Substituted pyridine compound as well as preparation method and application thereof

Abstract

The invention provides a substituted pyridine compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The substituted pyridine compound provided by the invention has a structure as shown in a formula I or a formula II, and the substituted pyridine compound can efficiently activate the activity of ALDH2 and can be used as an ALDH2 activator. The results of test cases show that the substituted pyridine compound provided by the invention has good ALDH2 agonist activity under the condition of 25 [mu] M, which indicates that the substituted pyridine compound has a potential good treatment effect on nervous system degenerative diseases such as Alzheimer's disease. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a substituted pyridine compound, a preparation method and an application thereof. Background Art

[0002] Aldehyde dehydrogenase 2 (ALDH2) is a tetrameric protein with three domains: a coenzyme-binding domain, a catalytic domain, and an oligomerization domain. ALDH2 activators are of great significance in medicine and health, especially in addressing diseases associated with ALDH2 functional defects or insufficient activity. Specifically, ALDH2 is a key acetaldehyde-metabolizing enzyme responsible for metabolizing acetaldehyde to acetic acid. For people with ALDH2 gene mutations (such as ALDH2*2), ALDH2 activators can enhance residual enzyme activity, accelerate acetaldehyde metabolism, alleviate discomfort such as flushing and headaches after drinking, and reduce the risk of cancers (such as esophageal cancer and liver cancer) caused by long-term acetaldehyde accumulation. By reducing the discomfort caused by acetaldehyde toxicity, it may indirectly reduce the desire to drink excessively and assist in the treatment of alcohol dependence. At the metabolic level, ALDH2 is the key enzyme that converts nitroglycerin into nitric oxide. ALDH2 activators can improve nitroglycerin resistance in patients with mutated genes and enhance the effectiveness of emergency treatment for angina pectoris. Furthermore, ALDH2 activators can reduce oxidative stress and cell apoptosis by clearing toxic aldehydes (such as 4-HNE) in myocardial ischemia-reperfusion injury, thereby lowering the risk of worsening cardiac function after myocardial infarction. They can also inhibit damage to the vascular endothelium caused by lipid peroxidation products and slow the progression of arteriosclerosis. The accumulation of toxic aldehyde compounds is associated with β-amyloid deposition and neuronal damage in the brains of patients with Alzheimer's disease (AD). ALDH2 activators may slow the progression of neurodegeneration by clearing these toxic aldehyde compounds.

[0003] Therefore, the significance of ALDH2 activators lies not only in compensating for the insufficient enzyme activity caused by genetic defects or disease states, but also in providing innovative treatment strategies for various chronic diseases through multi-target interventions (such as alcohol metabolism, cardiovascular protection, neuroprotection, and anti-cancer). The development of a wider range of ALDH2 activators will promote the development of precision medicine and has the potential to provide targeted health solutions for the hundreds of millions of people worldwide with ALDH2 deficiency. Summary of the Invention

[0004] The object of the present invention is to provide a substituted pyridine compound and a preparation method and application thereof. The substituted pyridine compound provided by the present invention can efficiently activate ALDH2 activity.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a substituted pyridine compound having a structure shown in Formula I or Formula II:

[0007]

[0008] In Formula I and Formula II, X and Y are independently selected from -O-, -S- or -NH-, and R is a C1-C4 alkyl group.

[0009] Preferably, in Formula I and Formula II, R is selected from -CH3, -CH2CH3, -CH2CH2CH3 or -CH2CH2CH2CH3.

[0010] Preferably, the substituted pyridine compound is any one of the following compounds:

[0011]

[0012]

[0013]

[0014]

[0015] The present invention provides a method for preparing the substituted pyridine compound described in the above technical solution, comprising the following steps:

[0016] (a) When X in Formula I or Formula II is -S-, the preparation method of the substituted pyridine compound comprises the following steps:

[0017] Compound V, sodium bisulfate and an alcohol solvent are mixed to carry out a first nucleophilic substitution reaction to obtain compound VI;

[0018] Mixing the compound VI, compound VII, potassium hydroxide and a non-protonic polar organic solvent to carry out a second nucleophilic substitution reaction to obtain the substituted pyridine compound;

[0019] The compound VII is compound VIIa or compound VIIb;

[0020] The compound V has a structure shown in Formula V, the compound VI has a structure shown in Formula VI, the compound VIIa has a structure shown in Formula VIIa, and the compound VIIb has a structure shown in Formula VIIb:

[0021]

[0022]

[0023] In the formula VIIa, Y and R are as defined in formula I, and in the formula VIIb, Y and R are as defined in formula II;

[0024] (b) When X in Formula I or Formula II is -O- or -NH-, the preparation method of the substituted pyridine compound comprises the following steps:

[0025] Mixing compound V, compound VIII, potassium carbonate and a non-protonic polar organic solvent to perform a third nucleophilic substitution reaction to obtain the substituted pyridine compound;

[0026] The compound VIII is compound VIIIa or compound VIIIb, the compound VIIIa has the structure shown in formula VIIIa, and the compound VIIIb has the structure shown in formula VIIIb:

[0027]

[0028] In the formula VIIIa, X, Y, and R are as defined in formula I, and in the formula VIIIb, X, Y, and R are as defined in formula II.

[0029] The present invention provides the use of the substituted pyridine compound described in the above technical solution in the preparation of an ALDH2 activator.

[0030] The present invention provides an ALDH2 activator, the active ingredient of which includes the substituted pyridine compound described in the above technical solution.

[0031] The present invention provides the use of the substituted pyridine compounds described in the above technical solution in the preparation of drugs for treating degenerative diseases of the nervous system.

[0032] Preferably, the neurodegenerative disease is Alzheimer's disease.

[0033] The present invention provides a medicine for treating degenerative diseases of the nervous system, wherein the active ingredient comprises the substituted pyridine compound described in the above technical solution.

[0034] Preferably, the dosage form of the drug for treating neurodegenerative diseases includes tablets, injections or oral solutions.

[0035] Beneficial Effects: The present invention provides a substituted pyridine compound that can efficiently activate ALDH2 activity and can be used as an ALDH2 activator. Test results show that the substituted pyridine compound of the present invention has good ALDH2 agonist activity at a concentration of 25 μM, indicating that the substituted pyridine compound has potential therapeutic effects for neurodegenerative diseases such as Alzheimer's disease.

[0036] The present invention also provides a method for preparing the substituted pyridine compound. The method for preparing the substituted pyridine compound is simple to operate and has a high yield. DETAILED DESCRIPTION

[0037] The present invention provides a substituted pyridine compound having a structure shown in Formula I or Formula II:

[0038]

[0039] In Formula I and Formula II, X and Y are independently selected from -O-, -S- or -NH-, and R is a C1-C4 alkyl group.

[0040] As an embodiment of the present invention, in Formula I and Formula II, R is selected from -CH3, -CH2CH3, -CH2CH2CH3 or -CH2CH2CH2CH3.

[0041] As an embodiment of the present invention, X and Y in Formula I may be the same or different; and X and Y in Formula II may be the same or different.

[0042] As an embodiment of the present invention, the substituted pyridine compound can be any one of the following compounds:

[0043]

[0044]

[0045]

[0046]

[0047] The present invention provides a method for preparing the substituted pyridine compounds described in the above technical solution, which is specifically prepared by different methods according to the structure of the substituted pyridine compounds, which is described in detail below.

[0048] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared using methods well known to those skilled in the art.

[0049] In the present invention, when X in Formula I or Formula II is -S-, the preparation method of the substituted pyridine compound comprises the following steps:

[0050] Mixing compound V, sodium bisulfate and an alcohol solvent to carry out a first nucleophilic substitution reaction to obtain compound VI;

[0051] Mixing the compound VI, compound VII, potassium hydroxide and a non-protonic polar organic solvent to perform a second nucleophilic substitution reaction to obtain the substituted pyridine compound;

[0052] The compound VII is compound VIIa or compound VIIb;

[0053] The compound V has a structure shown in Formula V, the compound VI has a structure shown in Formula VI, the compound VIIa has a structure shown in Formula VIIa, and the compound VIIb has a structure shown in Formula VIIb:

[0054]

[0055] In the formula VIIa, Y and R are as defined in formula I, and in the formula VIIb, Y and R are as defined in formula II.

[0056] The present invention first prepares compound V. As one embodiment of the present invention, the preparation method of compound V comprises the following steps:

[0057] Compound III, compound IV, potassium carbonate, 1,1'-bis(diphenylphosphino)ferrocene, water and 1,4-dioxane are mixed and subjected to a Suzuki coupling reaction to obtain the compound V;

[0058] The compound III has a structure shown in formula III, and the compound IV has a structure shown in formula IV:

[0059]

[0060] As one embodiment of the present invention, the molar ratio of compound III to compound IV can be 1:0.8-1, specifically 1:0.8, 1:0.9 or 1:1; the molar ratio of compound III to potassium carbonate can be 1:2-3, specifically 1:2, 1:2.5 or 1:3; the molar ratio of compound III to 1,1'-bis(diphenylphosphino)ferrocene can be 1:0.01-0.1, specifically 1:0.01, 1:0.05 or 1:0.1. As one embodiment of the present invention, the volume ratio of water to 1,4-dioxane can be 1:4-6, specifically 1:5; the water and 1,4-dioxane are used as solvents. The present invention does not specifically limit the amount of water and 1,4-dioxane used, as long as the reaction proceeds smoothly.

[0061] As one embodiment of the present invention, the temperature of the Suzuki coupling reaction can be 15 to 35°C, and the Suzuki coupling reaction can be carried out at room temperature, and the room temperature of the present invention is specifically 25°C; the time of the Suzuki coupling reaction can be 12 to 24h, and specifically 12h, 18h or 24h; the Suzuki coupling reaction is preferably carried out in a protective atmosphere, and the protective atmosphere can be specifically nitrogen.

[0062] As one embodiment of the present invention, after the Suzuki coupling reaction, the method preferably further comprises: subjecting the product system obtained after the Suzuki coupling reaction to silica gel column chromatography purification, and spin-drying the resulting eluate to remove the solvent to obtain the compound V. As one embodiment of the present invention, the eluent used for the silica gel column chromatography purification can be petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate can be 20:1; the present invention does not specifically limit the conditions for the spin-drying, as long as the solvent can be fully removed.

[0063] After obtaining Compound V, the present invention mixes Compound V, sodium bisulfate, and an alcohol solvent to perform a first nucleophilic substitution reaction to obtain Compound VI. In one embodiment of the present invention, the molar ratio of Compound V to sodium bisulfate can be 1:1-2, specifically 1:1, 1:1.5, or 1:2. In another embodiment of the present invention, the alcohol solvent can be methanol; the present invention does not specifically limit the amount of the alcohol solvent used, as long as it ensures smooth reaction.

[0064] As one embodiment of the present invention, the first nucleophilic substitution reaction is preferably carried out under reflux conditions. For example, when the alcohol solvent is methanol, the first nucleophilic substitution reaction can be carried out at 55°C. The time of the first nucleophilic substitution reaction can be 12 to 24 hours, specifically 12 hours, 18 hours or 24 hours. The first nucleophilic substitution reaction is preferably carried out in a protective atmosphere, and the protective atmosphere can be specifically nitrogen.

[0065] As one embodiment of the present invention, after the first nucleophilic substitution reaction, the process preferably further comprises: extracting the product system obtained after the first nucleophilic substitution reaction with ethyl acetate and hydrochloric acid, collecting the organic phase, washing and drying in sequence, and then purifying it by silica gel column chromatography, and then removing the solvent by reduced pressure distillation to obtain the compound VI. As one embodiment of the present invention, the concentration of the hydrochloric acid can be 0.1M; the washing can include washing with water and washing with saturated salt water in sequence, and the number of washings with water and saturated salt water is preferably 3 times; the reagent used for drying is anhydrous sodium sulfate; the eluent used for purification by silica gel column chromatography can be methanol and dichloromethane, and the volume ratio of methanol to dichloromethane can be 20:1; the conditions of the reduced pressure distillation are not particularly limited in the present invention, as long as the solvent can be fully removed.

[0066] After obtaining compound VI, the present invention mixes compound VI, compound VII, potassium hydroxide, and an aprotic polar organic solvent to perform a second nucleophilic substitution reaction to obtain the substituted pyridine compound. As one embodiment of the present invention, the molar ratio of compound VI to compound VII can be 1:1-2, specifically 1:1, 1:1.5, or 1:2; the molar ratio of compound VI to potassium hydroxide can be 1:5-7, specifically 1:5, 1:6, or 1:7. As one embodiment of the present invention, the aprotic polar organic solvent can be N,N-dimethylformamide. The present invention does not specifically limit the amount of the aprotic polar organic solvent used, as long as it ensures the reaction proceeds smoothly.

[0067] As an embodiment of the present invention, the temperature of the second nucleophilic substitution reaction can be -2 to 2°C, specifically 0°C. In the embodiment, the second nucleophilic substitution reaction is carried out under ice bath conditions; the time of the second nucleophilic substitution reaction can be 5 to 10 minutes, specifically 5 minutes, 8 minutes or 10 minutes; the second nucleophilic substitution reaction is preferably carried out in a protective atmosphere, and the protective atmosphere can be specifically nitrogen.

[0068] As an embodiment of the present invention, after the second nucleophilic substitution reaction, the method preferably further comprises: extracting the product system obtained after the second nucleophilic substitution reaction with ethyl acetate and water, collecting the organic phase, washing and drying in sequence, and then purifying it by silica gel column chromatography, and then removing the solvent by reduced pressure distillation to obtain the substituted pyridine compound. As an embodiment of the present invention, the washing may include washing with water and washing with saturated salt water in sequence, and the number of washings with water and saturated salt water is preferably 3 times; the reagent used for the drying is anhydrous sodium sulfate; the eluent used for the silica gel column chromatography purification may be petroleum ether and dichloromethane, and the volume ratio of petroleum ether to dichloromethane may be 20:1; the present invention does not specifically limit the conditions of the reduced pressure distillation, as long as the solvent can be fully removed.

[0069] In the present invention, when X in Formula I or Formula II is -O- or -NH-, the preparation method of the substituted pyridine compound comprises the following steps:

[0070] Mixing compound V, compound VIII, potassium carbonate and a non-protonic polar organic solvent to perform a third nucleophilic substitution reaction to obtain the substituted pyridine compound;

[0071] The compound VIII is compound VIIIa or compound VIIIb, the compound VIIIa has the structure shown in formula VIIIa, and the compound VIIIb has the structure shown in formula VIIIb:

[0072]

[0073] In the formula VIIIa, X, Y, and R are as defined in formula I, and in the formula VIIIb, X, Y, and R are as defined in formula II.

[0074] Compound V of the present invention can be prepared by referring to the above method, which will not be described in detail here. As one embodiment of the present invention, the molar ratio of Compound V to Compound VIII can be 1:1-2; the molar ratio of Compound V to potassium carbonate can be 1:1-2. As one embodiment of the present invention, the aprotic polar organic solvent can specifically be N,N-dimethylformamide; the present invention does not specifically limit the amount of the aprotic polar organic solvent used, as long as it ensures the smooth progress of the reaction.

[0075] As an embodiment of the present invention, the temperature of the third nucleophilic substitution reaction is preferably selected according to the type of the aprotic polar organic solvent used; when the boiling point of the aprotic polar organic solvent is <150°C, the third nucleophilic substitution reaction can be carried out under reflux conditions; when the boiling point of the aprotic polar organic solvent is ≥150°C, the temperature of the third nucleophilic substitution reaction can be 90-110°C; for example, when the aprotic polar organic solvent is N,N-dimethylformamide, the third nucleophilic substitution reaction can be carried out at 90-110°C, and further at 100-110°C; the time of the third nucleophilic substitution reaction can be 12-24h, and further can be 12-15h; the third nucleophilic substitution reaction is preferably carried out in a protective atmosphere, and the protective atmosphere can specifically be nitrogen.

[0076] As an embodiment of the present invention, after the third nucleophilic substitution reaction, the method preferably further comprises: extracting the product system obtained after the third nucleophilic substitution reaction with ethyl acetate and water, collecting the organic phase, washing and drying in sequence, then purifying by silica gel column chromatography, and then removing the solvent by reduced pressure distillation to obtain the substituted pyridine compound. As an embodiment of the present invention, the washing may include washing with water and washing with saturated salt water in sequence, and the number of washings with water and saturated salt water is preferably 3 times; the reagent used for drying is anhydrous sodium sulfate; the eluent used for purification by silica gel column chromatography may be petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate may be 10:1; the conditions of the reduced pressure distillation are not particularly limited in the present invention, as long as the solvent can be fully removed.

[0077] The present invention provides the use of the substituted pyridine compound described in the above technical solution in the preparation of an ALDH2 activator. As one embodiment of the present invention, the ALDH2 can be ALDH2 in living tissue, which can include cells; the ALDH2 can also be ALDH2 produced using recombinant protein technology.

[0078] The present invention provides the use of the substituted pyridine compound described in the above technical solution in the preparation of a drug for treating a neurodegenerative disease. As one embodiment of the present invention, the neurodegenerative disease may be Alzheimer's disease.

[0079] The present invention provides a drug for treating degenerative diseases of the nervous system, wherein the active ingredient includes the substituted pyridine compound described in the above technical solution. As one embodiment of the present invention, the content of the active ingredient in the drug for treating degenerative diseases of the nervous system can be 10 to 20 wt%; the drug for treating degenerative diseases of the nervous system also includes a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier can include one or more of nanoparticles, liposomes, and microspheres. As one embodiment of the present invention, the dosage form of the drug for treating degenerative diseases of the nervous system can include tablets, injections, or oral solutions; the administration method can include oral or injection; and the dosage can be 50 to 100 mg each time.

[0080] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0081] The raw materials used in the following examples are all commercially available products well known to those skilled in the art or are prepared using methods well known to those skilled in the art.

[0082] Example 1 Synthesis of Compound A4

[0083] (1) Preparation of Compound V

[0084]

[0085] Compound III (1.0 eq, 3.07 mmol), compound IV (0.8 eq), potassium carbonate (3 eq), 1,1'-bis(diphenylphosphino)ferrocene (0.05 eq), 2 mL of water and 10 mL of 1,4-dioxane were mixed and reacted under nitrogen protection at room temperature (25°C) for 12 h. After the reaction, the resulting product system was purified by silica gel column chromatography (the eluent used was petroleum ether: ethyl acetate = 20:1 by volume), and the resulting eluate was spin-dried to remove the solvent to obtain compound V.

[0086] (2) Preparation of Compound VI

[0087]

[0088] The compound V (1 eq, 0.31 mmol), sodium bisulfate (1 eq) and 5 mL of methanol were mixed and reacted under nitrogen protection and reflux (55°C) for 12 h. After the reaction, the resulting product system was extracted with ethyl acetate and 0.1 M hydrochloric acid, and the organic phase was collected and washed with water and saturated brine three times each, then dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (the eluent used was methanol: dichloromethane = 20:1 by volume), and then the solvent was removed by distillation under reduced pressure to obtain compound VI.

[0089] (3) Preparation of Compound A4

[0090]

[0091] Compound VI (1 eq, 0.24 mmol), compound VII (specifically ethyl 4-chloroacetoacetate, 1 eq), potassium hydroxide (6 eq), and 170 μL of N,N-dimethylformamide were mixed and reacted in an ice bath (0°C) for 5 min. After completion of the reaction, the resulting product system was extracted with ethyl acetate and water. The collected organic phase was washed with water and saturated brine three times each, then dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane = 20:1 by volume). The solvent was then removed by distillation under reduced pressure to obtain Compound A4 (total yield of 24% for all three steps). ESI-MS (m / z): 411 [M+H] + .

[0092] Examples 2 to 12

[0093] The operation was carried out according to the method of Example 1, except that the type of compound VII used was different, as shown in Table 1.

[0094] Table 1 Yields and characterization data of target compounds in Examples 2 to 12

[0095]

[0096]

[0097] Example 13 Synthesis of Compound B4

[0098]

[0099] Compound V (1 eq, 0.31 mmol), Compound VIII (specific species, see Table 2, 1 eq), potassium carbonate (1 eq), and 5 mL of N,N-dimethylformamide were mixed and reacted at 100°C under nitrogen for 12 h. After completion of the reaction, the resulting product system was extracted with ethyl acetate and water. The collected organic phase was washed with water and saturated brine three times each, then dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 by volume). The solvent was then removed by distillation under reduced pressure to obtain Compound B4 (yield: 21%). ESI-MS (m / z): 437.3 [M+H]. + .

[0100] Compounds 14-36

[0101] The operation was carried out according to the method of Example 13, except that the type of compound VIII used was different, as shown in Table 2.

[0102] Table 2 Yields and characterization data of target compounds in Examples 13 to 36

[0103]

[0104]

[0105]

[0106] Examples 37 to 48

[0107] The operation was carried out in accordance with the method of Example 1, except that the type of compound VII used was different, as shown in Table 3.

[0108] Table 3 Yields and characterization data of target compounds in Examples 37 to 48

[0109]

[0110] Examples 49 to 72

[0111] The operation was carried out according to the method of Example 13, except that the type of compound VIII used was different, as shown in Table 4.

[0112] Table 4 Yields and characterization data of target compounds in Examples 49 to 72

[0113]

[0114]

[0115]

[0116] Test Example 1 Agonistic effect of compound A4 on ALDH2

[0117] Compound A4 (1 mg) was dissolved in dimethyl sulfoxide (DMSO) to obtain a 10 mM A4 probe stock solution. The A4 probe stock solution was added with PBS buffer of ALDH2 and diluted with PBS buffer to a final concentration of 0 (i.e., no compound A4 was added) and 25 μM of compound A4, and a final concentration of 90 nM of ALDH2. Acetaldehyde (final concentration of 2 mM) and nicotinamide adenine dinucleotide (oxidized state, NAD) were then added with a spray gun. + The reaction was carried out at 25°C for 4 hours, and the absorbance intensity at 340 nm was recorded. The results showed that under the same ALDH2 concentration, the absorbance intensity at a final concentration of 25 μM Compound A4 was higher than that at a final concentration of 0, indicating that Compound A4 can activate ALDH2 enzyme activity. The increase in the absorbance intensity at 340 nm at a final concentration of 25 μM Compound A4 compared to the absorbance intensity at 0 at a final concentration of 0 can be used to calculate agonist activity.

[0118] The agonist activity of other compounds was tested with reference to the above experiment, and the specific results are shown in Table 3. It can be seen that the agonist activity of compound A4 at 25 μM is 90%, and the other compounds also have good agonist activity.

[0119] Table 3 Agonist activity of each compound

[0120]

[0121]

[0122]

[0123] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A substituted pyridine compound, characterized in that: It has the structure shown in Formula I or Formula II: In Formula I and Formula II, X and Y are independently selected from -O-, -S- or -NH-, and R is a C1-C4 alkyl group.

2. The substituted pyridine compound according to claim 1, characterized in that In the formula I and formula II, R is selected from -CH3, -CH2CH3, -CH2CH2CH3 or -CH2CH2CH2CH3.

3. The substituted pyridine compound according to claim 1 or 2, characterized in that The substituted pyridine compound is any one of the following compounds:

4. The method for preparing a substituted pyridine compound according to any one of claims 1 to 3, characterized in that: The following steps are involved: (a) When X in Formula I or Formula II is -S-, the preparation method of the substituted pyridine compound comprises the following steps: Compound V, sodium bisulfate and an alcohol solvent are mixed to carry out a first nucleophilic substitution reaction to obtain compound VI; Mixing the compound VI, compound VII, potassium hydroxide and a non-protonic polar organic solvent to carry out a second nucleophilic substitution reaction to obtain the substituted pyridine compound; The compound VII is compound VIIa or compound VIIb; The compound V has a structure shown in Formula V, the compound VI has a structure shown in Formula VI, the compound VIIa has a structure shown in Formula VIIa, and the compound VIIb has a structure shown in Formula VIIb: In the formula VIIa, Y and R are as defined in formula I, and in the formula VIIb, Y and R are as defined in formula II; (b) When X in Formula I or Formula II is -O- or -NH-, the preparation method of the substituted pyridine compound comprises the following steps: Mixing compound V, compound VIII, potassium carbonate and a non-protonic polar organic solvent to perform a third nucleophilic substitution reaction to obtain the substituted pyridine compound; The compound VIII is compound VIIIa or compound VIIIb, the compound VIIIa has the structure shown in formula VIIIa, and the compound VIIIb has the structure shown in formula VIIIb: In the formula VIIIa, X, Y, and R are as defined in formula I, and in the formula VIIIb, X, Y, and R are as defined in formula II.

5. Use of the substituted pyridine compound according to any one of claims 1 to 3 in the preparation of an ALDH2 activator.

6. An ALDH2 activator, characterized in that The active ingredient comprises the substituted pyridine compound according to any one of claims 1 to 3.

7. Use of the substituted pyridine compound according to any one of claims 1 to 3 in the preparation of a medicament for treating degenerative diseases of the nervous system.

8. The use according to claim 7, characterized in that The neurodegenerative disease is Alzheimer's disease.

9. A drug for treating degenerative diseases of the nervous system, characterized in that: The active ingredient comprises the substituted pyridine compound according to any one of claims 1 to 3.

10. The drug for treating degenerative diseases of the nervous system according to claim 9, characterized in that: The dosage form of the drug for treating neurodegenerative diseases includes tablets, injections or oral solutions.

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