2-hydroxynicotinic acid dexcamphanol or fenchol ester derivative and pharmaceutical application thereof

Abstract

The invention relates to dexcamphanol or fenchol ester derivatives of 2-hydroxynicotinic acid and pharmaceutical application of the dexcamphanol or fenchol ester derivatives, and belongs to the technical field of biological medicine. The structural general formula of the derivative disclosed by the invention is # imgabs0 #, wherein R1 is selected from-H,-Cl, alkyl with 1 to 8 carbon atoms,-CF3,-CF2H,-CN,-SCH3,-OH,-CHO,-CH2OH,-CH2NH2,-COOH, halogenated phenyl or-NR4R5; r4 and R5 are independently selected from-H or-CH3; r2 is selected from-H, alkyl with 1-6 carbon atoms, and acyl or carbamoyl with 2-7 carbon atoms; r3 is selected from # imgabs1; # X is selected from-CH = or-N =. The derivative disclosed by the invention has a good inflammation inhibition effect; and under the condition of high concentration, the compound has lower cytotoxicity and is safer. The compound can be used for preparing medicines for treating inflammation and inflammation-related diseases such as cerebral apoplexy, neuropathic pain, depression and senile dementia.

Description

Technical Field

[0001] The 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 basic pathological process that is mainly a defensive response when biological tissues are stimulated by certain stimuli such as trauma, infection and other damaging factors. The local manifestations of inflammation are redness, swelling, heat, pain and dysfunction, and are also accompanied by systemic reactions such as fever and changes in peripheral blood leukocyte counts. Inflammation is an important cause of many diseases, including cardiovascular disease, diabetes, cerebrovascular disease, Alzheimer's disease, and even cancer. More and more studies have found that neuroinflammation plays an important role in ischemic stroke. The mechanism of secondary injury after cerebral ischemia may be due to the generation of inflammation in the brain after ischemic stroke. The inflammatory response accelerates the formation of ischemic damage and affects neuronal death and neural tissue regeneration. The characteristics of neuroinflammatory response after cerebral ischemia are the activation of microglia, astrocytes and the increase of inflammatory bodies. Microglia are rapidly activated within a few minutes of the acute phase of ischemic stroke, reaching a peak 2-3 days after ischemia and lasting for several weeks. After a stroke, about 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 immunostimulatory ability. As a type of mouse-derived immune cell, RAW264.7 macrophages 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] Dextromethorphan is a bicyclic monoterpene compound, and its mechanism of action is to inhibit the expression of inflammatory factors during cerebral infarction, thereby reducing brain cell death. Dextromethorphan is poorly soluble in water. When it is made into an injection, a large amount of organic solvent needs to be added, which increases the difficulty of drug injection preparations. Dextromethorphan is volatile and has a bad odor, and its oral bioavailability is low, which increases the difficulty of oral administration preparations. ZL006-05 is a salicylate derivative of dextromethorphan, which has shown effects in animal models to reduce nerve damage after stroke, anti-depression, and treatment of neuropathic pain. It has now entered Phase 3 clinical trials. However, ZL006-05 has poor water solubility and low oral bioavailability, making it difficult to achieve oral administration.

[0005] Alzheimer's disease is another serious disease that threatens human health. Literature reports that fenchol significantly reduces excessive accumulation of Aβ and neuronal death by stimulating FFAR2 signaling (microbiome sensing mechanism), which can help protect the brain from pathological damage in Alzheimer's disease. Fenchol is poorly soluble in water and has low oral bioavailability, which also increases the difficulty of oral administration.

[0006] Since long-term medication is required for post-stroke neurological function restoration, Alzheimer's disease and other diseases, oral preparations are more suitable for clinical needs. Patent CN 116283588A discloses a class of 4-alkoxy-substituted 2,6-dihydroxybenzyl dextran or fenchol ester compounds and their pharmaceutical uses. However, the half-decay period of this class of compounds is relatively short (less than 1h), and the oral bioavailability is still not significantly improved (about 5%). Summary of the invention

[0007] In order 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 2-hydroxynicotinic acid dextranol or fenchol ester derivatives, the general structural formula of which is shown below:

[0009]

[0010] Among them, R 1 Selected from -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;

[0011] R 2 Selected from -H, alkyl groups of 1 to 6 carbon atoms, acyl groups of 2 to 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, the compound is selected from the following:

[0015]

[0016]

[0017] The second object of the present invention is to provide a class of pharmaceutically acceptable salts of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid. The phenolic hydroxyl groups in the structure of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid of the present invention are acidic and can form sodium salts, potassium salts, or complex salts with alkaline organic substances such as basic amino acids, meglumine, etc. The phenolic hydroxyl groups in the structure can be etherified, esterified, or amino-formylated to become prodrugs. In vivo, these prodrugs can metabolize phenolic hydroxyl groups in vivo and exert drug activity.

[0018] The third object of the present invention is to provide a class of pharmaceutical compositions, the active ingredients of which are the dextran or fenchol ester derivatives of 2-hydroxynicotinic acid, and the pharmaceutically acceptable salts of the dextran or fenchol ester derivatives of 2-hydroxynicotinic acid.

[0019] The fourth object of the present invention is to provide a class of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid, the 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.

[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 over the prior art:

[0022] (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. The nitrogen atom is introduced into the benzene ring, and the benzene ring is changed to a pyridine ring or a quinoline ring, which not only changes the skeleton structure but also obtains a novel structure. More importantly, due to the small number of free phenolic hydroxyl groups in the molecule, the half-decay period of this type of compound is relatively long (about 2 hours), and the oral bioavailability is improved to a certain extent (about 10%).

[0023] (2) The dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid of the present invention have good anti-inflammatory effects; at high concentrations, they have 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.

[0024] (3) The dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid described in the present invention have relatively good oral efficacy and are effective for depression and neuralgia, showing good medicinal prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] 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:

[0026] Figure 1 The effect of acute injection of compound 4 in test example 5 of the present invention on cerebral infarction area and nerve damage after stroke; wherein, the left figure is the effect on cerebral infarction area, and the right figure is the effect on nerve damage;

[0027] Figure 2 This is the dose-effect relationship of compound 4 in Test Example 6 of the present invention on post-stroke neurological recovery by oral administration during the recovery period;

[0028] Figure 3 This is the long-term effect of oral administration of compound 4 in the recovery period of test example 7 of the present invention on post-stroke neurological recovery;

[0029] Figure 4 The inhibitory effects of compounds 4, 34, and 46 on neuropathic pain by intragastric administration in Test Example 8 of the present invention;

[0030] Figure 5 The effect of oral administration of compound 4 in Test Example 9 of the present invention on the behavior of depression model mice;

[0031] Figure 6 The compound 4 in Test Example 10 of the present invention improves the motor function of Alzheimer's disease. DETAILED DESCRIPTION

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

[0033] In the present invention, unless otherwise specified, the statistical processing results in the specification are expressed as mean ± standard error, and statistical analysis was performed using SPSS26.0 software, *p<0.05, **p<0.01, ***p<0.001.

[0034] Example 1 Synthesis of Compound 1 (2-Hydroxy-6-methylnicotinate)

[0035]

[0036] 0.78g (5mmol) of 2-hydroxy-6-methylnicotinic acid and 0.62g (4mmol) of right-borneol were dissolved in 100mL of dichloromethane, and 1.54g (7.5mmol) of dicyclohexylcarbodiimide (DCC) and 0.12g (1mmol) of 4-dimethylaminopyridine (DMAP) were added, and the mixture was reacted at 55°C for 6h. After the reaction was completed, the filtrate was filtered and dried, and 100mL of ethyl acetate (EA) was added to dissolve the mixture, and the mixture was washed three times with 100mL of saturated brine, and the organic layer was collected and dried, and then sand was made, and the mixture was passed through a column with petroleum ether (PE, 60°C-90°C): ethyl acetate (EA) = 30:1, and the product was dried and pulped 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 borneol ester) Reference Compound 1, using 2-hydroxynicotinic acid and borneol 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 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

[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 Synthesis of Compound 4 (2-hydroxy-6-trifluoromethylnicotinic acid borneol ester) Reference Compound 1, using 2-hydroxy-6-trifluoromethylnicotinic acid and borneol as raw 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 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

[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 Synthesis of Compound 6 (2-hydroxy-6-isopropylnicotinate) Reference Compound 1, using 2-hydroxy-6-isopropylnicotinate and borneol as raw 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 Synthesis of Compound 7 (2-hydroxy-6-isobutylnicotinic acid borneol ester) Reference compound 1, using 2-hydroxy-6-isobutylpropylnicotinic acid and borneol as raw 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 Synthesis of Compound 8 (2-hydroxy-6-isopentylnicotinate) Reference Compound 1, using 2-hydroxy-6-isopentylnicotinic acid and borneol as raw 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 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

[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)ethyl nicotinate) Reference Compound 1, using 2-hydroxy-6-(2-phenyl)ethyl nicotinate and borneol as raw 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-methylnicotinate)

[0065]

[0066] 0.29g (1mmol) of 2-hydroxy-6-methylnicotinate was dissolved in 10mL of dichloromethane, and 0.32g (1.1mmol) of dicyclic amidine (DBU) and 0.15g (1.1mmol) of dimethyl sulfate were added in turn to react at room temperature for 3h. After the reaction was completed, the filtrate was filtered and dried, and 100mL of ethyl acetate (EA) was added to dissolve it, and it was washed three times with 100mL of saturated brine, and the organic layer was collected and dried, and sand was made, and petroleum ether (PE, 60℃-90℃): ethyl acetate (EA) = 30:1 was passed through a column to obtain a white solid. 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 Synthesis of Compound 12 (2-methoxy-6-trifluoromethyl nicotinate) Reference Compound 11, using 2-hydroxy-6-trifluoromethyl nicotinate and dimethyl sulfate as raw materials

[0068]

[0069] 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). 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-methylnicotinate) Reference Compound 11, using 2-hydroxy-6-methylnicotinate and diethyl sulfate as raw 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 Synthesis of Compound 14 (2-ethoxy-6-trifluoromethyl nicotinate) Reference Compound 11, using 2-hydroxy-6-trifluoromethyl nicotinate and diethyl sulfate as raw materials

[0074]

[0075] 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.

[0076] Example 15 Synthesis of Compound 15 (2-isopropoxy-6-methylnicotinate)

[0077]

[0078] 290 mg of 2-hydroxy-6-methyl-nicotinic acid bornyl ester was placed in an eggplant-shaped bottle, THF was added to dissolve it, and then 228 mg of potassium carbonate and 132 mg of ethyl bromide were added to react at room temperature for 5 hours. After the reaction was completed, the filtrate was filtered and dried, and 100 mL of ethyl acetate (EA) was added to dissolve it, and it was washed three times with 100 mL of saturated brine. The organic layer was collected and dried, and sand was made. It was passed through a column under the condition of petroleum ether (PE, 60℃-90℃): ethyl acetate (EA) = 30:1 to obtain a colorless oil. 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-methylnicotinate) Reference Compound 15, using 2-hydroxy-6-methylnicotinate and isobutyl bromide as raw materials

[0080]

[0081] 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). 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-methylnicotinate) Reference Compound 15, using 2-hydroxy-6-methylnicotinate and cyclohexyl bromide as raw materials

[0083]

[0084] Pale yellow oil. 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-methylnicotinate)

[0086]

[0087] 0.29g (1mmol) of 2-hydroxy-6-methylnicotinate was dissolved in 10mL of dichloromethane, and 0.15g (1.5mmol) of acetic anhydride and 0.10g (1mmol) of triethylamine were added in sequence, and the mixture was reacted at room temperature for 3h. After the reaction was completed, the filtrate was filtered and dried, and then sand was made and passed through a column with 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 Synthesis of Compound 19 (2-acetoxy-6-trifluoromethyl nicotinate) Reference Compound 18, using 2-hydroxy-6-trifluoromethyl nicotinate and acetic anhydride as raw materials

[0089]

[0090] 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). 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 Synthesis of Compound 20 (2-propionyloxy-6-trifluoromethyl nicotinate) Reference Compound 18, using 2-hydroxy-6-trifluoromethyl nicotinate and propionic anhydride as raw materials

[0092]

[0093] Colorless oil. 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-methylnicotinate) Reference Compound 15, using 2-hydroxy-6-methylnicotinate and isobutyric anhydride as raw 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 Synthesis of Compound 22 (2-cyclohexanoyloxy-6-methylnicotinate) Reference Compound 18, using 2-hydroxy-6-methylnicotinate and cyclohexylcarbonyl chloride as raw materials

[0098]

[0099] Colorless oil. 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-methylnicotinate)

[0101]

[0102] To 500 mg of 2-hydroxy-6-methyl nicotinate bornyl ester, add 30 mL of dichloromethane and 300 mg of triphosgene, inject 0.5 mL of triethylamine, react for 5 h, directly add dimethylamine without post-treatment, react for 2 h, spin-dry the solvent dichloromethane, add water and ethyl acetate for extraction, take the organic phase, add anhydrous Na2SO4 and dry it, spin-dry the organic phase, column chromatography (PE:EA=100:1) to 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-trifluoromethylnicotinate) hydrochloride

[0104]

[0105] 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, and the solution was monitored by spot plate. The solution was filtered and the solvent was directly dried by spin drying. The solution was purified by column chromatography (DCM: MeOH = 100: 1) to obtain 24300 mg of a colorless oily compound.

[0106] Compound 24 was dissolved in 10 mL of ethyl acetate and salified with 2 mol / L hydrochloric acid and ethyl acetate to obtain compound 24 hydrochloride. 1HNMR (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-trifluoromethylnicotinate)

[0108]

[0109] Compound 4 (500 mg, 1.46 mmol) was placed in a two-necked flask, 10 mL of DCM was added, Cs2CO3 (1.42 g, 4.37 mmol) was added, N2 was protected, placed in an ice bath, cooled to 0°C, and a 10 mL DCM solution of triphosgene (172.59 mg, 0.58 mmol) was slowly added dropwise. After stirring for 10 min, the mixture was moved to room temperature and stirred at room temperature for 4 h. After TLC monitoring, the reaction was not completed (a DCM solution of intermediate 25-1 was obtained), and tert-butyl (S )-2-((Methylamino)methyl)pyrrolidinyl-1-carbonate (936.53 mg, 4.37 mmol), stirred at room temperature for 8 h; washed the reaction solution with 50 mL of water and 50 mL of saturated brine, collected the organic layer, dried by spin-drying, column chromatography (DCM:MeOH=100:1), dried the eluent by spin-drying to obtain the intermediate 25-2 as a transparent oil; dissolved it with 10 mL of ethyl acetate, added 1.0 mL of 2 mol / L hydrochloric acid ethyl acetate, stirred at room temperature for 4 h to obtain 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.

[0110] 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

[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 fenchol ester) Reference Compound 1, using 2-hydroxy-6-chloronicotinic acid and fenchol 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 fenchyl alcohol ester) Reference Compound 1, using 2-hydroxy-6-trifluoromethylnicotinic acid and fenchyl alcohol as raw 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 fenchyl alcohol ester) Reference Compound 1, using 2-hydroxynicotinic acid and fenchyl alcohol 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-methylnicotinate) Reference Compound 15, using 2-hydroxy-6-trifluoromethylnicotinate and ethyl bromide as raw materials

[0123]

[0124] 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.

[0125] Example 31 Synthesis of Compound 31 (2-propionyloxy-6-methylnicotinate) Reference Compound 18, using 2-hydroxy-6-methylnicotinate and propionic anhydride as raw 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 (Synthesis of 2-(4-methylpiperazinyl)formyloxy-6-methylnicotinate) Reference compound 25, using 2-hydroxy-6-trifluoromethylnicotinate and 1-methylpiperazine as raw 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-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.

[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-trifluoromethylnicotinate)

[0135]

[0136] Compound 4) 0.343g (0.01mol) was dissolved in 15mL DCM, (R)-(3-((tert-butyldimethylsilyl)oxy)butanoic acid) 0.240g (0.011mol) and 4-dimethylaminopyridine (DMAP) 0.134g (0.011mol), and stirred at room temperature for 30min. Then, N,N'-dicyclohexylcarbodiimide (DCC) 0.2270g (0.011mol) was added, and the mixture was reacted at room temperature for 6h. 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, and 10mL of methanol solution was added to dissolve the mixture. The mixture was stirred at 0℃ for 10min. Then, 0.046g (0.003mol) of trimethylsilyl bromide was slowly added dropwise. After the addition was complete, the mixture was restored to room temperature for reaction for 3h. The reaction was monitored by TLC. After the reaction was complete, the mixture was purified by silica gel column with PE:EA20:1 eluent 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 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

[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 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

[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 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

[0144]

[0145] In a 250 mL eggplant-shaped flask, ethyl formate (14.8 g, 200 mmol) and tetrahydrofuran (100 mL) were added as raw materials. 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 ether (50 mL) to obtain 15.0 g of yellow solid intermediate 37-1 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 37-1 (15.0 g, 88 mmol) was added. The resulting mixture was heated to reflux for 5 h and then cooled to room temperature. Hydrochloric acid was added to the mixture under stirring until the mixture was acidic and solids 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 with a yield of 41.52%.

[0147] Take a 250mL eggplant-shaped bottle, add a mixture of intermediate 37-2 (8.3g, 42mmol) and KOH aqueous solution (80% w / 150mL) and heat the reaction in an oil bath at 150°C for 24h. Stop the reaction, cool the reaction solution to room temperature, pour it into 300mL of water, and adjust the pH to 4 under ice bath conditions. Filter and collect the solid product, wash and dry. The crude product is recrystallized using acetic acid as a solvent to obtain 7.5g of intermediate 37-3 off-white solid with a yield of 81%.

[0148] In a 250 mL eggplant-shaped flask, raw material borneol (5.0 g, 32.4 mmol) and dichloromethane 165 mL 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, and 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 with a yield of 48.8%.

[0149] In 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 it was 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 in vacuo to obtain a crude product. The crude product was recrystallized with 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.

[0150] Example 38 Synthesis of Compound 38 (2-Hydroxy-6-Methanol Nicotinate)

[0151]

[0152] Compound 37 (2.0 g, 6.6 mmol) was added to a 100 mL eggplant-shaped flask, and 35 mL of ethanol was added thereto for dissolution; 300 mg of sodium borohydride was added in small portions, and the mixture was reacted at room temperature for 2 h. The reaction was detected by TLC until it was complete. The reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate and water, and 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 obtain 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-Methanol Nicotinate)

[0154]

[0155] Compound 37 (1.0 g, 3.3 mmol) was added to a 100 mL eggplant-shaped bottle, and 25 mL of ethanol was added thereto to dissolve. 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 detected by TLC until the reaction was complete to obtain intermediate 39-1. No purification was required, and methanol was directly added as a solvent 25 mL to dissolve, and Pd / C was added 300 mg. The reaction was carried out under a hydrogen atmosphere for 6 h. The reaction was detected by TLC until the reaction was complete, and the organic phase methanol was concentrated in vacuo. The crude product was recrystallized with ethyl acetate solvent to obtain 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-Methanol Nicotinate)

[0157]

[0158] 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 thereto to dissolve; dimethyldibutylene (7 equivalents), sodium dihydrogen phosphate (4 equivalents), sodium chlorite 1.3 eq / water solution 27 equivalents, reacted at room temperature for 3 h, and the reaction was detected by TLC until the reaction was complete. Na2SO3 (1.3 equivalents) was added, the temperature was controlled at 0 degrees, and stirred at room temperature for 15 min; the pH was adjusted to 5 with saturated ammonium chloride aqueous solution, and EA was extracted 3 times with 100 mL*3 times. The organic phases were combined, and the crude product was chromatographed on a silica gel column (dichloromethane / methanol=30:1) to obtain 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 (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

[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 (2-methyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester)

[0163]

[0164] Weigh acetamidine hydrochloride (2.50 g, 26.44 mmol) and add it to the reaction bottle, add an appropriate amount of anhydrous ethanol solution, move to an ice bath and cool to 0°C, add 2 eq anhydrous sodium ethanol (3.60 g, 52.88 mmol) solution, then slowly drop 1 eq 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 drop 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 with ethyl acetate 3 times, wash the lipid layer with saturated brine, dry over anhydrous sodium sulfate, and pass sand through a column to obtain intermediate 42-2 as a white solid.

[0165] The 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 mixture 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 was precipitated (about pH = 6). The filter cake was filtered and washed with a small amount of water, and the filter cake was dried to obtain the intermediate 42-3 as a white solid.

[0166] Weigh the intermediate 42-3 (400 mg, 2.60 mmol) and add it to a reaction bottle, add an appropriate amount of acetonitrile, then add 1 eq of right-borneol (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; spin dry the reaction solution, add an appropriate amount of DCM, water, and saturated brine to wash the reaction solution, dry it over anhydrous sodium sulfate, and pass it 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.

[0167] Example 43 Synthesis of Compound 43 (2-tert-butyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using tert-butylformamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 (2-amino-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using guanidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 45 (2-cyclopropyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using cyclopropylcarboxamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 46 (2-isopropyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using isopropylformamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 (2-ethyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference Compound 42, using propionamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 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

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

[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 Synthesis of Compound 51 (2-o-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-chlorobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 (2-p-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using p-chlorobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 53 (2-m-chlorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using m-chlorobenzamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 54 (2-o-fluorophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-fluorobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 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

[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 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

[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 Synthesis of Compound 57 (2-o-bromophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using o-bromobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 58 (2-p-bromophenyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using p-bromobenzamide hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 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

[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 Synthesis of Compound 60 (2-thiophene-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using thiophene carboxamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 61 (2-pyridyl-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using pyridine 3-carboxamidine hydrochloride, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 62 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylic acid borneol ester) Reference compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylenemalonate and borneol as raw 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 Synthesis of Compound 63 (2-isopropyl-4-hydroxy-5-pyrimidinecarboxylic acid isocyanate) Reference compound 42, using isopropylformamidine hydrochloride, diethyl ethoxymethylenemalonate and isocyanate as raw 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 Synthesis of Compound 64 (N,N-dimethylamino-4-hydroxy-5-pyrimidinecarboxylic acid d-ol ester) Reference Compound 42, using 1,1-dimethylguanidine hemisulfate, diethyl ethoxymethylenemalonate and d-ol as raw 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 Determination of the effect of compounds on the proliferation of RAW264.7 macrophages in vitro

[0236] The cells were digested and counted, and a RAW264.7 cell suspension of 7×10 4 / mL, add 100μL cell suspension to each well of a 96-well cell culture plate; place in a 37°C, 5% CO2 incubator for 24h; dilute the drug with culture medium to the required working solution concentration, add 100μL of the corresponding drug-containing culture medium to each well, and set up a negative control group at the same time; culture in a 37°C, 5% CO2 incubator for 24h; add 20μL CCK-8 to each well, and continue to culture in the incubator for 2h-3h; gently mix on a shaker for 10min to remove bubbles in the 96-well plate; λ=450nm, read the OD value of each well with an enzyme 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 a higher concentration (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.

[0241] Test Example 2 Effects of Compounds on Inflammatory Factors in RAW264.7 Macrophages Induced by LPS

[0242] The cells were digested and counted, and a RAW264.7 cell suspension of 7×10 4 / mL, 100μL of cell suspension was added to each well of a 96-well cell culture plate; the plate was placed in a 37°C, 5% CO2 incubator for 24h; the drug was diluted with culture medium to the required concentration, 100μL of the corresponding drug-containing culture medium was added to each well, and a negative control group was set up at the same time; the plate was cultured in a 37°C, 5% CO2 incubator for 2h; 100μg / L of LPS was added and incubated for 24h, the supernatant was collected, and the content of IL-1β and TNF-α was detected according to the instructions of the ELISA kit, as shown in Table 2:

[0243] Table 2 Effects of compounds on inflammatory factors in RAW264.7 macrophages induced by lipopolysaccharide (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: The measured values ​​of inflammatory factors are 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 plantar swelling in rats by intravenous injection of compound

[0248] SD rats (male, SPF grade, 6-8 weeks old, weighing 250-280g) were randomly divided into groups, 6 rats in each group. The normal group and the model group were intravenously injected with the same amount of solvent, and each drug group was intravenously injected with 20μmol / kg of each compound. 0.5h after administration, the normal group was subcutaneously injected with 100μL of normal saline at the toes of the hind limbs, and the other groups were injected with 100μL of 1% carrageenan. The toe volume of the rats was measured at 0h and 4h after the injection of carrageenan, and the foot swelling rate (%) of the rats was calculated. The results are shown in Table 3:

[0249] Table 3 Inhibitory effect of compounds on carrageenan-induced paw swelling in rats

[0250]

[0251]

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

[0253] As can be seen from Table 3, ZL006-05, celecoxib and the compound have a significant inhibitory effect on rat paw swelling caused by carrageenan. However, the compound of the present invention is significantly stronger than ZL006-05 in the inhibition rate of rat paw swelling. This is because the electron cloud density on the pyridine ring of the compound of the present invention is relatively low relative to the benzene ring, resulting in a stronger acidity of the hydroxyl group, which is easier to combine with the relevant drug target and obtain a stronger drug effect.

[0254] Test Example 5 Preliminary drug metabolism study of compound 4

[0255] Animals: SD rats / male, 3 rats in each 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) intragastric gavage route: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h;

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

[0260] Table 4 PK test results of 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 can be seen from Table 4, preliminary drug metabolism studies of compound 4 showed that the oral bioavailability of compound 4 was 14.9%.

[0263] Test Example 5 Acute administration of compound 4 to the brain protective effect of ischemic stroke model rats

[0264] Preparation of focal cerebral ischemia-reperfusion (MCAO) model: SD rats were anesthetized by intraperitoneal injection of 7% chloral hydrate (6 mL / kg), and the rats in anesthesia were fixed on the operating table in a supine position. The neck was incised in the middle, the subcutaneous tissue was bluntly separated, 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, an incision was made from the distal end of the ligature of the external carotid artery, and the embolism line was inserted, passing 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 embolism line was gently pulled out, blood supply was restored for reperfusion, the skin was sutured, and disinfection was performed.

[0265] 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-mentioned dosage setting principle, the drug was administered intravenously 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 the infarct range. The results are shown in the figure. Figure 1 As shown. Figure 1 It can be seen that compared with the model group, intravenous administration of compound 4 can significantly improve the neurological deficit symptoms of animals and significantly reduce the scope of cerebral infarction in model animals. The efficacy of compound 4 + edaravone group is better.

[0266] Test Example 6: Dose-effect relationship study of the brain protective effect of compound 4 orally administered during the recovery period on mice with permanent ischemic stroke model

[0267] Preparation of light-induced cerebral ischemia model: Rose Bengal was induced by light to produce oxygen free radicals, which damaged vascular endothelial cells, thereby forming a focal cerebral ischemia model to simulate cerebral ischemia. Adult mice were anesthetized with 2% isoflurane gas and fixed on a stereotaxic instrument. The skull was exposed through a midline incision of the scalp, and the connective tissue was removed and blown dry. A cold light source with a luminous circular spot of 2 mm in diameter was vertically attached to the top of the skull, and the center of the circle was offset 1.5 mm to the right of the bregma. After intraperitoneal injection of rose Bengal (100 mg / kg) for 5 minutes, the intensity of the cold light source was adjusted to 12000 Lux for 15 minutes. After the irradiation, the cold light source was removed, sutured and disinfected. During the entire operation, the body temperature of the animals was adjusted by a temperature-controlled infrared lamp and maintained at 37±0.5℃. The sham operation group was anesthetized, the scalp was cut and rose Bengal was injected, but no cold light source was irradiated. After the operation, the animals were returned to their respective cages and carefully monitored until they woke up.

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

[0269] Animal behavior measurement: On the 4th and 12th day after the surgery, the rodents' neuromuscular strength and coordination were assessed using the grid test, and their motor function and contralateral limb use were assessed using the cylinder test. The test results were as follows: Figure 2 As shown. Figure 2 It can be seen that compared with the model group, oral administration of compound 4 (10 mg / kg) once a day 5-11 days after the operation can significantly improve the neurological deficit symptoms of animals, indicating that it is effective for the recovery of stroke.

[0270] Test Example 7 Study on the long-term effect of oral administration of compound 4 during the recovery period on the brain protection of mice with permanent damage to ischemic stroke model

[0271] The animal model and administration time were the same as those in Test Example 6, and the dosage was 10 mg / kg;

[0272] Animal behavior measurement: 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 were as follows: Figure 3 As shown. Figure 3 It can be seen that compared with the model group, oral administration of compound 4 (10 mg / kg) once a day 5-11 days after the operation can significantly improve the neurological deficit symptoms of animals, indicating that it is effective for the recovery of stroke and has a long-term effect.

[0273] Test Example 8 Inhibitory effect of compound 4, 34, 46 on neuropathic pain by intragastric administration

[0274] Preparation method of neuropathic pain model: The neuropathic pain model was prepared by spinal nerve ligation (SNL). Mice were anesthetized by intraperitoneal injection of 2% chloral hydrate (0.2mL / l0g). After the righting reflex disappeared, the mice were fixed in a prone position. The model was prepared by the method of Kim and Chung: a median skin incision of about 3cm-5cm was bluntly separated from the L4-S2 level on the back of the mouse, the paravertebral muscles were separated to the sixth lumbar process, the right L5 / L6 articular process was exposed and removed, and the L6 transverse process was partially bitten open, so that the right L4-L6 spinal nerves could be exposed, the L5 nerve was gently separated, and L5 was tightly ligated with 5-0 silk thread. Then the incision was sutured layer by layer, the skin was disinfected with iodine, and the animals continued to be raised. The animals had abnormal gait after surgery, and there were no other deformities except mild valgus and tight toes of the hind limbs on the operated side.

[0275] Analgesic effect determination: C57BL / 6 mice (male, clean grade, 7-8 weeks old, weighing 22±2g) with 50% mechanical stimulation withdrawal threshold baseline were divided into compound 24 group and solvent group, and then SNL surgery was performed. On the 7th day after surgery, compounds 4, 34, and 46 (10 mg / kg) were gavaged for 3 consecutive days. The mechanical stimulation withdrawal threshold was measured 4h after the 3rd day. The test results are shown in Figure 4 As shown. Figure 4 It can be seen that intragastric administration of compounds 4, 34, and 46 all had significant analgesic effects.

[0276] Test Example 9 Effect of Compound 4 on the Behavior Improvement of Depression Model Mice by Oral Administration

[0277] 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 feeding, etc., for a total of 21 days.

[0278] C57BL / 6 mice were divided into physiological control group, model group, compound 4 (2.5 mg / kg) group, compound 4 (5 mg / kg) group, compound 4 (10 mg / kg) group, ZL006-05 (30 mg / kg) group, and ZL006-05 (60 mg / kg) group. After three weeks of stress according to the above method, the compounds were gavaged to each group for 7 days. Stress stimulation was also given during the administration period. After the last administration, the tail suspension test (TST) was performed. The test results are shown in Figure 5 As shown. Figure 5 It can be seen that continuous oral administration 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.

[0279] Test Example 10 Effect of Compound 4 on Improving Alzheimer's Disease (AD)

[0280] Experimental animals: Zebrafish were maintained in fish culture water at 28°C;

[0281] Detection method: Wild-type AB strain zebrafish at 4 days post-fertilization (4dpf) were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were given water-soluble, the concentration of the positive control donepezil hydrochloride was 3.33μg / mL, and the concentrations of compound 4 in the experimental group were 0.100μg / mL, 0.330μg / mL, and 1.00μg / mL, respectively. A normal control group and a model control group were set up at the same time, and the capacity of each well was 3mL; except for the normal control group, the rest of the experimental groups were given aluminum chloride hexahydrate in water to establish the zebrafish AD model; after 1 day of treatment at 28℃, 10 zebrafish were randomly selected from each experimental group and transferred to a 96-well plate, 200μL / tail, 1 tail / well, and data were collected using a behavior analyzer to analyze the total movement distance of the zebrafish. The statistical analysis results of this indicator were used to evaluate the efficacy of the sample in improving AD. The results are as follows Figure 6 As shown. 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 examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A class of 2-hydroxynicotinic acid dextranol or fenchol ester derivatives, characterized in that: The general structural formula is shown below; Among them, R 1 Selected from -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 Selected from -H, alkyl groups of 1 to 6 carbon atoms, acyl groups of 2 to 7 carbon atoms or carbamoyl groups; 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 derivatives of 2-hydroxynicotinic acid according to any one of claims 1 or 2, the pharmaceutically acceptable salts of the dextranol or fenchol ester derivatives of 2-hydroxynicotinic acid according to claim 3, and the pharmaceutical composition according to claim 4 in the preparation of drugs 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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