred for 4 hours. TLC confirmed the complete reaction (a DCM solution of 25-1 was obtained). Tert-butyl (S)-2-((methylamino)methyl)pyrrolidinyl-1-carbonate (936.53 mg, 4.37 mmol) was added and stirred at room temperature for 8 hours. The reaction mixture was washed with 50 mL of water and 50 mL of saturated brine, respectively. The organic layer was collected, dried, and purified by column chromatography (DCM:MeOH = 100:1). The eluent was dried to obtain a clear oil (25-2). The product was dissolved in 10 mL of ethyl acetate, and 1.0 mL of 2 M hydrochloric acid and ethyl acetate was added, followed by stirring at room temperature for 4 h to obtain compound 25 hydrochloride as a light 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.

[0082] Example 26 Synthesis of Compound 26 (2-hydroxy-6-methylnicotinic acid fenchyl alcohol ester) Reference Compound 1, using 2-hydroxy-6-methylnicotinic acid and fenchyl alcohol as raw materials

[0083] 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.

[0084] Example 27 Synthesis of Compound 27 (2-hydroxy-6-chloronicotinic acid fenchyl alcohol ester) Reference Compound 1, using 2-hydroxy-6-chloronicotinic acid and fenchyl alcohol as raw materials

[0085] 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.

[0086] Example 28 Synthesis of Compound 28 (2-hydroxy-6-trifluoromethylnicotinic acid fenchyl alcohol ester) Reference Compound 1, using 2-hydroxy-6-trifluoromethylnicotinic acid and fenchyl alcohol as raw materials

[0087] 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.

[0088] Example 29 Synthesis of Compound 29 (2-Hydroxynicotinic Acid Fenchyl Ester) Reference Compound 1, using 2-hydroxynicotinic acid and fenchyl alcohol as raw materials

[0089] 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). 13 C 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.

[0090] Example 30 Synthesis of Compound 30 (2-ethoxy-6-methylnicotinate) Reference Compound 15, using 2-hydroxy-6-trifluoromethylnicotinate and ethyl bromide as raw materials

[0091] Colorless oil. 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.

[0092] Example 31 Synthesis of Compound 31 (2-propionyloxy-6-methylnicotinate) Reference Compound 18, using 2-hydroxy-6-methylnicotinate and propionic anhydride as raw materials

[0093] White solid. 1 H NMR(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.

[0094] Example 32 (Synthesis of 2-(4-methylpiperazinyl)formyloxy-6-methylnicotinate) Reference compound 25, using 2-hydroxy-6-trifluoromethylnicotinate and 1-methylpiperazine as raw materials

[0095] 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). 13 C NMR(101MHz,DMSO-d 6) 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.

[0096] Example 33 Synthesis of Compound 33 (2-(N-methyl-2-(N-methyl)aminoethylamino)formyloxy-6-trifluoromethylnicotinate) Referring to Compound 25, 2-hydroxy-6-trifluoromethylnicotinate and methyl tert-butyl [2-(methylamino)ethyl]carbamic acid were used as raw materials, and Compound 33 and hydrochloric acid were used as raw materials to obtain Compound 33 hydrochloride.

[0097] 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). 13 CNMR(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.

[0098] Example 34 Synthesis of Compound 34 (2-(N-methyl-2-(N-methyl)aminoethylamino)formyloxy-6-trifluoromethylnicotinate)

[0099] 0.343 g (0.01 mol) of 2-hydroxy-6-trifluoromethylnicotinate (Compound 4) was dissolved in 15 mL of DCM, 0.240 g (0.011 mol) of (R)-(3-((tert-butyldimethylsilyl)oxy)butanoic acid) and 0.134 g (0.011 mol) of 4-dimethylaminopyridine (DMAP). After stirring at room temperature for 30 min, 0.2270 g (0.011 mol) of N,N'-dicyclohexylcarboximide (DCC) was added. The mixture was reacted at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was purified by silica gel column with PE:EA 100:1 eluent. 10 mL of methanol was added to dissolve the mixture. The mixture was stirred at 0°C for 10 min. 0.046 g (0.003 mol) of trimethylsilyl bromide was slowly added dropwise. After the addition was complete, the mixture was returned to room temperature for 3 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was purified by PE:EA 100:1 eluent. The 20:1 eluate was purified by silica gel column to obtain compound 34 as an oil. 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). 13 CNMR(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.

[0100] Example 35 Synthesis of Compound 35 (2,4-dihydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 1, using 2-methylmercapto-4-dihydroxy-5-pyrimidinecarboxylic acid and borneol as raw materials

[0101] 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.

[0102] Example 36 Synthesis of Compound 36 (2-hydroxy-6-cyanonicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-cyanonicotinic acid and borneol as raw materials

[0103] 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.

[0104] Example 37 Synthesis of Compound 37 (2-hydroxy-6-formaldehyde nicotinic acid borneol ester) Reference Compound 1, using 2-hydroxy-6-formaldehyde nicotinic acid and borneol as raw materials

[0105] To a 250 mL eggplant-shaped flask, ethyl formate (14.8 g, 200 mmol) 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). After stirring at room temperature overnight, the reaction was detected by TLC to be complete. The organic tetrahydrofuran phase was removed by rotation, and the product was washed twice with diethyl ether (50 mL) to obtain 15.0 g of intermediate 37-1 as a yellow solid in a yield of 56.8%.

[0106] 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 becomes alkaline), and 100 mL of water were placed in a round-bottom flask, followed by the addition of intermediate 37-1 (15.0 g, 88 mmol). The resulting mixture was heated under reflux for 5 h and then cooled to room temperature. The mixture was acidified by the addition of hydrochloric acid while stirring until the mixture became acidic and a solid precipitated. The crude product was filtered and recrystallized from a mixed solvent of ethanol and water to obtain 8.3 g of intermediate 37-2 as a white solid in a yield of 41.52%.

[0107] A mixture of intermediate 37-2 (8.3 g, 42 mmol) and aqueous KOH (80% w / 150 mL) was added to a 250 mL eggplant-shaped flask and heated in an oil bath at 150°C for 24 h. The reaction was stopped, the reaction mixture was cooled to room temperature, poured into 300 mL of water, and the pH was adjusted to 4 in an ice bath. The solid product was collected by filtration, washed, and dried. The crude product was recrystallized from acetic acid to obtain 7.5 g of intermediate 37-3 as an off-white solid (81% yield).

[0108] To a 250 mL eggplant-shaped flask, raw material dextroborneol (5.0 g, 32.4 mmol) and 165 mL of dichloromethane were added, and 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. After reacting at room temperature for 8 h, TLC detected that the reaction was complete. The organic phase (dichloromethane) was concentrated in vacuo, ethyl acetate was added and filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain 5.0 g of intermediate 37-4 as a white solid in a yield of 48.8%.

[0109] To a 100 mL eggplant-shaped flask, intermediate 37-4 (5.0 g, 14.3 mmol) was added, and 80 mL of (acetic acid: water = 1:1) was added thereto. The mixture was heated and stirred at 60 degrees overnight. The reaction was detected by TLC until completion. The mixture was extracted with ethyl acetate, and the organic phase was washed three times with water. The collected organic phase was dried over anhydrous sodium sulfate, and the obtained organic phase was concentrated in vacuo to obtain a crude product. The crude product was recrystallized from ethanol and water to obtain 3.2 g of a 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.

[0110] Example 38 Synthesis of Compound 38 (2-Hydroxy-6-Methanol Nicotinate)

[0111] Compound 37 (2.0 g, 6.6 mmol) was added to a 100 mL eggplant-shaped flask, and 35 mL of ethanol was added to dissolve the mixture. 300 mg of sodium borohydride was added in small portions and allowed to react at room temperature for 2 h. The reaction was complete after TLC. The reaction was quenched with dilute hydrochloric acid and extracted with ethyl acetate and water. The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give 1.50 g of a white solid in a yield of 74.6%. 1H 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.

[0112] Example 39 Synthesis of Compound 39 (2-Hydroxy-6-Methanol Nicotinate)

[0113] Compound 37 (1.0 g, 3.3 mmol) was added to a 100 mL eggplant-shaped flask and dissolved in 25 mL of ethanol. Hydroxylamine (165 mg, 4.95 mmol) was added at room temperature and allowed to react for 3 h. The reaction was complete by TLC. Intermediate 39-1 was obtained without purification. 25 mL of methanol was added as solvent for dissolution. 300 mg of Pd / C was added and the reaction was continued under a hydrogen atmosphere for 6 h. The reaction was complete by TLC. The organic methanol phase was concentrated under vacuum. The crude product was recrystallized from ethyl acetate to obtain 200 mg of a white solid. 1 H NMR (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). 13C 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.

[0114] Example 40 Synthesis of Compound 40 (2-Hydroxy-6-Methanol Nicotinate)

[0115] Compound 37 (1.0 g, 3.3 mmol) was added to a 100 mL eggplant-shaped flask, and 25 mL of tert-butanol was added to dissolve the mixture. Dimethyldibutylene (7 equiv), sodium dihydrogen phosphate (4 equiv), and 1.3 eq of sodium chlorite / water solution (27 equiv) were added and reacted at room temperature for 3 h. The reaction was detected by TLC until completion. Na2SO3 (1.3 equiv) was added, the temperature was controlled at 0°C, and the mixture was stirred at room temperature for 15 min. The pH was adjusted to 5 with saturated aqueous ammonium chloride solution, and the mixture was extracted with EA (100 mL*3 times). The organic phases were combined and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give 430 mg of a white solid with a yield of 41.6%. 1 H 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.

[0116] Example 41 Synthesis of Compound 41 (2-methylmercapto-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 1, using 2-methylmercapto-4-hydroxy-5-pyrimidinecarboxylic acid and borneol as raw materials

[0117] White solid. 1H 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.

[0118] Example 42 Synthesis of Compound 42 (2-methyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester)

[0119] Weigh acetamidine hydrochloride (2.50 g, 26.44 mmol) and add it to the reaction flask, add an appropriate amount of anhydrous ethanol solution, move to an ice bath and cool to 0°C, add 2 eq of anhydrous sodium ethanol (3.60 g, 52.88 mmol) solution, and then slowly dropwise add 1 eq of diethyl ethoxymethylenemalonate (5.72 g, 26.44 mmol), stir for 10 min, then move to an oil bath and heat under reflux to 80°C. React overnight and monitor by TLC; move the reaction to room temperature, slowly add a small amount of water to quench the reaction, spin dry the ethanol in the reaction system, add water to dissolve, adjust the reaction solution to pH 6 with 2 mol / L dilute hydrochloric acid, extract the reaction solution 3 times with ethyl acetate, wash the lipid layer with saturated brine, dry over anhydrous sodium sulfate, and pass through a sand column to obtain intermediate 42-2 as a white solid.

[0120] Intermediate 42-2 was dissolved in an appropriate amount of anhydrous ethanol solution, and an excess of saturated aqueous sodium hydroxide solution was added. The reaction was heated to 60°C and monitored by TLC. The reaction was complete in 2 hours. The reaction was cooled to room temperature, the ethanol solution was dried, and a small amount of water was added until the precipitated solid was dissolved. A 22 mol / L dilute hydrochloric acid solution was slowly added dropwise until a large amount of solid precipitated (approximately pH = 6). The filter cake was filtered and washed with a small amount of water. The filter cake was dried to obtain Intermediate 42-3 as a white solid.

[0121] Intermediate 42-3 (400 mg, 2.60 mmol) was weighed and added to a reaction flask. An appropriate amount of acetonitrile was added, followed by 1 eq of dextroborneol (400.92 mg, 2.60 mmol) and 2.1 eq of NMI (447.16 mg, 5.45 mmol). The mixture was stirred for 30 min, and 1.2 eq of TCFH (875.41 mg, 3.12 mmol) was added. The mixture was reacted at room temperature and stirred overnight. The reaction solution was spin-dried and washed with appropriate amounts of DCM, water, and saturated brine, respectively. The reaction solution was dried over anhydrous sodium sulfate and passed through a sand column 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.

[0122] Example 43 Synthesis of Compound 43 (2-tert-butyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using tert-butylformamidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0123] 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). 13C 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.

[0124] Example 44 Synthesis of Compound 44 (2-amino-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using guanidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0125] 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.

[0126] Example 45 Synthesis of Compound 45 (2-cyclopropyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using cyclopropylformamidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0127] White solid. 1H 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.

[0128] Example 46 Synthesis of Compound 46 (2-isopropyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using isopropylformamidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0129] 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). 13 C 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.

[0130] Example 47 Synthesis of Compound 47 (2-ethyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using propionamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0131] 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.

[0132] Example 48 Synthesis of Compound 48 (2-butyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using pentamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0133] White solid. 1 H 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).

[0134] 13CNMR(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.

[0135] Example 49 Synthesis of Compound 49 (2-propyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using butyramidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0136] 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).

[0137] Example 50 Synthesis of Compound 50 (2-phenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using benzamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0138] White solid. 1H NMR (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.

[0139] Example 51 Synthesis of Compound 51 (2-o-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-chlorobenzamide hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0140] 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). 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.

[0141] Example 52 Synthesis of Compound 52 (2-p-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using p-chlorobenzamide hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0142] 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.

[0143] Example 53 Synthesis of Compound 53 (2-m-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using m-chlorobenzamidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0144] White solid. 1 H 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.

[0145] Example 54 Synthesis of Compound 54 (2-o-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-fluorobenzamide hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0146] 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.

[0147] Example 55 Synthesis of Compound 55 (2-p-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using p-fluorobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0148] 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). 13C 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.

[0149] Example 56 Synthesis of Compound 56 (2-m-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using m-fluorobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0150] 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). 13 C 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.

[0151] Example 57 Synthesis of Compound 57 (2-o-bromophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-bromobenzamide hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0152] White solid. 1H 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.

[0153] Example 58 Synthesis of Compound 58 (2-p-bromophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using p-bromobenzamide hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0154] 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). 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.

[0155] Example 59 Synthesis of Compound 59 (2-m-tolyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using m-toluamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0156] 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.

[0157] Example 60 Synthesis of Compound 60 (2-thiophene-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using thiophene carboxamidine hydrochloride, diethyl ethoxymethylmalonate and borneol as raw materials

[0158] 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 C NMR (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.

[0159] Example 61 Synthesis of Compound 61 (2-pyridyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using pyridine 3-formamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw materials

[0160] 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.

[0161] Example 62 Synthesis of Compound 62 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylmalonate and borneol as raw materials

[0162] 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.

[0163] Example 63 Synthesis of Compound 63 (2-isopropyl-4-hydroxy-5-pyrimidinecarboxylic acid pyrimidine alcohol ester) Reference compound 42, using isopropylformamidine hydrochloride, diethyl ethoxymethylmalonate and pyrimidine alcohol as raw materials

[0164] 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.

[0165] Example 64 Synthesis of Compound 64 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylic acid dapoxetine) Reference Compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylmalonate and dapoxetine as raw materials

[0166] 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.

[0167] Comparative Example 1

[0168] Test Example 1 Determination of the Effect of Compounds on the Proliferation of RAW264.7 Macrophages in Vitro

[0169] The cells were digested and counted, and a RAW264.7 cell suspension of 7×10 4100 μL of cell suspension was added to each well of a 96-well cell culture plate; the plate was incubated at 37°C, 5% CO2 for 24 hours; the drug was diluted with culture medium to the desired working solution concentration, and 100 μL of the corresponding drug-containing culture medium was added to each well. A negative control group was also established; the plate was incubated at 37°C, 5% CO2 for 24 hours; 20 μL of CCK-8 was added to each well, and the plate was incubated in the incubator for another 2-3 hours; the plate was gently mixed on a shaker for 10 minutes to remove bubbles from the 96-well plate; the OD value of each well was read on a microplate reader at λ = 450 nm, and the inhibition rate was calculated; 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:

[0170] Table 1 Inhibitory effect of compounds on the growth of RAW264.7 macrophages (6 μmol / L) Note: A: 40%-50%, B: 10%-5%, C: 5%-0%.

[0171] As can be seen from Table 1, at higher concentrations (6 μmol / L), celecoxib and ZL006-05 have stronger cytotoxicity (40%-50%), while the cytotoxicity of the compounds of the present invention is less than 10%, indicating that they have better safety.

[0172] Effects of Test Example 2 Compounds on Inflammatory Factors in RAW264.7 Macrophages Induced by Lipopolysaccharide

[0173] The cells were digested and counted, and a RAW264.7 cell suspension of 7×10 4 100 μL of cell suspension was added to each well of a 96-well cell culture plate; the cells were cultured in a 37°C, 5% CO2 incubator for 24 hours; the drug was diluted with culture medium to the desired concentration, and 100 μL of the corresponding drug-containing culture medium was added to each well. A negative control group was also established; the cells were cultured in a 37°C, 5% CO2 incubator for 2 hours; 100 μg / L of LPS was then added and incubated for 24 hours. The supernatant was collected and the IL-1β and TNF-α levels were detected according to the ELISA kit instructions, as shown in Table 2:

[0174] Table 2 Effects of compounds on inflammatory factors in RAW264.7 macrophages induced by lipopolysaccharide (1 μmol / L) Note: Inflammatory factor measurement values ​​A: 200%-151%, B: 150%-101%, C: 100%-76%, D: 75%-51%, E: 50%-25%.

[0175] 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.

[0176] Test Example 3 Inhibition rate of carrageenan-induced paw swelling in rats by intravenous injection of compound

[0177] SD rats (male, SPF, 6-8 weeks old, weighing 250-280g) were randomly divided into groups of 6. The normal and model groups were intravenously injected with an equal volume of vehicle, while each drug group was intravenously injected with 20 μmol / kg of each compound. 0.5 h after administration, the normal group received a subcutaneous injection of 100 μL of normal saline into the hind paw, while the remaining groups received a 100 μL injection of 1% carrageenan. The paw volume of the rats was measured at 0 and 4 h after carrageenan injection, and the paw swelling rate (%) was calculated. The results are shown in Table 3:

[0178] Table 3 Inhibitory effect of compounds on carrageenan-induced paw swelling in rats Note: A: 1.50%-1.40%, B: 1.30%-1.20%, C: 1.20%-1.10%.

[0179] As can be seen from Table 3, ZL006-05, celecoxib, and compound have significant inhibitory effects on rat paw swelling caused by carrageenan. However, the compound of the present invention is significantly better than ZL006-05 in terms of rat paw swelling inhibition rate. This is because the electron cloud density on the pyridine ring of the compounds of the present invention is relatively low relative to the phenyl ring, causing the acidity of the hydroxyl group to be stronger, making it easier to combine with the relevant drug target, thereby obtaining stronger drug effect.

[0180] Test Example 5 Preliminary drug metabolism study of compound 4

[0181] Animals: SD rats / male, 3 per group;

[0182] Solvent: 5% DMSO / 20% PEG400 / 75% (30% Solutol in water);

[0183] Dosage: 2 mg / kg (IV), 10 mg / kg (PO);

[0184] Blood collection time: (1) Injection route: 0.0833h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h; (2) Oral gavage route: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h;

[0185] The test results are shown in Table 4:

[0186] Table 4 PK experimental results of compound 4

[0187] As can be seen from Table 4, preliminary drug metabolism studies of compound 4 showed that the oral bioavailability of compound 4 was 14.9%.

[0188] Test Example 5: Acute administration of compound 4 to the brain protective effect of ischemic stroke model rats

[0189] Preparation of focal cerebral ischemia-reperfusion (MCAO) model: SD rats were anesthetized by intraperitoneal injection of 7% chloral hydrate (6 mL / kg) and fixed on the operating table in the supine position. 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 peeled off, and the external carotid artery was ligated and cut. The proximal end of the common carotid artery was clamped, and an incision was made from the distal end of the ligature of the external carotid artery. The suture was inserted through the bifurcation of the common carotid artery into the internal carotid artery, and then slowly inserted until there was slight resistance (about 20 mm from the bifurcation), blocking all blood supply to the middle cerebral artery. After 2.0 h of right cerebral ischemia, the suture was gently pulled out, blood supply was restored for reperfusion, the skin was sutured, and disinfection was performed.

[0190] SD rats were divided into 3 groups: model group, compound 4 (1 mg / kg) group, and compound 4 (1 mg / kg) + edaravone (2 mg / kg) group. After the cerebral ischemia model was prepared according to the above method, the animals were randomly and equally divided into each group in a single blind manner. During the operation, animals with abnormal conditions due to anesthesia, surgery, etc. must be eliminated. According to the above dosage setting principle, the drug was intravenously administered once immediately after ischemia and reperfusion. The modified Bederson 5-point system was used to evaluate the symptoms of neurological deficits 24 hours after cerebral ischemia, and then the animals were killed, the brains were removed, stained, and photographed. The photos were processed with Image J software, and the corresponding area of ​​the left brain and the non-infarct area of ​​the right brain were calculated according to the formula to calculate the percentage of infarct range. The results are shown in Figure 1. As can be seen from Figure 1, compared with the model group, intravenous administration of compound 4 can significantly improve the neurological deficit symptoms of animals and significantly reduce the range of cerebral infarction in model animals. The efficacy of the compound 4 + edaravone group is better.

[0191] Test Example 6: Dose-effect relationship study on the brain protective effect of compound 4 after oral administration during the recovery period on mice with permanent damage in ischemic stroke model

[0192] Preparation of a light-induced cerebral ischemia model: A focal cerebral ischemia model was established by irradiating Rose Bengal with light to generate oxygen free radicals, which damage vascular endothelial cells. Adult mice were anesthetized with 2% isoflurane gas and fixed in a stereotaxic apparatus. A midline scalp incision was made to expose the skull, and connective tissue was removed and air-dried. A cold light source with a 2 mm diameter circular spot was placed vertically above the skull, with the center offset 1.5 mm to the right of bregma. Five minutes after intraperitoneal injection of Rose Bengal (100 mg / kg), the cold light source was adjusted to 12,000 lux and irradiated for 15 minutes. After irradiation, the cold light source was removed, and the wound was sutured and disinfected. Throughout the surgery, the animal's body temperature was maintained at 37 ± 0.5°C using a temperature-controlled infrared lamp. In the sham-operated group, the scalp was incised and injected with Rose Bengal, but no cold light exposure was performed. After surgery, the animals were returned to their respective cages and carefully monitored until they regained consciousness.

[0193] Administration: Compound 4 (10 mg / kg) was administered by oral gavage once a day for 5-11 days after surgery.

[0194] Animal Behavior Assessment: On days 4 and 12 after surgery, the rodents' neuromuscular strength and coordination were assessed using a grid test, and their motor function and contralateral limb use were assessed using a cylinder test. The test results are shown in Figure 2. As shown in Figure 2, once-daily oral administration of Compound 4 (10 mg / kg) 5-11 days after surgery significantly improved the animals' neurological deficits compared to the model group, suggesting its effectiveness in stroke recovery.

[0195] Test Example 7 Study on the long-term effect of oral administration of compound 4 on the brain protection of mice with permanent damage in ischemic stroke model during the recovery period

[0196] The animal model and administration time were the same as those in Test Example 6, and the dosage was 10 mg / kg;

[0197] Animal behavioral assessment: On days 4, 12, 19, 26, and 33 after surgery, the rodents' neuromuscular strength and coordination were assessed using a grid test, and their motor function and contralateral limb use were assessed using a cylinder test. The test results are shown in Figure 3. As can be seen from Figure 3, compared with the model group, once-daily oral administration of Compound 4 (10 mg / kg) 5-11 days after surgery significantly improved the animals' neurological deficits, suggesting that it is effective for stroke recovery and has long-term effects.

[0198] Test Example 8 Inhibitory Effects of Compounds 4, 34, and 46 on Neuropathic Pain by Oral Administration

[0199] Method for establishing a neuropathic pain model: A neuropathic pain model was established using spinal nerve ligation (SNL). 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 method of Kim and Chung: a median skin incision approximately 3 cm to 5 cm long was made on the back of the mouse from the L4-S2 level with blunt dissection. The paravertebral muscles were separated to the sixth lumbar vertebral process, and the right L5 / L6 articular process was exposed and resected. The L6 transverse process was partially bitten to expose the right L4-L6 spinal nerves. The L5 nerve was gently isolated 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 kept in a stable environment. Postoperatively, the animals developed gait abnormalities. The hind limb on the operated side had mild valgus and clenched toes, but no other deformities were observed.

[0200] Analgesic Effect Assay: C57BL / 6 mice (male, clean grade, 7-8 weeks old, weighing 22±2 g) with a baseline 50% mechanical paw withdrawal threshold were divided into a compound 24 group and a vehicle group. The mice then underwent SNL surgery. On the 7th day after surgery, compounds 4, 34, and 46 (10 mg / kg) were administered orally for 3 consecutive days. The mechanical paw withdrawal threshold was measured 4 hours after administration on the 3rd day. The test results are shown in Figure 4. As can be seen from Figure 4, oral administration of compounds 4, 34, and 46 all had significant analgesic effects.

[0201] Test Example 9 Effect of Compound 4 on Behavior Improvement in Depression Model Mice by Oral Administration

[0202] Preparation of chronic mild stress model: Chronic mild stress (CMS) includes wet cage, restraint stress, forced swimming, day and night reversal, tilted cage, water and food deprivation, continuous light or continuous dark breeding, etc., for a total of 21 days.

[0203] 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, a ZL006-05 (30 mg / kg) group, and a ZL006-05 (60 mg / kg) group. After three weeks of stress as described above, each group was gavaged with the compound for 7 consecutive days. During the administration period, stress stimulation was also given. After the last administration, a tail suspension test (TST) was performed. The test results are shown in Figure 5. As can be seen from Figure 5, continuous gavage of compound 4 and ZL006-05 can significantly improve the immobility time of mice in the tail suspension test caused by CMS; compound 4 (10 mg / kg) and ZL006-05 (60 mg / kg) have comparable efficacy.

[0204] Test Example 10 Effect of Compound 4 on Improving Alzheimer's Disease (AD)

[0205] Experimental animals: Zebrafish were maintained in aquaculture water at 28°C;

[0206] Detection method: Wild-type AB strain zebrafish 4 days post-fertilization (dpf) were randomly selected and placed in a 6-well plate, with 30 zebrafish treated in each well (experimental group). The samples were administered in water. The positive control, donepezil hydrochloride, was administered at 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 set up, with a volume of 3 mL per well. Except for the normal control group, aluminum chloride hexahydrate was administered in water to establish the zebrafish AD model. After treatment at 28°C for 1 day, 10 zebrafish were randomly selected from each experimental group and transferred to a 96-well plate at 200 μL / fish, 1 fish / well. Data were collected using a behavioral analyzer, and the total movement distance of the zebrafish was analyzed. The statistical analysis results of this indicator were used to evaluate the sample's efficacy in improving AD, as shown in Figure 6. As can be seen from Figure 6, compound 4 has the effect of improving AD, specifically manifested in the recovery of motor dysfunction.

[0207] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A class of dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid, characterized in that: The general structural formula is shown below; Among them, R 1 -H, -Cl, a hydrocarbon group of 1 to 8 carbon atoms, -CF3, -CF2H, -CN, -SCH3, -OH, -CHO, -CH2OH, -CH2NH2, -COOH, a halogenated phenyl group or -NR 4 R 5 ; R 4 、R 5 Independently selected from -H or -CH3; R 2 is selected from -H, an alkyl group of 1 to 6 carbon atoms, an acyl group of 2 to 7 carbon atoms, or a carbamoyl group; R 3 Selected from X is selected from -CH= or -N=.

2. The dextranol or fenchol ester derivative of 2-hydroxynicotinic acid according to claim 1, characterized in that: Selected from the following compounds:

3. A pharmaceutically acceptable salt of the dextranol or fenchol ester derivative of 2-hydroxynicotinic acid according to claim 1 or 2.

4. A pharmaceutical composition, characterized in that: The active ingredient of the pharmaceutical composition is the dextran or fenchol ester derivative of 2-hydroxynicotinic acid according to claim 1 or 2, or the pharmaceutically acceptable salt of the dextran or fenchol ester derivative of 2-hydroxynicotinic acid according to claim 3.

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

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

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